# projects

application_id: 9586012
project_number: 1R21AI139956-01
project_title: Post-transcriptional regulation in Borrelia burgdorferi by the BpuR RNA-binding protein
administering_ic: NIAID
award_notice_date: 2018-06-11
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 139956
program_official: ILIAS, MALIHA R
project_start_date: 2018-06-11
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT All organisms from bacteria to humans need to recognize where they are and respond accordingly.A pathogen must sense its location in the infectious cycle then produce factors necessary for that site whilerepressing synthesis of inappropriate factors. It has become increasingly obvious that many bacteria utilizepost-transcriptional mechanisms to control levels of important proteins. In our studies of the Lyme diseasebacterium Borrelia burgdorferi we discovered that a previously-undescribed type of bacterial RNA-binding protein named BpuR is critical for mammalian infection. B. burgdorferi that were geneticallyengineered to dysregulate BpuR were found to be significantly impaired in ability to colonize mice.Transcriptomic and proteomic analyses indicate that BpuR exerts significant impacts upon expression levels ofa substantial number of B. burgdorferi proteins. A series of complementary yet independent studies isproposed to define mechanisms by which BpuR controls levels of infection-associated proteins in the bacteria.Results will greatly enhance understanding of pathogenic mechanisms of the Lyme disease spirochete inaddition to serving as models for post-transcriptional regulation in bacteria.

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

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


application_id: 9584574
project_number: 1R21DA046551-01
project_title: Using Mindfulness Training to Reduce Delay Discounting in Rural Adult Smokers
administering_ic: NIDA
award_notice_date: 2018-07-05
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: DA
serial_number: 046551
program_official: AKLIN, WILL
project_start_date: 2018-07-15
project_end_date: 2020-06-30
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 7740063
contact_pi: REYNOLDS, BRADY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAs a Trans-Disease Behavioral Process delay discounting is related to almost all addictive behaviorsincluding addition to tobacco alcohol cannabis stimulants opiates & gambling. Delay discounting is alsoassociated with treatment outcomes and relapse to addictive behaviors obesity attention-deficit/hyperactivitydisorder and even risky behaviors like texting while driving. To increase the public-health impact of researchinvolving delay discounting it is of critical importance to identify innovative methods of improving discountingthat are also scalable and accessible In response we are proposing to use a mindfulness training app(Headspace) to reduce delay discounting perceived stress and depression in rural adult smokers. We havechosen mindfulness training as our intervention because it has been shown to reduce cigarette smoking incollege students and because of demonstrated effects on many of the cognitive and neural systems thatunderlie delay discounting. Furthermore by using a web-based/app version of mindfulness training weincrease program flexibility for difficult-to-reach populations such as rural adult smokers. To explore use of thisapproach we will utilize a two-arm single blinded randomized control design. For the active treatmentcondition (n = 50) participants will complete a 30 day foundational program of mindfulness training(Headspace). In the control condition (n = 50) participants will listen to an audio book about mindfulnesstraining that is read by the same person guiding the mindfulness training for the active condition. This audiobook has been divided into 30 sections that are time-matched with the 30 sessions of the active Headspaceprogram and these audio book sections will be accessed by participants through the Headspace site just asthe active training program will be accessed by participants in that condition. Delay discounting depressionperceived stress mindfulness and tobacco use will be assessed before starting either of these two conditionsand also after every 10 days during the programs (days 10 20 and 30) to track the time course of anychanges. To conclude we will collect all of these data again 30 days post intervention to evaluate stability ofany observed effects. We hypothesize that in rural adult smokers mindfulness training will reduce delaydiscounting perceived stress and depression as well as cigarette smoking compared to the audio book controlcondition. If these hypotheses are confirmed online mindfulness training can be readily adapted as an adjunctto existing prevention and treatment programs to improve their outcomes. This research addresses asignificant public health issue by directly engaging central behavioral targets for cigarette smoking in a difficult-to-reach population.

project_terms:
Addictive Behavior;Address;Adult;Affect;Alcohols;Area;Attention deficit hyperactivity disorder;Automobile Driving;Behavioral;Books;Brain;Brain region;Cannabis;Cognitive;Data;Disease;Effectiveness;Female;Foundations;Gambling;Health Services Accessibility;Home environment;Human;Intervention;Lead;Link;Mediating;Mental Depression;Methods;Mindfulness Training;Obesity;Online Systems;Opioid;Outcome;Participant;Persons;Population;Prevention program;Process;Public Health;Randomized;Relapse;Research;Risk Behaviors;Role;Rural;Short-Term Memory;Single-Blind Study;Site;Smoker;Smoking;Stress;System;Text;Time;Tobacco;Tobacco use;Training;Training Programs;Treatment outcome;Work;active method;addiction;arm;base;cigarette smoking;density;design;discount;discounting;executive function;flexibility;follow-up;gray matter;improved;innovation;male;mindfulness;post intervention;programs;relating to nervous system;response;suburb;treatment program;university student

public_health_relevance:
PROJECT NARRATIVEDelay discounting perceived stress and depression are important behavioral targets related to cigarettesmokingwhich represents a significant threat to public health. This study will use and evaluate a mindfulnesstraining app to reduce delay discounting perceived stress and depression in rural adult smokers. If successfulmindfulness training can be added to prevention and treatment programs to improve their efficacy and reducesmoking in this difficult-to-reach population.


application_id: 9583536
project_number: 3R01AG054459-02S1
project_title: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model
administering_ic: NIA
award_notice_date: 2018-07-26
opportunity_number: PA-17-307
application_type: 3
activity_code: R01
ic: AG
serial_number: 054459
suffix: S1
program_official: WAGSTER, MOLLY V
project_start_date: 2017-07-01
project_end_date: 2022-04-30
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryApolipoprotein 4 (APOE4) allele is the strongest genetic risk factor for Alzheimers disease (AD).Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascularmetabolic and structural deficits decades before the aggregation of beta-amyloid (A) and neurofibrillary tautangles. Interventions that can restore these deficits to normal would be critical to potentially prevent thedevelopment of AD related neuropathology and cognitive impairment. The rationale of the study is to use thestate-of-the-art in vivo MRI methods to identify a potential intervention Rapamcyin for AD prevention in amouse model that overexpresses human A via 5 familial-AD mutations and expresses human APOE4(E4FAD). The central hypothesis is that multi-modal MRI can be used as surrogate markers to assess efficacyof Rapamycin for restoring brain vascular metabolic and structural functions in mice that carry APOE4 genes.We will also validate our MRI results by comparison with biochemical assays and finally compare withbehavioral outcomes. The hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis thatRapamycin restores neurovascular functions; 2) Test the hypothesis that Rapamycin protects neurometabolicfunctions; and 3) Test the hypothesis that Rapamycin preserves structural and cognitive functions. The projectis innovative because it employs cutting-edge multi-disciplinary novel technology to focus on earlyinterventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. Theproject is significant because with validation these multimodal MRI methods will dramatically enhance futureresearch for identifying potential therapeutics using animal models in the fields related to AD and other age-related neurodegenerative disorders. We can also translate our approach to future human studies because allthe MRI methods used in the proposal are readily able to be used in humans. Because Rapamycin is FDA-approved the findings from the study will also provide valuable information and may pave a way for futureRapamycin clinical trials to prevent dementia for pre-symptomatic APOE4 carriers.!

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

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


application_id: 9580066
project_number: 1R01AG060056-01
project_title: APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AG
serial_number: 060056
program_official: WISE, BRADLEY C
project_start_date: 2018-08-15
project_end_date: 2023-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease risk;Antioxidants;Apolipoprotein E;Astrocytes;Autopsy;Biological Assay;Brain;Brain Diseases;Cell Death;Cell Survival;Cells;Cerebrum;Coculture Techniques;Cognitive;Consensus;Data;Development;Disease;Down-Regulation;Enzymes;Genes;Genetic;Genotype;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glutathione;Glutathione Disulfide;Glycolysis;Human;Impaired cognition;In Vitro;Individual;Knowledge;Late Onset Alzheimer Disease;Link;Longevity;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;NADP;Neurons;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Pattern;Pentosephosphate Pathway;Pharmacology;Population;Protein Isoforms;Proteins;Proteomics;Radiolabeled;Reduced Glutathione;SLC2A1 gene;Sampling;Small Interfering RNA;Testing;Time;Tissues;Translating;age related;aged;base;brain tissue;cell type;cognitive function;enzyme pathway;genetic risk factor;glucose metabolism;glucose uptake;high risk;human tissue;in vivo;inhibitor/antagonist;innovation;knock-down;metabolomics;mouse model;multiple omics;neuronal survival;new therapeutic target;novel;overexpression;oxidative damage;prevent;response;stable isotope;therapeutic target;uptake


application_id: 9579462
project_number: 1R01HL142969-01
project_title: The role of soluble prorenin receptor in hypertension associated with obesity
administering_ic: NHLBI
award_notice_date: 2018-07-13
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 142969
program_official: VARAGIC, JASMINA
project_start_date: 2018-07-15
project_end_date: 2022-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353515
contact_pi: YIANNIKOURIS, FREDERIQUE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3T3-L1 Cells;Adipose tissue;Adrenergic Receptor;Affect;Angiotensin II;Angiotensin-Converting Enzyme Inhibitors;Angiotensinogen;Antihypertensive Agents;Binding;Biological Markers;Blood Pressure;Body Fluids;C57BL/6 Mouse;Calcium Channel Blockers;Cardiovascular Diseases;Cause of Death;Cell secretion;Cells;Chronic;Cleaved cell;Complex;Data;Diet;Drug usage;Epidemic;Fat-Restricted Diet;Fatty acid glycerol esters;Genes;Goals;HepG2;Hepatic;High Fat Diet;Homeostasis;Human;Hypertension;In Vitro;Incubated;Infusion procedures;Kidney;Knockout Mice;Liquid substance;Liver;Losartan;Mediating;Molecular;Mus;Obese Mice;Obesity;Outcome;Outcome Study;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Prevalence;Production;Recombinants;Renin;Renin-Angiotensin System;Resistant Hypertension;Risk;Role;Severities;Testing;Therapeutic;Tissues;Transcriptional Regulation;Transgenic Mice;United States;Urine;Vasoconstrictor Agents;Vasopressins;Work;antidiuretic;blood pressure regulation;cardiovascular risk factor;hypertension treatment;in vivo;insight;mortality;mouse model;nectin;neutralizing antibody;normotensive;novel;prevent;promoter;prorenin receptor;receptor;response;urinary


application_id: 9579390
project_number: 1R01CA230758-01
project_title: Characterize the role of EBF1 in breast cancer progression
administering_ic: NCI
award_notice_date: 2018-06-12
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 230758
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Attenuated;Autophagocytosis;B-Lymphocytes;Biogenesis;Bioinformatics;Brain;Breast Cancer Cell;Breast Cancer cell line;Cell Death;Cells;Cessation of life;Clinical;Data;Disease;EP300 gene;Early identification;Ensure;Environment;Event;Feedback;Gene Targeting;Genetic Transcription;Goals;Growth;HIF1A gene;Homeostasis;Human;Hypoxia;Hypoxia Inducible Factor;Immunocompetent;Interruption;Intrinsic factor;Knockout Mice;Knowledge;Luciferases;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;NCI-Designated Cancer Center;Neoplasm Metastasis;Nutrient;Oxygen;Pathogenesis;Pathologist;Pathway interactions;Patients;Play;Process;Reaction;Reagent;Regulation;Research;Response Elements;Role;Sampling;Signal Transduction;Specimen;Stress;System;Talents;Testing;Therapeutic;Tumorigenicity;Work;alternative treatment;base;breast cancer progression;cancer initiation;druggable target;in vivo;inhibitor/antagonist;innovation;insight;interest;knock-down;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;outcome forecast;overexpression;prevent;programs;response;targeted treatment;transcription factor;treatment strategy;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;uptake


application_id: 9579370
project_number: 1R01GM129532-01
project_title: Visceral fat gamma delta T cells in sepsis pathogenesis
administering_ic: NIGMS
award_notice_date: 2018-08-23
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: GM
serial_number: 129532
program_official: DUNSMORE, SARAH
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adipose tissue;Affect;Anti-inflammatory;Bioinformatics;Cells;Cellular biology;Clinical;Collaborations;Complex;Creatinine;Critical Care;Critical Illness;Data;Development;Endocrine Glands;Evaluation;Excision;Failure;Fatty acid glycerol esters;Flow Cytometry;Functional disorder;Future;Genes;Goals;Immune;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-17;Kidney;Knock-out;Knockout Mice;Link;Mediating;Mediator of activation protein;Metabolic Pathway;Molecular Biology;Mouse Strains;Mus;Operative Surgical Procedures;Organ;Pathogenesis;Pathologic;Patients;Physiology;Plasma;Plasminogen Activator Inhibitor 1;Play;Procedures;Production;Renal function;Role;Sampling;Sepsis;Series;Serum;Severities;Signal Transduction;Source;Specimen;T-Lymphocyte;Testing;Therapeutic;Thrombosis;Tissues;Transgenic Mice;Transplantation;Visceral;Wild Type Mouse;aged;clinically relevant;cytokine;design;experimental study;innovation;liver injury;lung injury;mortality;mouse model;multidisciplinary;multiorgan injury;novel;organ growth;patient population;pre-clinical;public health relevance;statistics;success;therapeutic target; T cells


application_id: 9579275
project_number: 1R01HL142973-01
administering_ic: NHLBI
award_notice_date: 2018-08-18
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 142973
program_official: VARAGIC, JASMINA
project_start_date: 2018-08-20
project_end_date: 2022-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-20
project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Accounting;Acetates;Affect;Age;Agonist;Aldosterone;American;Angiotensin II;Angiotensins;Animal Model;Aorta;Cardiovascular Diseases;Cessation of life;Circadian Rhythms;Country;Data;Deoxycorticosterone;Disease;Dissection;Estrogens;Female;Genes;Genetic Transcription;Goals;Gonadal Steroid Hormones;Heart failure;Human;Hypertension;Inflammatory;Interleukin 6 Receptor;Interleukin-6;Left Ventricular Hypertrophy;Link;Literature;Mediating;Mineralocorticoid Receptor;Mus;Myocardial Infarction;Operative Surgical Procedures;Orchiectomy;Ovariectomy;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Play;Prevalence;Reporting;Rheumatoid Arthritis;Role;Rupture;Scheme;Serum;Sex Characteristics;Signal Transduction;Smooth Muscle;Sodium Chloride;Stroke;Testing;Testosterone;Therapeutic;Transcriptional Regulation;United States;Up-Regulation;Variant;Vascular Diseases;Woman;base;circadian pacemaker;cytokine;effective therapy;genome wide association study;insight;male;men;mortality;neutralizing antibody;new therapeutic target;novel;novel therapeutics;pre-clinical;salt intake;sexual dimorphism;sham surgery;small molecule inhibitor


application_id: 9574794
project_number: 261201700017C-0-0-1
administering_ic: NCI
project_start_date: 2017-09-19
project_end_date: 2018-06-18
contact_pi_person_id: 15240605
contact_pi: YESHI, TSETEN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079703270
primary_uei: JK2VCZCBR8R4
duns_number: 079703270
uei: JK2VCZCBR8R4
fips: US
organization_id: 10038664
organization_name: HERA TESTING LABORATORIES, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405059002
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF SBIR TOPIC 355: Cell and Animal-Based Models to Advance Cancer Health Disparity Research. To contribute to studies of cancer health disparities by generating several patient-derived xenog

project_abstract:
Lung Cancer is the leading cause of cancer-related death worldwide. The most common form Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer related deaths. In recent years patient-derived xenograft (PDX) models have been established for various cancers and these models are increasingly used for preclinical studies of targeted therapies. Such studies highlight the ability of PDX models to better predict clinical tumor response compared to standard cell line-derived xenograft models. Furthermore PDX models also provides the opportunity to tailor treatments to specific tumor genotypes/phenotypes. The latest therapeutic strategies only show a minimal increase in NSCLC survivorship of 5% greater 5-year survival rate. The majority of patients that receive first-line treatment are not good candidates for further chemotherapy due to disease progression drug resistance side-effects severe toxicity and effects of comorbidity. The economic and survival rate impact of post first-line chemotherapy for NSCLC presents thecrucial need to optimize the selection of initial chemotherapy regimen. Here we propose to develop and characterize at least 5 PDX lines from NSCLC tumors derived from minoritypopulations. 20-40 tumor specimens obtained from patients that belong to Appalachian region African descent or Asian descent will be transplanted into NOD-SCID mice and SRG rats and serially transplanted for 4 generation (passages) to establish 5 NSCLC PDX lines that can be effectively grown in SCID rodents.

project_terms:
Advanced Malignant Neoplasm;Adverse effects;African;Animals;Appalachian Region;Asians;Cancer Etiology;Cancer Model;Cancer Patient;Cancer Survivorship;Cell Line;Cells;Cessation of life;Chemotherapy-Oncologic Procedure;Comorbidity;Cryopreservation;Disease Progression;Drug resistance;Economics;Engraftment;Epidermal Growth Factor Receptor;Generations;Genes;Genotype;Growth;Hot Spot;KRAS2 gene;Malignant neoplasm of lung;Minority;Modeling;Mutation Analysis;NOD/SCID mouse;Non-Small-Cell Lung Carcinoma;Patients;Phenotype;Population;Rattus;Research;Rodent;SCID Mice;Sampling;Serial Passage;Small Business Innovation Research Grant;Specimen;Survival Rate;Therapeutic;Toxic effect;Transplantation;Tumor-Derived;Xenograft Model;Xenograft procedure;base;cancer health disparity;chemotherapeutic agent;chemotherapy;clinical predictors;comparative;exome;implantation;individualized medicine;preclinical study;response;targeted treatment;tumor


application_id: 9572924
project_number: 5R13DC016831-02
project_title: International Society of Neurogastronomy Annual Meeting
administering_ic: NIDCD
award_notice_date: 2018-07-23
opportunity_number: PA-16-294
application_type: 5
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2020-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is a new society whose composition of scientists clinicians nutritionists foodservice professionals and chefs naturally predisposes it to focus on translational issuesfundamental to how the chemical senses impact human health. The first two specificobjectives are to provide a venue and opportunity that brings these groups together andfacilitates the synergies that arise when distinctly different fields interact productively. Thethird specific objective is to attract and stimulate the young scientists that are the future ofthe field of neurogastronomy. The fourth specific objective is to ensure that this new fieldembraces a culture of diversity weaving this principle into its early development byrecruiting persons of diverse backgrounds to the conference. !

project_terms:
Agriculture;Appalachian Region;Area;Chemicals;Clinical;Development;Diet Habits;Disabled Persons;Eating;Education;Ensure;Environment;Equation;Equilibrium;Event;Food;Food Services;Fostering;Funding;Future;Goals;Grant;Health;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Perception;Persons;Policies;Quality of life;Recruitment Activity;Rural;Science;Scientist;Societies;Stimulus;Structure;Training;Underrepresented Groups;Veterans;Work;design;drinking;ethnic minority population;experience;food consumption;improved;interest;meetings;member;multisensory;nutrition;preference;racial and ethnic;recruit;social;sound;symposium;synergism

public_health_relevance:
PROJECT NARRATIVEA major part of the mission of the International Society of Neurogastronomy (ISN) is topromote the study of flavor and its use to enhance the quality of human life channeling ourgrowing knowledge of neurogastronomy and chemosensory science into translationalaction needed to overcome the ways in which flavor preferences are often hijacked tocause unhealthy eating habits. ISN promotes cooperation between scientists and foodprofessionals towards altering the balance of this equation in our culture. ISNs annualmeeting provides an important mechanism for facilitating the interactions betweenchemosensory scientists neuroscientists clinicians nutritional scientists agriculturalscientists and food professionals needed to develop strategies for using flavor properly -strategies that are both practical and scientifically sound. !


application_id: 9572824
project_number: 1R21CA229057-01
project_title: A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath
administering_ic: NCI
award_notice_date: 2018-08-22
opportunity_number: RFA-CA-17-010
application_type: 1
activity_code: R21
ic: CA
serial_number: 229057
program_official: KRUEGER, KARL E
project_start_date: 2018-08-22
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZCA1 TCRB-W (M1)]
contact_pi_person_id: 10807170
contact_pi: FU, XIAO-AN
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Title:A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath7. Project Summary/Abstract Lung cancer has the highest mortality of all types of cancer. Early lung cancer detection is a key factor forincreasing survival rates of lung cancer patients. The analysis of exhaled breath samples has great potential tobecome a powerful non-invasive screening and diagnostic tool for early lung cancer detection. A number ofrecent publications have indicated that certain volatile organic compounds (VOCs) in exhaled breath may belung cancer metabolic output. However there are some critical challenges for the analysis of breath VOCs thathinder the use of breath analysis technology for clinical applications. These challenges include trace levels ofVOCs in breath much lower than the detection limits of most current analytical instruments; the complexity ofsorting a large number of VOCs; and matrix interferences imparted by abundant and/or structurally similarVOCs unrelated to cancers. These challenges make it very difficult to identify true metabolic markers of lungcancers. We have developed a microreactor approach that uses a quaternary aminooxy coating for chemoselectivecapture of carbonyl compounds in exhaled breath. Four carbonyl compounds have been identified to havesignificantly higher concentrations in the breath of lung cancer patients than in the breath of healthy controlsubjects. However the slow reaction kinetics of the quaternary aminooxy coating with unsaturated aldehydesand unstable nature of these compounds make the microreactor technology inadequate for quantification ofkey unsaturated aldehydes in exhaled breath. Many unsaturated aldehydes in exhaled breath are related tolung cancer dysfunction-induced oxidative stress. Unfortunately there is no current technology that can beused to adequately measure unsaturated aldehydes in exhaled breath. The goal of this project is to develop a microreactor chip platform technology for quantitative analysis ofunsaturated aldehydes in exhaled breath for differentiation of early lung cancer from benign pulmonarynodules. The technology will overcome all critical challenges of current breath analysis technologies andenable quantitative analysis of unsaturated aldehydes. The goal will be fulfilled by the following two specificaims: Specific Aim 1. Develop a novel microreactor platform for accurate measurement of unsaturatedaldehydes in exhaled breath; Specific Aim 2. Establish novel algorithms for diagnosis of lung cancer by breathanalysis. The proposed microreactor chip platform for quantitative analysis of unsaturated aldehydes will betransformative because it will enable measurement and identification of lung cancer metabolic aldehydes andestablish a non-invasive tool for differentiation of lung cancer from benign pulmonary nodules. Themicroreactor chip enabled quantitative analysis of unsaturated aldehydes in breath can also be used with lowdose CT screening for detection of early lung cancer and differentiation of lung cancer from benign pulmonarynodules. The proposed technology will be superior to current breath analysis approaches because of fourcritical innovations: (1) diagnosis of lung cancer by quantitative measurement of cancer metabolic unsaturatedaldehydes in exhaled breath; (2) a novel microreactor for decreasing sample evacuation time; (3) optimizedchemoselective coatings for efficient capture of unsaturated aldehydes; and (4) separation of analyte adductsand quantitation by UHPLC-MS.

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

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


application_id: 9572549
project_number: 5R21DA044251-02
project_title: Examining Social Influences on Syringe Exchange Uptake among Rural PWID at Risk for HIV
administering_ic: NIDA
award_notice_date: 2018-07-25
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: DA
serial_number: 044251
program_official: JENKINS, RICHARD A
project_start_date: 2017-09-30
project_end_date: 2021-08-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed study will conduct targeted formative research to identify key social-ecological factorsinfluencing the uptake of newly implemented syringe exchange programs (SEPs) among people who injectdrugs (PWID) in rural Appalachian Kentucky (KY). The recent initiation of SEPs in this rural resource poorarea provides a unique opportunity to examine social drivers impacting uptake of an evidence-based structurallevel HIV prevention intervention among a highly vulnerable and understudied population of PWID and todevelop complementary intervention strategies for enhancing SEP utilization. Serious health consequencesassociated with opioid injection are at crisis levels: KY has the highest rate of acute hepatitis C (HCV) in thenation particularly among persons aged 30 years residing in non-urban areas with a risk factor of injectiondrug use. In addition a recent analysis by the CDC identified 8 counties in Appalachian KY as among thenation's top 10 most vulnerable to the rapid dissemination of HIV and HCV among PWID. Despite well-documented rural-urban differences in drug use patterns and social characteristics there is a critical gap in ourknowledge of social drivers of SEP uptake and utilization among PWID in rural communities. Theimplementation of structural level HIV prevention programming has been virtually absent in rural locations andthe applicability of research findings from urban SEPs is largely unknown. Such data are urgently needed toinform the continued refinement of SEP policies and practices for vulnerable rural PWID and to developcomplementary multi-level prevention strategies to enhance access and utilization of rurally located SEPs.Guided by Social Ecological Theory the Specific Aims of this exploratory mixed methods study are to: 1)Examine the uptake of SEPs in three Appalachian county HDs (Clark Knox and Pike) through structuredinterviews with 350 PWID (175 SEP utilizers and 175 non-utilizers) to identify and compare the key differencesbetween utilizers and non-utilizers in social ecological domains including intrapersonal (e.g. HIV /HCVknowledge rural identity) interpersonal (e.g. kinship peer norms social isolation); institutional (e.g. justicesystem involvement law enforcement activity); community (e.g. community stigma geographic distance); andpublic policy factors (e.g. SEP policies and practices (privacy/anonymity hours locations distribution modelsecondary exchange)) that influence SEP uptake and utilization; and 2) Identify priority interventiontargets and develop strategies to enhance uptake of SEPs among rural PWID by conducting in-depthqualitative interviews with a strategically selected sample of PWID from Aim 1 as well as key healthdepartments directors and SEP staff local substance treatment providers law enforcement and othercommunity stakeholders to assess multi-level barriers to SEP utilization acceptability and feasibility ofcomplementary intervention strategies and to develop recommendations for intervention priorities and practicechanges to improve SEP uptake.

project_terms:
AIDS prevention;Acute Hepatitis C;Appalachian Region;Area;Centers for Disease Control and Prevention (U.S.);Communities;County;Data;Disease Outbreaks;Drug usage;Drug user;Economics;Epidemic;Geography;Growth;HIV;HIV risk;HIV/HCV;Health;Health Personnel;Health Services Accessibility;Heroin;Hour;Indiana;Infection;Injecting drug user;Injections;Intervention;Interview;Justice;Kentucky;Knowledge;Law Enforcement;Location;Methods;Modeling;Morbidity - disease rate;Needle-Exchange Programs;Overdose;Pattern;Perception;Persons;Pharmaceutical Preparations;Pike fish;Policies;Population;Prevention strategy;Preventive Intervention;Privacy;Program Accessibility;Public Health;Public Policy;Recommendation;Research;Resources;Risk;Risk Behaviors;Risk Factors;Rural;Rural Community;Sampling;Social Characteristics;Social Values;Social isolation;Structure;System;Time;aged;evidence base;experience;high risk;improved;injection drug use;mortality;opioid epidemic;opioid injection;peer;prescription opioid;prescription opioid abuse;rural area;social;social norm;social stigma;stressor;substance abuse treatment;theories;treatment services;uptake;virtual

public_health_relevance:
The proposed study will conduct targeted formative research to identify key social-ecological factorsinfluencing the uptake of newly implemented syringe exchange programs (SEPs) among people who injectdrugs (PWID) in rural Appalachian Kentucky (KY). Serious health consequences associated with opioidinjection are at crisis levels: KY has the highest rate of acute hepatitis C (HCV) in the nation and a recentanalysis by the CDC identified 8 counties in Appalachian KY as among the nation's top 10 most vulnerable tothe rapid dissemination of HIV among PWID. The significant public health impact of the study is indicated bythe potential to understand SEP uptake patterns in rural resource poor areas and to develop complementaryintervention strategies for enhancing access to evidence-based structural HIV prevention interventions forhighly vulnerable rural PWID.


application_id: 9572547
project_number: 5R44CA221487-02
project_title: Exosomal Drug Delivery
administering_ic: NCI
award_notice_date: 2018-07-16
opportunity_number: PAR-14-088
application_type: 5
activity_code: R44
ic: CA
serial_number: 221487
program_official: ZHAO, MING
project_start_date: 2017-09-26
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-OTC-T(10)B]
contact_pi_person_id: 2081643
contact_pi: SPENCER, WENDY A
other_pis: GUPTA, RAMESH C
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Technical Abstract As with many chemotherapeutic drugs taxanes exhibit poor oral bioavailability; hence they areadministered intravenously (i.v.). This regimen results in significant toxicities due to both the high drug dose andvehicle (Cremophore ELR) used. Attempts made to develop an oral chemotherapeutic using liposomes andpolymeric nanoparticles as carriers have not made it to the clinic due to their inherent limitations. In Phase I 3PBiotechnologies proposed to develop a platform technology for the oral delivery of chemo drugs and othertherapeutics via bovine milk-derived nanoparticles known as exosomes. The Phase I specific aims were to (1)isolate and characterize milk exosomes; (2) prepare exosomal (Exo) formulations of the chemo drug paclitaxel(PAC) and the plant therapeutic withaferin A (WFA); and (3) show that Exo formulations enhance therapeuticresponses while lacking toxicity. Phase I proved feasible based on the following findings: a) differentialcentrifugation of raw bovine milk provided exosomes; b) exosomes were taken up by cells in vitro and in vivo; c)Exo formulations of PAC (ExoPACTM) WFA (ExoWFATM) and other compounds were developed which showedhigher anti-proliferative anti-inflammatory and anti-cancer activities vs. the free drugs against lung cancer cellsboth in vitro and in vivo; and d) milk exosomes lacked cross-species reactivity in wild-type mice. Additional datagenerated preliminary to Phase II showed that bovine colostrum powder produces exosomes with a yield andpurity that are several-fold higher than can be obtained from fresh milk resulted in significantly higher drugloading than milk and that exosomes can be functionalized with folic acid for tumor targeting. In Phase II a teamof multidisciplinary researchers will advance this technology by pursuing the following specific aims: 1) Establishthe reproducibility of colostrum exosome yield maximize drug loading of the taxane PAC identify and optimizeloading of a tumor-targeting ligand and test the resulting formulations for antiproliferative and anti-inflammatoryactivities against human lung cancer cells in vitro. 2) Determine the efficacy of Exo formulation of PAC(ExoPACTM) and functionalized-ExoPACTM for tumor targetability minimizing off-target sites using orthotopicxenograft patient-derived tumor xenograft (PDX) and K-ras spontaneous tumors. 3) Determine toxicities of theExoPACTM and functionalized-ExoPACTM formulations analyze blood and tissue levels of PAC (PK/PD studies)and determine stability of the formulations. The innovation lies in the use of standardized colostrum-derivedfunctionalized exosomes for oral delivery for cancer therapeutics to circumvent bioavailability issues. The currenttaxane therapeutic market is dominated by a single product Abraxane an i.v. albumin-PAC product. A productthat performs similar to or better than Abraxane would potentially generate U.S. and worldwide markets of over$7 billion and $28 billion respectively. If we are successful in achieving our objectives we will apply for Phase IIbwhere we will establish large-scale production of ExoPACTM and will conduct Phase 1/2 clinical trials. Oncologistson the Advisory Board of 3P Biotechnologies will guide as we advance these drug formulations.

project_terms:
Abraxane;Accounting;Adverse effects;Albumins;Anti-inflammatory;Biological Availability;Biotechnology;Blood;Bone Marrow;Cancer Cell Growth;Cancer Survivor;Capital;Cattle;Cell Culture Techniques;Cells;Centrifugation;Clinic;Clinical Trials;Colon Carcinoma;Colostrum;Data;Data Analyses;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Formulations;Drug usage;Excision;Exhibits;Folic Acid;Formulation;Funding;Goals;Harvest;Healthcare Systems;Human;Immune;Immune response;Immunologist;In Vitro;Intravenous;KRAS2 gene;Label;Ligands;Liposomes;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Milk;Modeling;Mus;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nude Mice;Oncologist;Operative Surgical Procedures;Oral;Oral Administration;Paclitaxel;Pathologist;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Plants;Polymers;Powder dose form;Publishing;Radiation;Reaction;Recovery;Recurrence;Regimen;Relapse;Reporting;Reproducibility;Research;Research Personnel;Rodent Model;Site;Solvents;Source;Specificity;Spleen;Standardization;Technology;Test Result;Therapeutic;Tissues;Toxic effect;Tumor-Derived;Wild Type Mouse;Xenograft procedure;anticancer activity;base;cancer cell;cancer therapy;chemotherapy;drug efficacy;drug testing;exosome;hydrophilicity;in vivo;innovation;large scale production;lipophilicity;malignant breast neoplasm;mouse model;multidisciplinary;nano;nanoparticle;neoplastic cell;public health relevance;taxane;treatment response;tripterine;tumor;tumor xenograft

public_health_relevance:
Narrative (Public Health Relevance Statement) In this project we will develop oral formulations of the widely used chemotherapeutic drug paclitaxel. Thisformulation (ExoPACTM) will use nanoparticles (exosomes) isolated from standardized bovine colostrumpowder to treat lung cancer. The drug formulation will be tagged with a tumor-targeting ligand to increasetumor-cell specificity thus minimizing or eliminating adverse effects associated with the current practice of high-dose intravenous chemotherapy. The oral formulation of paclitaxel will be highly patient friendly and besidesreducing adverse effects it will also significantly reduce financial burden to both patients and the health caresystem. The exosomes per se (in the absence of any drug) will provide additional benefits due to their intrinsicanti-inflammatory activity and by inhibiting the growth of cancer cells.


application_id: 9572039
project_number: 1R24AI138963-01
administering_ic: NIAID
award_notice_date: 2018-07-23
opportunity_number: PAR-16-412
application_type: 1
activity_code: R24
ic: AI
serial_number: 138963
program_official: BREEN, JOSEPH J
project_start_date: 2018-07-23
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZAI1 JTS-I (M1)]
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: SMITH, MELISSA LAIRD
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-23
project_terms:
African;Alleles;Antibodies;Antibody Repertoire;Antibody Response;Asians;Autoimmunity;B-Lymphocytes;Biological Assay;Catalogs;Clinical;Communities;Complex;Copy Number Polymorphism;Data;Data Analyses;Data Set;Databases;Deposition;Development;Diploidy;Disease;Ensure;European;Evaluation;Foundations;Future;Genbank;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Research;Genetic Variation;Genome;Genomics;Genotype;Haplotypes;Health;Human;Human Resources;IGL@ gene cluster;Immune;Immune System Diseases;Immunogenetics;Immunoglobulins;Immunology;Individual;Infection;Information Systems;International;Knowledge;Libraries;Light;Link;Malignant Neoplasms;Methods;Nucleic Acid Regulatory Sequences;Nucleotides;Outcome;Population;Positioning Attribute;Resolution;Resources;Role;Sampling;Single Nucleotide Polymorphism;Update;Variant;Work;adaptive immunity;cohort;design;direct application;ethnic diversity;genetic association;high standard;human reference genome;immunoglobulin light chain locus;improved;insight;inter-individual variation;novel;novel strategies;personalized medicine;population survey;precision medicine;reference genome;tool;vaccine response


application_id: 9571498
project_number: 1R21CA216722-01A1
project_title: NOVEL PAN-RALGEF INHIBITORS TO BLOCK PANCREATIC CANCER.
administering_ic: NCI
award_notice_date: 2018-07-06
opportunity_number: PAR-16-176
application_type: 1
activity_code: R21
ic: CA
serial_number: 216722
suffix: A1
program_official: ARYA, SURESH
project_start_date: 2018-07-06
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZCA1 TCRB-Q (M1)]
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Background: Pancreatic cancer exhibits almost 100% morbidity and is almost 100% associated withactivation of the Ras oncoprotein. Therefore targeting Ras is the most logical approach to developingenhanced therapy for this disease. So far all attempts at inhibiting Ras directly have failed in the clinic. Rasacts in large part by binding and activating the oncogenic effectors Raf PI3 Kinase and RalGEFs. Inhibitorsfor Raf and PI3 kinase have been developed but have yet to show efficacy in the clinic against pancreaticcancer. To date no inhibitors of the third arm of the Ras effector system the RalGEFs have been described inthe literature. We have developed what appears to be the first pan-RalGEF inhibitor.Specific Aims: 1. To characterize the binding and action of novel specific inhibitors of RalGEFs. 2. To determine if suppression of the RalGEF pathway prevents tumorigenesis andmetastasis in pdx and transgenic models of cancer in vivo.Objective: To define the mechanism of action on suppression of the tumorigenic phenotype in vitro of novelsmall molecules that inhibit the Ras/RalGEF pathway. To determine if the molecule/s exhibit anti-tumor effectsin an in vivo model of pancreatic cancer.Hypotheses: Targeting multiple RalGEFs will be an effective strategy for inhibiting Pancreatic cancer.Significance: There is no effective treatment for pancreatic cancer. Pancreatic cancer is driven by Rasactivation. Ras driven cancers are highly dependent upon the Ras/RalGEF pathway. We describe the firstinhibitor of this pathway.Relevance to public health: Pancreatic cancer has no effective therapies. This proposal seeks to develop anovel therapeutic small molecule for Pancreatic cancer.Unique features and innovation: The project used a combination of in silico and in vitro assays to identifyand optimize novel inhibitors of RalGEF. As no such inhibitors have yet been reported the project isintrinsically innovative.Methodology: In silico computer screens of large molecular libraries were used to identify potential RalGEFbinding compounds based on the known structure of the Ras binding domain of RalGDS. The compoundswere bioassayed to identify those that act as anticipated. The interaction of the compounds with their targetwill be defined by NMR and bioassays perfomed to determine their main biological modes of action in vitro.They will then tested in highly physiological animal models of human pancreatic cancer.Expected results: We will identify the first pan-RalGEF inhibitor and it will inhibit pancreatic cancer.Affects on other research areas: The molecules we identify may serve as powerful scientific tools toinvestigate Ras/RalGEF function in vivo and may lead to novel therapeutics for Ras driven cancer.

project_terms:
1-Phosphatidylinositol 3-Kinase;Affect;Agar;Animal Model;Animals;Area;Binding;Biological;Biological Assay;Biological Models;Cancer Model;Cancer cell line;Clinic;Collaborations;Computer Simulation;Computers;Development;Disease;Disseminated Malignant Neoplasm;Exhibits;Genetic;Goals;Growth;Human;In Vitro;KRAS2 gene;Lead;Literature;Malignant Neoplasms;Malignant neoplasm of pancreas;Methodology;Modeling;Molecular Bank;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Oncogenic;Oncoproteins;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Physiological;Point Mutation;Positioning Attribute;Primary Neoplasm;Proteins;Public Health;RALGDS gene;Raf Kinase Inhibitor;Ras Inhibitor;Reporting;Research;Signal Pathway;Structure;Structure of parenchyma of lung;Survival Rate;System;Testing;Therapeutic;Toxic effect;Transgenic Mice;Transgenic Model;Treatment Efficacy;Variant;Xenograft procedure;antitumor effect;arm;base;cell transformation;drug development;effective therapy;experience;experimental study;human model;in vitro Assay;in vivo;in vivo Model;inhibitor/antagonist;innovation;kinase inhibitor;molecular modeling;mouse model;neglect;novel;novel therapeutics;pancreatic cancer cells;pancreatic neoplasm;physiologic model;prevent;raf Kinases;ral A GTP-Binding Protein;ras Oncogene;screening;small molecule;small molecule inhibitor;small molecule therapeutics;tool;tumor;tumor growth;tumorigenesis;tumorigenic

public_health_relevance:
Ras is the most frequently activated oncoprotein found in human cancer. No effective anti-Ras drugs are yetavailable in the clinic. This proposal seeks to validate novel small molecules that block the ability of Ras topromote cancer/metastasis by inhibiting its ability to interact with the RalGEF class of Ras effector proteins.


application_id: 9570623
project_number: 5R42AG044187-03
project_title: Commercialization of a Novel Therapeutic for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2018-06-25
opportunity_number: PA-16-092
application_type: 5
activity_code: R42
ic: AG
serial_number: 044187
program_official: MARTIN, ZANE
project_start_date: 2012-09-30
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1-ETTN-M(11)B]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 841834083
primary_uei: JK7PN2MFXEU2
duns_number: 841834083
uei: JK7PN2MFXEU2
fips: US
organization_id: 10022006
organization_name: COPLEX THERAPEUTICS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTTraditional mon-therapeutic target driven approaches to drug development for Alzheimersdisease (AD) are becoming increasingly expensive and in many cases disappointinglyunsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel smallmolecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate;(BNC-1)) that significantly decreases neuroinflammation and production of A42 in mousemodels of AD pathology through Elk-1 mediated transcriptional repression of presenilin-1 butnot presenilin-2. Although our preliminary data show BNC-1 effectively modulates 2 of the mainpathologic features of AD without the adverse effects associated with current mono-therapeutics there is a need for characterization of its basic pharmacology/toxicity and foridentification of the most efficacious treatment regimen in a well characterized mouse model ofA deposition and neuroinflammation (5X FAD mice). If successful the data obtained in thisproposal will provide necessary pharmacology/safety toxicology data to de-risk the drug forpotential corporate partners thus increasing the likelihood of successful commercialization.

project_terms:
APP-PS1;Abeta synthesis;Adrenal Glands;Adverse effects;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Amyloid deposition;Anti-inflammatory;Autopsy;Biological Availability;Blood specimen;Body Weight;Brain;Chromosome abnormality;Clinical;Clinical Chemistry;Clinical Pathology;Clinical Services;Clinical Trials;Collaborations;Data;Deposition;Development;Diet;Disease;Dose;Drug Kinetics;Female;Formic Acids;Future;Guidelines;Hematology;High Pressure Liquid Chromatography;Histopathology;In Vitro;Inflammatory;Intestines;Intravenous;Isotope Labeling;Kentucky;Kidney;Learning;Legal patent;Liver;Maximum Tolerated Dose;Mediating;Memory;Methods;Modeling;Mono-S;Mus;Mutation;Naphthyridines;Oral;Outcome;PS2 protein (alzheimer-associated);Pancreas;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacology and Toxicology;Phase;Phenotype;Positioning Attribute;Presenile Alzheimer Dementia;Prevention;Production;Proteins;Radial;Rattus;Recovery;Regimen;Risk;Rivers;Role;Safety;Series;Spleen;Sprague-Dawley Rats;Tail;Testing;Therapeutic;Time;Toxic effect;Toxicokinetics;Toxicology;Transcription Repressor/Corepressor;Treatment Protocols;Universities;Veins;Water;amyloid formation;animal resource;arm;base;behavior measurement;carboxylate;commercialization;cytokine;drug development;drug efficacy;efficacy testing;familial Alzheimer disease;food consumption;gamma secretase;gene repression;improved;in vivo;inhibitor/antagonist;male;mouse model;mutant;neuroinflammation;notch protein;novel;novel therapeutics;object recognition;pre-clinical;presenilin-1;respiratory;small molecule;therapeutic target

public_health_relevance:
NarrativeIn preliminary studies we identified a novel small molecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate; (BNC-1) that lowers beta amyloid (A) production andpro-inflammatory cytokines but increases anti-inflammatory cytokines and significantly improvesbehavioral measures in a mouse model of Alzheimers disease. Future studies described in thisproposal aim to determine the pharmacokinetics and toxicology of BNC-1 and to test the efficacy forprevention of beta amyloid (A) formation and deposition and neuroinflammation in a well-establishedalternative mouse model of A pathology (5X FAD mice). Together these studies will help de-risk BNC-1 for potential partners and better position the compound for further commercialization.


application_id: 9568835
project_number: 5R21NS104807-02
project_title: GABAergic circuit interactions within the behaving mouse dLGN
administering_ic: NINDS
award_notice_date: 2018-08-23
opportunity_number: RFA-NS-17-015
application_type: 5
activity_code: R21
ic: NS
serial_number: 104807
program_official: DAVID, KAREN KATE
project_start_date: 2017-09-25
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-T(50)]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract The flow of visual information from the retina through the dorsal lateral geniculate nucleus(dLGN) to the cortex is regulated by behavior. However the dynamic circuit interactions that occur inthe dLGN of awake animals and their modulation by behavior have yet to be revealed. The purposeof this proposal is to develop tools to determine how inhibitory circuits of the dLGN (which utilize theneurotransmitter gamma amino butyric acid GABA) interact in vivo and how they collectively shapevision in the context of behavior. The premise of this study is based on two key pieces of information:1) Our previous ultrastructural analyses and in vitro optogenetic experiments suggest that twoextrinsic GABAergic inputs to the dLGN originating from the thalamic reticular nucleus (TRN) andpretectum (PT) serve to suppress or enhance retinogeniculate transmission respectively. 2) Previousstudies suggest that the TRN and PT are active during different behavioral states. Thus wehypothesize that these two sources of inhibition serve to suppress or enhance visual signals in thedLGN during different behavioral states. We propose to test this hypothesis by recording dLGN visualresponses in behaving mice while selectively and independently manipulating TRN and/or PTterminals within the dLGN. In head-fixed alert mice we will record the visual responses of dLGNneurons to computer-generated visual displays while simultaneously recording running speed eyemovements and pupil diameter. The Aim 1 experiments will test the hypothesis that the PT functionsto enhance retinogeniculate transmission immediately following eye movements to boost corticalactivation following visual target acquisition. For this aim geniculate responses will be recordedduring optogenetic silencing or activation of PT terminals chemogenetic silencing of TRN terminalsor the combined optogenetic/chemogenetic manipulation of PT and TRN terminals. The Aim 2experiments will test the hypothesis that the TRN dampens retinogeniculate transmission duringquiescent states. For this aim geniculate responses will be recorded during optogenetic silencing oractivation of TRN terminals chemogenetic silencing of PT terminals or the combinedoptogenetic/chemogenetic manipulation of TRN and PT terminals. The development of techniques tomanipulate circuits in vivo in addition to our existing anatomical and in vitro experiment strategieswill provide a powerful multipronged approach to deciphering how the individual components of braincircuits are integrated. Once these in vivo methods are perfected our methodologically-integratedapproach can be used to answer a wide variety of outstanding questions regarding thalamic function.

project_terms:
Action Potentials;Acute;Address;Affect;Anatomy;Animals;Area;Attention;Behavior;Behavioral;Brain;Butyric Acids;Caliber;Cannulas;Cell Nucleus;Cells;Disease;Disinhibition;Dorsal;Drug Delivery Systems;Electrodes;Elements;Epilepsy;Eye Movements;Fiber Optics;Frequencies;Goals;Head;In Vitro;Individual;Injury;Interneurons;Intervention;Knowledge;Lateral Geniculate Body;Light;Link;Mediating;Membrane Potentials;Methodology;Methods;Modeling;Movement;Mus;Neurons;Neurotransmitters;Output;Pattern;Physiology;Pupil;Reporting;Retina;Running;Schizophrenia;Shapes;Signal Transduction;Sleep;Slice;Source;Speed;Synapses;Techniques;Testing;Thalamic structure;Tungsten;Vision;Visual;Whole-Cell Recordings;active vision;awake;base;behavior measurement;computer generated;experimental study;extracellular;in vivo;insight;nervous system disorder;neural circuit;optogenetics;response;retinogeniculate;technique development;tool;transmission process;visual information

public_health_relevance:
NarrativeThese studies will provide valuable information about how inhibitory circuits affect thalamicsignaling during different behavioral states and offer insight into the study and treatment ofneurological disorders that result from abnormal patterns of connectivity between GABAergicneurons and thalamocortical relay neurons. Such perturbations have been implicated in anumber of neurological disorders associated with sleep attention eye movements epilepsy andschizophrenia. Knowledge gained from these studies will also have important implications forunderstanding and predicting how thalamic circuits respond to disease or injury.


application_id: 9567171
project_number: 5R01ES026657-02
project_title: Microenvironment and Arsenic Lung Tumorigenesis
administering_ic: NIEHS
award_notice_date: 2018-08-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026657
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-09-30
project_end_date: 2022-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
A/J Mouse;Animal Model;Animals;Antibodies;Arsenic;Binding;CD4 Positive T Lymphocytes;CD4/CD8 ratio procedure;CD8B1 gene;Cancer Patient;Cell Count;Cell membrane;Cells;Cellular Structures;Chronic;Data;Development;Dose;Environmental Exposure;Environmental Risk Factor;Epithelial Cells;Equilibrium;Flow Cytometry;Functional disorder;Genes;Human;Immune;Immune Checkpoint;Immune system;Immunity;Immunologic Monitoring;Immunologic Surveillance;In Vitro;Incidence;Injections;Interleukin-6;Investigation;Knock-out;Lead;Lung;Lung Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Modeling;Monitor;Mus;Outcome;PDCD1LG1 gene;Pathway interactions;Pharmacologic Substance;Play;Process;Receptor Inhibition;Regulation;Reporting;Role;SLEB2 gene;STAT3 gene;Skin Cancer;T-Lymphocyte;T-Lymphocyte Subsets;Tumor Escape;Tumor Immunity;Up-Regulation;cell transformation;cell type;cytotoxic;genetic approach;immune activation;in vivo;inhibiting antibody;inhibitor/antagonist;innovation;lung carcinogenesis;lung tumorigenesis;mouse model;neoplastic cell;novel;novel strategies;prevent;promoter;tumor;tumor initiation;tumorigenesis


application_id: 9566892
project_number: 5R01GM118541-02
project_title: A melatonin-sensitive circadian oscillator in the human gut commensal Enterobacter aerogenes
administering_ic: NIGMS
award_notice_date: 2018-07-30
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 118541
program_official: SESMA, MICHAEL A
project_start_date: 2017-09-15
project_end_date: 2021-07-31
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 1862567
contact_pi: CASSONE, VINCENT M
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Circadian rhythms are fundamental features of many if not all organisms on Earth. Amonganimals the molecular mechanisms underlying these rhythms are remarkably conserved. Yetoutside animals known mechanisms among the few model systems are disparate which is notsurprising due to the billions of years of separation among these taxa. Among prokaryotes onlyone species has been shown to exhibit circadian rhythms the cyanobacterium Synechococcuselongatus whose clock derives from cycles of autophosphorylation and phosphatase activity inkey clock proteins Kai AB and C. We have discovered a new biomedically important modelbacterium Enterobacter aerogenes which expresses a temperature-compensated circadianclock which is synchronized by the gut hormone melatonin and is entrained by cycles oftemperature using swarming behavior and motA-driven luciferase bioluminescence. We proposeto fully characterize this exciting new clock system. We will determine whether the clock systemregulates multiple physiological processes in parallel by asking whether gene expression withdifferent promoter elements and luciferase are expressed rhythmically and/or respond tomelatonin similar to motA-driven rhythms. We will determine whether melatonin is a trueZeitgeber for this clock and we will characterize the effects of temperature cycles which entrainthis clock testing the hypotheses that host melatonin secretion and/or TB synchronize this entericbacterium. Secondly we will knock out candidate genes that bear molecular similarity to Kaiproteins characterize these knockouts and complement those that exhibit clock phenotypes. Inaddition we will conduct a broad mutant screen searching for clock mutants. Thirdly we willcharacterize the biological activity clock function and melatonin sensitivity of all knockout andmutant strains discovered here. If this clock does indeed share a common ancestor with thecyanobacterial clock the data have broad and important evolutionary significance placing theevolution of the circadian clock before the emergence of O2 generating photosynthesis some 3.5billion years ago. In addition these observations point to an integrated circadian organization inwhich master pacemakers in the brain synchronize peripheral oscillators which in turn mayregulate aspects of the microbiota through entrainment of the bacterial clock. This has importantimplications for biomedical science and therapeutics.

project_terms:
5'-Nucleotidase;Animals;Back;Bacteria;Behavior;Biological;Biological Models;Bioluminescence;Body Temperature;Brain;Candidate Disease Gene;Circadian Rhythms;Clock protein;Complement;Cyanobacterium;Data;Dephospho-CoA kinase;Disease;Elements;Enteral;Enterobacter aerogenes bacterium;Enterobacteriaceae;Evolution;Exhibits;Funding;Gene Expression;Genes;Hormones;Human;Knock-out;Lead;Luciferases;Manganese;Melatonin;Modeling;Molecular;Mutagenesis;Organism;Pacemakers;Pattern;Periodicity;Peripheral;Phase;Phase response curves;Phenotype;Phosphoric Monoester Hydrolases;Photosynthesis;Phylogenetic Analysis;Physiologic pulse;Physiological;Physiological Processes;Physiology;Planet Earth;Plasmids;Process;Prokaryotic Cells;Promoter Regions;Proteins;Protocols documentation;Regulation;Reporter;Science;Signal Transduction;Synechococcus;System;TYRP1 gene;Temperature;Testing;Therapeutic;Ursidae Family;catalase;cell motility;circadian pacemaker;commensal bacteria;gastrointestinal;gut bacteria;gut microbiota;human microbiota;knockout gene;microbiota;mutant;promoter;response

public_health_relevance:
The human biological circadian clock orchestrates a diverse array of processes throughthe coordination and entrainment of peripheral circadian oscillators whereby disruption ofcircadian organization can lead to disease. We have discovered that at least one commensalgut bacterium Enterobacter aerogenes also expresses an endogenous circadian clock that isresponsive to signals from the hosts circadian system the hormone melatonin and changes intemperature. This project is likely to identify the components of this first prokaryotic circadianclock outside of the cyanobacterial phylum and the first in an organism that interacts directlywith humans the results of which are likely to have broad implications for the regulation of thehuman microbiota and gut physiology.


application_id: 9566329
project_number: 5K01TW010271-03
project_title: Metabolic Syndrome and Epigenetic Markers of Breast Cancer in Nigerian Women
administering_ic: FIC
award_notice_date: 2018-09-03
opportunity_number: PAR-15-291
application_type: 5
activity_code: K01
ic: TW
serial_number: 010271
program_official: MICHELS, KATHLEEN M
project_start_date: 2016-09-28
project_end_date: 2019-01-31
study_section: International and Cooperative Projects - 1 Study Section[ICP1]
contact_pi_person_id: 9235849
contact_pi: AKINYEMIJU, TOMI F
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTDeveloping countries accounted for 45% of new breast cancer cases globally in 2009 and 57% in 2012 withthese proportions projected to increase to 70% by 2030. Nigeria has experienced a three-fold increase inbreast cancer incidence between 1973 and 2012 coinciding with an increase in the prevalence of so-called`diseases of affluence' including obesity hypertension and diabetes a cluster of biochemical abnormalitiesthat constitute Metabolic Syndrome (MetS). Recent studies in the US and Europe have shown a consistentpositive association between MetS and breast cancer risk suggesting that rising breast cancer rates in Nigeriamay be a biological consequence of increasing rates of MetS. Once diagnosed with breast cancer Nigerianwomen similar to other women of African descent are also more likely to present at younger ages with highlyaggressive hormone-receptor negative tumors associated with higher mortality. The reason for a higherprevalence of these tumor types in women of African descent is unclear. Epigenetic changes through DNAmethylation histone modification and micro RNA changes are critical aspects of breast cancer tumorigenesisand are influenced by both genetic background and environmental exposures. Multiple US studies haveobserved significant differences in DNA methylation levels of critical breast cancer genes between African-Americans and whites including BRCA1 and BRCA2 CYP1A1 H-ras-1 and Cyclin D1. DNA methylationlevels in critical breast cancer genes among Nigerian women have never been examined and this may be thekey to understanding racial differences in breast cancer phenotypes. Identification of race-specific epigeneticpatterns could potentially be used as an intermediary marker of the association between exposures such asMetS and breast cancer incidence or as prognostic markers for clinical management and therapeuticinterventions. Using a sample of newly diagnosed breast cancer cases and age-matched healthy controls thisstudy aims to examine the association between MetS and breast cancer overall and by sub-type in Nigeria. Inaddition we plan to identify genome-wide DNA methylation differences between breast cancer tumor andadjacent normal tissue among women with and without MetS. These findings will provide critical information onthe influence of MetS on breast cancer in Nigeria and improve our understanding of the specific epigeneticchanges that occur with breast cancer in Nigerian women; this is likely to be different from epigenetic changesobserved among African American women with significantly different environmental exposures.

project_terms:
Address;Africa;African;African American;Age;Alcohol consumption;Applications Grants;BRCA1 gene;BRCA2 gene;Biochemical;Biological;Blood;Blood Glucose;Blood specimen;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer gene;CYP1A1 gene;Cancer Prognosis;Case-Control Studies;Cause of Death;Clinical Management;Communicable Diseases;Country;Cyclin D1;DNA;DNA Methylation;Data;Developing Countries;Diabetes Mellitus;Diagnosis;Disease;Economic Development;Environmental Exposure;Epidemic;Epidemiology;Epigenetic Process;Europe;Foundations;Freezing;Genes;Genetic;Goals;High Density Lipoproteins;High Prevalence;Hospitals;Hypertension;Incidence;International;Kidney Diseases;Laboratories;Lasers;Life Style;Link;Mammary Gland Parenchyma;Mentors;Metabolic syndrome;MicroRNAs;Molecular;Molecular Epidemiology;Newly Diagnosed;Nigeria;Nigerian;Normal tissue morphology;Obesity;Pathway interactions;Pattern;Phenotype;Population;Positioning Attribute;Prevalence;Prognostic Marker;Questionnaires;RAS genes;Race;Research;Residual state;Risk Factors;Role;Sampling;Sampling Studies;Ships;Smoking;Therapeutic Intervention;Tissue Sample;Tissues;Training;Triglycerides;Tumor Suppression;Waist-Hip Ratio;Woman;Women's Group;World Bank;breast cancer diagnosis;cancer subtypes;early onset;epigenetic marker;experience;genome-wide;global health;histone modification;hormone receptor-negative;improved;low and middle-income countries;malignant breast neoplasm;metabolic rate;methylation pattern;mortality;outcome forecast;racial difference;recruit;triple-negative invasive breast carcinoma;tumor;tumor DNA;tumorigenesis;urban area

public_health_relevance:
NARRATIVEBreast cancer rates in Nigeria are increasing very rapidly and are predominantly of aggressive sub-types withpoor prognosis. However few studies have determined the factors associated with the increasing rates. Thisstudy provides critical information on the influence of metabolic syndrome as a risk factor for breast cancer inthis population and examines potential biological mechanisms through which it influences breast cancer.


application_id: 9565640
project_number: 5R21HL140213-02
project_title: Latexin in human hematopoietic stem cell expansion
administering_ic: NHLBI
award_notice_date: 2018-08-17
opportunity_number: RFA-HL-17-022
application_type: 5
activity_code: R21
ic: HL
serial_number: 140213
program_official: OCHOCINSKA, MARGARET J
project_start_date: 2017-09-14
project_end_date: 2020-08-31
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The goal of this study is to develop new strategies to expand human hematopoietic stem cells (HSC) byutilizing cryopreserved umbilical cord blood (CB) in NHLBI Biorepository. HSC transplantation is currentlybeing used as regenerative medicine for the treatment of congenital deficiencies and malignant diseases of theblood and immune systems. A major roadblock of success of this therapy is the limited number of HSC perharvest and the poorly understood expansion and differentiation behavior. This proposal aims to increase CBHSC ex vivo expansion by targeting a newly identified molecular pathway. Natural genetic diversity offers animportant yet largely untapped reservoir for deciphering molecular regulatory mechanisms of HSCs andhematopoiesis. We previously identified the first and probably so far the only stem cell regulatory gene latexin(Lxn) by employing genetic diversity approach. Lxn is a negative regulator of HSC number and function. Ourpreliminary work in Lxn knockout mice showed that Lxn inactivation increases HSC numbers and theexpansion is controlled within the physiological range of variation. The expanded HSCs maintain the capacityof self-renewal and multilineage differentiation. Considering the nature of Lxn as a natural variant regulator ofHSCs we speculate that Lxn may function similarly in human population. Our preliminary studies demonstratethe negative correlation between HSC numbers and Lxn expression in human samples. We thereforehypothesize that Lxn negatively regulates human HSCs and its inhibition leads to HSC expansion byincreasing self-renewal while maintaining multi-lineage differentiation capacity. Specific aims are to: 1)determine whether knockdown of Lxn can expand human HSCs while maintaining their self-renewal andmultilineage differentiation capacity and 2) Determine the molecular mechanisms by which Lxn-Thbs1signaling pathway regulates human HSC expansion and function. This research will provide new insight intothe potential utility of Lxn inhibition to promote HSC expansion thereby benefiting patients needing HSCtransplantation.

project_terms:
Behavior;Blood;Blood Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell physiology;Cells;Development;Down-Regulation;Genes;Genetic Variation;Goals;Harvest;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Human;Immune System Diseases;In Vitro;Knockout Mice;Life;Malignant - descriptor;Mediating;Messenger RNA;Modeling;Molecular;National Heart Lung and Blood Institute;Nature;PC3.1 antigen;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Physiological;Population;Production;Proteins;Quality of life;Radiation therapy;Recovery;Regenerative Medicine;Regulation;Regulator Genes;Research;Role;Sampling;Savings;Signal Pathway;Stem cell transplant;Stem cells;System;Testing;Therapeutic;Thrombospondin 1;Treatment Efficacy;Umbilical Cord Blood;Variant;Work;Xenograft procedure;base;biobank;in vivo;insight;knock-down;novel;self-renewal;success

public_health_relevance:
PROJECT NARRATIVEEfficient hematopoietic (blood-forming) stem cells (HSCs) expansion and accelerated hematopoietic recoveryare critical for the quality of life of cancer patients receiving radiotherapy and bone marrow transplantation.This study will investigate the cell-intrinsic role of latexin gene in HSC expansion that will have greattherapeutic value.


application_id: 9565612
project_number: 5R01GM126181-02
project_title: Chronic muscle weakness in sepsis survivors
administering_ic: NIGMS
award_notice_date: 2018-08-30
opportunity_number: PA-16-160
application_type: 5
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_abstract:
ABSTRACTThe objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscledysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained thisproject will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1million sepsis survivors are now discharged from the hospital every year and a majority of these survivorsreport reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge.However the lack of an appropriate animal model has been a critical barrier to identifying the changes whichpersist long after recovery from sepsis. We recently developed a new mouse model that has enabled us toevaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstratethat sepsis-surviving mice exhibit significant skeletal muscle weakness even after bacterial infection andinflammation are resolved and muscle mass is recovered giving us the unique opportunity to evaluatemolecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles fromthese sepsis-surviving mice also show histological abnormalities significant nitro-oxidative damage andprofound structural and functional defects in mitochondria. These preliminary results support our centralhypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric proteindamage both of which remain long after sepsis recovery and these are the major contributors to the sustainedskeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determinemitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damageand its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to amelioratepost-sepsis chronic muscle weakness.

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

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


application_id: 9564859
project_number: 5R36DA043714-02
project_title: Alprazolam and Simulated Driving Performance: Next Day Effects
administering_ic: NIDA
award_notice_date: 2018-08-17
opportunity_number: PA-16-443
application_type: 5
activity_code: R36
ic: DA
serial_number: 043714
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)F]
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
arra_indicator: N
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;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;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: 9564808
project_number: 5K99AG056635-02
project_title: Stress and Immunosenescence: Protective Effects of Emotion Regulation
administering_ic: NIA
award_notice_date: 2018-05-31
opportunity_number: PA-16-193
application_type: 5
activity_code: K99
ic: AG
serial_number: 056635
program_official: NIELSEN, LISBETH
project_start_date: 2017-09-15
project_end_date: 2019-08-31
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
contact_pi_person_id: 11895122
contact_pi: REED, REBECCA G
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYIdentifying factors that influence age-related immune dysfunction (immunosenescence) in older adults iscentral to promoting well-being and reducing morbidity  an increasing public health concern given the rapidlyexpanding aging population. Evidence from observational and experimental studies suggests that stress isassociated with poorer immune function in older adults. However less is known about the dynamic(intraindividual variability) emotional and physiological mechanisms by which stress influences older adults'immune function. In addition emotion regulation may be a protective factor that can buffer stress-relatedimmunosenescence in later life but there is a dearth of knowledge in this area. This K99/R00 proposal lays thefoundation for an independent research career focused on characterizing adaptive emotional andimmunological mechanisms that contribute to healthy aging during stress. The proposed career developmentplan will provide the candidate: (1) expertise in theories and methodologies of aging research (2) advancedknowledge in immunosenescence and age-related immune changes and (3) training in emotion and emotionregulation processes focused specifically on contexts of aging and stress. The mentored phase capitalizes onsubstantial research and professional development resources at the University of Kentucky (UK) and theexpertise of an inter-disciplinary mentoring team (UK: Dr. Segerstrom and Dr. Lutz; UC Berkeley: Dr. Mauss;Penn State University: Dr. Ram UCLA: Dr. Effros). These experiences will supplement the candidate's existingbackground in stress emotions health and quantitative methods. The present study has three aims to testdifferent components of a proposed model. Aim 1 (K99): To examine whether emotion regulation moderatesthe association between life stressors and immunosenescence. Aim 2 (K99): To explain how daily stressorsare associated with elevated stress biomarkers through intraindividual variability in negative emotion. Aim 3(R00): To test the moderated mediation pathways of the entire proposed biopsychosocial model. The researchincorporates a rigorous approach to test the proposed model by examining its interacting components acrossdifferent time domains (i.e. life stressors that occur over years and daily hassles that occur on a more microlevel) in various samples (community-dwelling older adults and a large nationally representative sample) andacross several markers of immunosenescence (lymphocyte senescence inflammation a chief proinflammatorytranscription factor and a latent virus that may drive senescence). Concurrent and prospective laggedmoderation and mediation models using multilevel modeling and regression will be used to test relationshipsamong stressors emotional and physiological responses to stress immunosenescence and emotionregulation. Ultimately this project will increase understanding of the dynamic mechanisms by which stressorsinfluence immunosenescence in older adults and the role of emotion regulation in promoting healthy aging.

project_terms:
Adult;Affective;Age;Aging;Antibody titer measurement;Area;Biological Markers;Buffers;Chronic Disease;Communicable Diseases;Communities;Cytomegalovirus;Data;Development Plans;Elderly;Emotional;Emotions;Event;Feeling;Fostering;Foundations;Goals;Health;Hydrocortisone;Immune;Immune System Diseases;Immunity;Immunologics;Incidence;Individual;Inflammation;Interleukin-6;Kentucky;Knowledge;Latent Virus;Life;Link;Lymphocyte;Mediation;Mediator of activation protein;Mentors;Methodology;Methods;Modeling;Morbidity - disease rate;NF-kappa B;Natural Killer Cells;Nature;Observational Study;Pathway interactions;Personal Satisfaction;Phase;Physiological;Process;Psychological Stress;Public Health;Research;Research Project Grants;Resource Development;Resources;Risk;Role;Sampling;Science;Severities;Stress;T-Lymphocyte;Testing;Time;Training;Universities;Virus Latency;age related;aging population;biopsychosocial;career;career development;diaries;emotion regulation;experience;experimental study;healthy aging;immune function;immunosenescence;mortality;multilevel analysis;physical conditioning;prospective;protective effect;protective factors;resilience;response;senescence;stress management;stressor;theories;trait;transcription factor

public_health_relevance:
Psychological stress can accelerate age-related decline in immune function (immunosenescence) thatincreases risk of poor health. Greater understanding of how this happens and what may foster resilient healthin the face of stress is needed. This project examines emotional and physiological mechanisms by whichstressors influence immunosenescence and the potential protective role of emotion regulation in reducingnegative effects.


application_id: 9564784
project_number: 5R01AG055449-02
project_title: Contributions of Alzheimer's Pathology and Cerebrovascular Factors to Cognitive Aging
administering_ic: NIA
award_notice_date: 2018-04-27
opportunity_number: PAR-15-357
application_type: 5
activity_code: R01
ic: AG
serial_number: 055449
program_official: WAGSTER, MOLLY V
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_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;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: 9564290
project_number: 1R56ES025188-01A1
project_title: Prenatal Tobacco Exposure and Mechanisms of Offspring Obesity
administering_ic: NIEHS
award_notice_date: 2017-09-20
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: ES
serial_number: 025188
suffix: A1
program_official: JOUBERT, BONNIE
project_start_date: 2017-09-30
project_end_date: 2019-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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_abstract:
PROJECT SUMMARYIt has been shown that in utero tobacco exposure increases offspring risk for a number of diseases includingobesity and diabetes which are significant burdens on the healthcare system in the US and worldwide. As partof a pilot study in Kentucky 30% of pregnant mothers reported that they actively smoked cigarettes during theirpregnancy and it was shown that tissues from babies born to smoking mothers had altered metabolic geneexpression and DNA methylation levels compared to babies born to nonsmokers. Further primary fibroblastsisolated from babies born to smokers took up more lipids and had impaired insulin signaling compared to cellsisolated from babies born to nonsmokers. These observations form the basis of the hypotheses that 1) theDNA methylation pattern and expression of key energy metabolism genes and their resulting proteins will besignificantly altered in the neonatal tissue of babies born to active smokers compared to those born tononsmokers 2) living cells isolated from babies born to active smokers will be functionally dysregulatedcompared to cells taken from babies of nonsmokers and 3) biomarkers that are identified will be predictive ofincreased growth rates and pediatric obesity. The goal of Specific Aim 1 is to establish biomarkers andpotential mechanisms contributing to offspring obesity and diabetes risk resulting from in utero cigaretteexposure. Gene expression and epigenetic alterations will be quantified in neonatal tissue in order to establishdifferences between exposure groups. Specific Aim 2 will determine the extent to which neonatal cells areuniquely programmed by in utero smoke exposure. Primary skin fibroblasts will be isolated from neonates andgrown in culture. Glucose uptake and susceptibility to differentiate into adipocyte-like cells will be assessed asit is likely these cells are already dysfunctional at birth. Finally the goal of Specific Aim 3 is to use geneexpression data DNA methylation changes and cell function measures as potential biomarkers that willpredict increased growth rates and obesity susceptibility in male infants that were exposed to tobacco smoke inutero. Using primary fibroblasts isolated from neonates in order to measure adipogenesis and glucose uptakein live cells is not currently possible using any other model system to explore the effects of maternal smokingon offspring. The proposed study provides a human system to demonstrate the mechanisms through whichtobacco smoke exposure in utero contributes to the epidemic of childhood obesity. Research findings and thissystem could also provide an innovative approach to understand the effects of various other in utero exposureson metabolic outcomes in children. Future work can also utilize this model to investigate new preventative andintervention approaches targeting these pathways.

project_terms:
3 year old;Adipocytes;Adult;Adult Children;Biochemical;Biological Assay;Biological Markers;Biological Models;Birth;Body Composition;Cell Culture System;Cell physiology;Cells;Child;Childhood;Cigarette;DNA Methylation;Data;Dermal;Development;Diabetes Mellitus;Disease;Energy Metabolism;Epidemic;Epigenetic Process;Exposure to;Fibroblasts;Future;Gene Expression;Genes;Glucose;Goals;Growth;Health;Healthcare Systems;Human;Impairment;Individual;Infant;Kentucky;Lipids;Male Circumcision;Measures;Medical center;Metabolic;Modeling;Monitor;Mothers;Neonatal;Non-smoker;Obesity;Outcome;Pathway interactions;Pilot Projects;Populations at Risk;Predisposition;Pregnancy;Preventive Intervention;Proteins;Recruitment Activity;Reporting;Research;Risk;Sampling;Signal Transduction;Skin;Smoke;Smoker;Smoking;Suggestion;System;Testing;Tissues;Tobacco smoke;Universities;Variant;Woman;Work;boys;cigarette smoking;cohort;diabetes risk;epigenetic marker;epigenetic regulation;experimental study;fetal tobacco exposure;glucose uptake;in utero;innovation;insulin signaling;lipid biosynthesis;mRNA Expression;male;maternal cigarette smoking;methylation pattern;neonate;novel;novel strategies;obesity in children;obesity risk;offspring;penis foreskin;potential biomarker;pregnant;prenatal exposure;prospective;protein expression;specific biomarkers;tobacco exposure;uptake

public_health_relevance:
PROJECT NARRATIVEMaternal smoking increases offspring risk for a number of diseases including obesity and diabetes. Theproposed studies introduce a powerful new approach that will identify biomarkers of the specific harmassociated with in utero cigarette exposure and will elucidate the potential mechanisms that contribute toincreased pediatric obesity and diabetes risk.


application_id: 9564235
project_number: 5R21NS103433-02
project_title: Glial-specific gene expression after contusive spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-08-02
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: NS
serial_number: 103433
program_official: JAKEMAN, LYN B
project_start_date: 2017-09-15
project_end_date: 2019-08-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
No clinically applicable treatments exist to improve functional outcome after spinal cord injury (SCI). In partsuch a lack of progress is due to poor understanding of the complex pathology of this injury. The SCI responseis cell type-specific and evolves with time post-injury. Acutely after injury oligodendrocytes (OL) displaydisruption of proteostasis including endoplasmic reticulum stress (ERSR) and integrated stress (ISR)responses. The ISR leads to apoptosis and white matter loss that underlies many deficits of sensation andlocomotion. Later oligodendrocyte precursor cells (OPCs) proliferate in an attempt to repair lost myelin.However that response is limited by inhibitory signals that block OPC differentiation. While global spinal cordtranscriptomics have enabled a systematic knowledge about the SCI response conclusions from these effortsare limited by technological barriers and the complexity of spinal cord anatomy. Thus SCI-associated changesin mRNA levels may not translate into parallel effects on protein expression. Moreover homogenizedfragments of whole spinal cord used for traditional transcriptomic experiments make identification of novelcomponents of the cell-specific injury response challenging. These limitations may be overcome by TranslatingRibosome Affinity Purification (TRAP) technology which isolates and analyzes only mRNAs that are associatedwith ribosomes (i.e. being likely translated) from specific cell populations that were marked genetically with aribosomal tag. Thus we propose to apply TRAP to test the hypothesis that after SCI both transcriptional andtranslational reprogramming regulate the expression of critical components of the injury response in a cell type-specific manner. Furthermore translational regulation will be of particular significance to launch proteostasisresponses in OPCs and OLs. We also propose that in the context of OPC/OLs that respond to SCI identifyingtranslated mRNAs for transcription factors will uncover new targets that can be targeted for OL protectionand/or remyelination. Focusing on the injury epicenter we will characterize translated transcriptome profiles ofOPC/OLs at 2 10 and 42 days after moderate mouse contusive SCI inOPC/OLs from transgenic mice thatexpress EGFP-L10 ribosome tag in a Cre dependent manner selectively in these cells (specific aim 1). Inaddition we will use the resulting data sets to identify transcription factors (TF) that orchestrate OPC/OLresponses to SCI (specific aim 2). We expect to characterize SCI-associated gene expression events inOPC/OLs with unprecedented accuracy. By focusing on ribosome-associated transcripts our data will paint alandscape of complete gene expression events that reach the protein level. Such a landscape is unavailablefor SCI-challenged OPC/OLs on a whole genome scale. Therefore this high risk/high reward proposal mayredefine the SCI response of OPC/OLs and identify novel targets for white matter protection and/orremyelination therapies.

project_terms:
ATF6 gene;Acute;Affect;Affinity Chromatography;Anatomy;Apoptosis;Binding Sites;Biological Assay;Biological Process;Cell Differentiation process;Cells;Cellular Structures;Cessation of life;Chest;Chronic;Clinical;Complex;Data;Data Set;Esthesia;Event;Expression Profiling;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Immunohistochemistry;In Situ Hybridization;Injury;Knowledge;Label;Locomotion;Mediating;Messenger RNA;Motor;Mus;Myelin;Neuroglia;Nucleic Acid Regulatory Sequences;Oligodendroglia;Ontology;Outcome;Paint;Pathogenesis;Pathology;Pathway Analysis;Population;Post-Transcriptional Regulation;Principal Component Analysis;Proliferating;Proteins;Proteolipids;Publishing;Rattus;Recovery of Function;Research;Resolution;Ribosomal Proteins;Ribosomes;Role;Signal Transduction;Site;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stress;System;Tamoxifen;Technology;Testing;Therapeutic Intervention;Time;Transcript;Transgenic Mice;Translating;Translational Regulation;Untranslated RNA;Up-Regulation;Work;XBP1 gene;biological adaptation to stress;cell type;clinical application;differential expression;effective therapy;endoplasmic reticulum stress;experimental study;functional outcomes;genome-wide;high reward;high risk;improved;improved outcome;injured;insight;knock-down;new technology;new therapeutic target;novel;oligodendrocyte precursor;overexpression;precursor cell;protein expression;proteostasis;remyelination;repaired;response;response to injury;sensor;transcription factor;transcription factor CHOP;transcriptome;transcriptome sequencing;transcriptomics;white matter;white matter damage;whole genome

public_health_relevance:
Project narrativeCurrently there are no clinically effective treatments to improve outcome after traumatic spinal cord injury(SCI). This proposal will use a novel technology known as translating ribosome affinity purification assay toobtained unprecedented insight into gene expression changes in specific populations of spinal cord glia withwell established roles in the pathogenesis of SCI. This research may identify new targets for therapeuticinterventions after SCI.


application_id: 9564110
project_number: 5R35ES028373-02
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2018-08-13
opportunity_number: RFA-ES-16-008
application_type: 5
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2025-08-31
study_section: ZES1-LWJ-K(R)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Academia;Address;Adolescent;Adult;Affect;Animal Model;Area;Cardiovascular Diseases;Cessation of life;Chemical Exposure;Chemicals;Child;Cirrhosis;Collaborations;Data;Development;Diabetes Mellitus;Endocrine;Environment;Environmental Health;Epidemiologist;Exposure to;Fatty Liver;Goals;Government Agencies;Health;Hepatocyte;Industry;Lipids;Liver;Liver diseases;Malignant neoplasm of liver;Medical Societies;Metabolism;Methods;Mission;National Institute of Environmental Health Sciences;Nutrient;Obesity;Physicians;Poisons;Policies;Polychlorinated Biphenyls;Population;Practice Guidelines;Reproducibility;Research;Resources;Scientist;Strategic Planning;Time;Training and Education;Transplantation;Vinyl Chloride;Vision;Work;chronic liver disease;diagnostic biomarker;disease registry;environmental chemical;global health;human subject;innovation;multiple omics;next generation;programs;sex


application_id: 9564055
project_number: 5R01AG057290-02
project_title: Programming amylin secretion to slow brain aging - an animal model
administering_ic: NIA
award_notice_date: 2018-05-28
opportunity_number: RFA-AG-17-050
application_type: 5
activity_code: R01
ic: AG
serial_number: 057290
program_official: GUO, MAX
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: ZAG1-ZIJ-6(A1)
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: THINAKARAN, GOPAL
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
APP-PS1;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloidosis;Animal Model;Behavior;Biological;Biological Neural Networks;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Cerebrum;Data;Deposition;Development;Diabetes Mellitus;Disease Progression;Early Onset Familial Alzheimer's Disease;Feasibility Studies;Functional disorder;Genes;Goals;Heart;Heart failure;Hormones;Human;Impaired cognition;Individual;Injury;Insulin;Intravenous;Intravenous infusion procedures;Investigation;Islets of Langerhans;Kidney;Late Onset Alzheimer Disease;Link;Longevity;Mediating;Microglia;Molecular;Mus;Neuraxis;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pathogenesis;Pathology;Pericytes;Peripheral;Pre-Clinical Model;Protein Isoforms;Rattus;Structure of beta Cell of islet;Synapses;Testing;Time;Transgenes;Transgenic Mice;aging brain;amyloid formation;apolipoprotein E-4;behavior change;beta amyloid pathology;cognitive performance;design;diabetic patient;early onset;in vivo;islet amyloid polypeptide;mouse model;non-diabetic;novel;overexpression;proteostasis;transgene expression;transgenic model of alzheimer disease;uptake


application_id: 9563469
project_number: 3P30ES026529-01A1S1
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2017-09-19
opportunity_number: PA-17-317
application_type: 3
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2022-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P3)-1]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Air;Analytical Chemistry;Appalachian Region;Area;Arsenic;Asthma;Atherosclerosis;Awareness;Bioinformatics;Chemicals;Child health care;Chromium;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Computational Biology;Cor pulmonale;Core Facility;Development;Diabetes Mellitus;Disease;Ecology;Environment;Environmental Health;Environmental Risk Factor;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Professional;Health Sciences;Healthcare;Heart;Heart Diseases;Heavy Metals;Human;Incidence;Individual;Integrative Medicine;Interest Group;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentorship;Metabolic Diseases;Mining;National Institute of Environmental Health Sciences;Nickel;Obesity;Outcome;Particulate;Pilot Projects;Population;Positioning Attribute;Public Health;Radon;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resources;Rivers;Rural;Science;Scientist;Stimulus;Structure;Talents;Toxic Environmental Substances;Toxicology;Training;Training Activity;Translations;Universities;Vision;Water;base;career;career development;early life exposure;innovation;interest;member;metabolomics;neonate;novel;population health;programs;socioeconomic disadvantage;water quality


application_id: 9562180
project_number: 3R44OD018231-03S1
project_title: A non-surgical embryo transfer device for producing gene modified rats
administering_ic: OD
award_notice_date: 2017-09-22
opportunity_number: PA-14-071
application_type: 3
activity_code: R44
ic: OD
serial_number: 018231
suffix: S1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2010-07-15
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-S(10)B]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): ParaTechs Corporation develops innovative technologies for biomedical research while seeking to improve animal welfare for laboratory animals. One of ParaTechs' major goals is to further the guiding principles of ethical animal use by 'reducing replacing and refining' the use of animals in research according to the guidelines of Russell and Burch's 3Rs of animal research. ParaTechs already has brought to market a non-surgical embryo transfer device (NSETTM) for mice which replaces surgical embryo transfers with a non-surgical method that has been proven to cause less stress in research animals. The goal of this project is to develop a device and a research protocol for nonsurgical embryo transfer in rats. The device and protocol is to be rapid easy to use cost effective and efficien for embryo transfer. Poof of principle for the project was established during Phase I where multiple prototypes of a rat NSET device were designed manufactured and tested. Rat embryos were transferred and viable rat pups were obtained demonstrating the first successful nonsurgical embryo transfer in rats. The goal of Phase II is to further establish the parameters ofrat NSET technology and to develop the device for commercialization to the biomedical research community. Four objectives are proposed to achieve this goal. First we will determine the efficiency of non-surgical embryo transfer relative to surgical embryo transfer in Sprague-Dawley and Fischer 344 rats for both morula and blastocyst stage embryos. This study will have broad applications for transfer of cryopreserved embryos and for transfer of genetically modified embryos after introduction of embryonic stem cells. Second we will transfer in vitro cultured embryos using the rNSET and compared efficiency to surgical embryo transfer techniques. This aim will address successful transfer of rat embryos that may be modified very early in development; for example after pronuclear injection for the purpose of genetic modification. Third we will test the use of the rat NSET for artificial insemination as an alternative to surgical techniques. This aim will support the use of the device as an alternative t surgical artificial insemination and as a possible alternative to in vitro fertilization. Fourth w will assess the level of stress reduction of the NSET procedure compared to surgical embryo transfer. These aims are consistent with ParaTechs' overall goal to improve animal welfare and support more effective and humane use of animal models in biomedical research.

project_terms:
Address;Adopted;Animal Experimentation;Animal Model;Animal Welfare;Animals;Artificial Insemination;Assisted Reproductive Techniques;Award;Behavior;Biological Markers;Biomedical Research;Birth;Businesses;Cardiovascular Diseases;Categories;Cell Culture Techniques;Collaborations;Communities;Data;Development;Device Designs;Devices;Distress;Embryo;Embryo Transfer;Ethics;Female;Fertilization in Vitro;Funding;Gene-Modified;Genetic;Gills;Goals;Guidelines;Implant;In Vitro;Individual;Injection of therapeutic agent;Institution;Knock-out;Laboratories;Laboratory Animals;Laboratory Rat;Laboratory Research;Lead;Letters;Life;Maintenance;Measures;Methods;Modeling;Modification;Morals;Morula;Mus;Operative Surgical Procedures;Outcome;Pain;Painless;Pharmaceutical Preparations;Phase;Physiology;Procedures;Protocols documentation;Rat Strains;Rattus;Research;Research Personnel;Resources;Rivers;Savings;Services;Societies;Stress;Techniques;Technology;Technology Transfer;Testing;Tissue Sample;Toxicology;Transgenic Organisms;blastocyst;commercialization;cost;cost effective;design;embryonic stem cell;genetic manipulation;human disease;human tissue;improved;innovative technologies;method development;mouse model;prototype;public health relevance;pup;sperm cell;tissue culture

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The ability to genetically modify the laboratory rat is producing increasingly valuable and unique strains to investigate human disease. Currently this technology is dependent on implanting embryos in female rats by surgical means. ParaTechs proposes to develop and commercialize a unique device and technology for fast simple and painless nonsurgical embryo transfer (NSET) in rats which will support the Office of Laboratory Animal Welfare (OLAW) objectives of reducing pain and distress for laboratory animals because it will provide an alternative to surgical methods for assisted reproductive techniques.


application_id: 9560970
project_number: 3P30CA177558-05S5
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2017-09-19
opportunity_number: PAR-11-005
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S5
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2018-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The Markey Cancer Center (MCC) a dedicated matrix cancer center established as an integral part of the University of Kentucky (UK) and the UK Healthcare enterprise has undergone dramatic expansion in recent years under the leadership of MCC Director Dr. B. Mark Evers. At this point in the center's development the MCC seeks support through the National Cancer Institute (NCI) Cancer Center Support Grant to capitalize on this momentum and to drive a measurable reduction in cancer mortality in Kentucky particularly Appalachian Kentucky through a comprehensive program of cancer research prevention and patient care. The need for NCI Cancer Center designation is particularly acute in a state that leads the nation across numerous cancer indicators including the highest rate of cancer deaths in the nation. Situated on a campus with all six health professions colleges in proximity to each other the MCC offers a history of rich transdisciplinarycollaboration an outstanding program of cancer prevention and control that has produced seminal work in Appalachian Kentucky nationally acclaimed basic research programs in cancer biology and DNA repair and oxidative stress and a translational therapeutics program complemented by a top five College of Pharmacy.       These strengths have coalesced in MCC's four thematic research programs:  Cancer Cell Biology and Signaling; Cancer Prevention and Control; Drug Discovery Delivery and Translational Therapeutics; and Redox Injury and Repair. Currently the MCC's 108 Research and Associate Research members hold appointments in 24 departments in 7 colleges across the university (25 new faculty were recruited in the last 3 years). MCC members hold grants for 144 research projects funded in the annual composite (direct + indirect) amount of more than $30.5 million of which over $11.3 million (37%) comes from the NCI. Accrual to therapeutic clinical trials has increased over 130% in three years and MCC assignable space has increased 40% including a doubling of state-of-the-art research space. In addition six shared resources facilitate cutting-edge research by providing a robust infrastructure for specialized expertise and advanced methods. They include:  Biospecimen and Tissue Procurement; Biostatistics; Cancer Research Informatics; Clinical Research and Data Management; Flow Cytometry and Cell Sorting; and Free Radical Biology in Cancer. The MCC is currently well positioned to take on new challenges and to continue to evolve in key strategic directions that take maximum advantage of these strengths.

project_terms:
Acute;Appalachian Region;Appointment;Basic Science;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Death Rates;Cancer Research Project;Cell Separation;Cellular biology;Clinical Data;Clinical Research;Complement;DNA Repair;Development;Faculty;Flow Cytometry;Free Radicals;Funding;Grant;Health;Health Occupations;Healthcare;Incidence;Informatics;Kentucky;Leadership;Malignant Neoplasms;Measurable;Methods;National Cancer Institute;Outcome;Oxidation-Reduction;Oxidative Stress;Patient Care;Patients;Pharmacy facility;Positioning Attribute;Postdoctoral Fellow;Prevention;Recording of previous events;Recruitment Activity;Research;Research Infrastructure;Research Project Grants;Resource Sharing;Science;Seminal;Signal Transduction;Therapeutic;Therapeutic Clinical Trial;Tissue Procurements;United States;Universities;Work;anticancer research;bench to bedside;cancer prevention;cancer research center director;cancer site;college;data management;drug discovery;health disparity;injury and repair;interdisciplinary collaboration;member;mortality;programs

public_health_relevance:
RELEVANCE (See instructions): As a state with the second highest all-site cancer Incidence rate and the highest rate of cancer deaths in the United States Kentucky suffers from particularly intractable cancer health challenges. The Markey Cancer Center seeks support to further develop its capacities in cutting-edge science to accelerate "bench to bedside" translational outcomes which will reduce this serious health disparity and significantly impact our patients our state and the nation through cancer prevention patient care and research.


application_id: 9560007
project_number: 1R34DA045563-01A1
project_title: Social media HIV prevention intervention for rural women drug users
administering_ic: NIDA
award_notice_date: 2018-03-21
opportunity_number: PA-15-268
application_type: 1
activity_code: R34
ic: DA
serial_number: 045563
suffix: A1
program_official: JENKINS, RICHARD A
project_start_date: 2018-04-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1 AARR-G (02)]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTThe overall aim of this R34 application is to adapt and feasibility test an evidence-based intervention for HIVprevention for a high-risk group of rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase the reach and scope of prevention interventions using social media aswell as advance knowledge about the high-risk drug use behaviors of this underserved group. Considering theneed for prevention interventions among this high-risk group and the popularity of Facebook the purpose of thisR34 proposal is to adapt an evidence-based HIV prevention intervention for social media delivery and tofeasibility test through a randomized control trial with 60 high-risk rural women drug users. The following aimsguide the proposed study: (1) Adapt the NIDA Standard for HIV prevention for delivery via Facebook; and (2)Examine the feasibility of the adapted intervention with high-risk rural women through a randomized control pilot.The proposed use of Facebook in this study is promising because it is a stable widely used cost-efficientplatform that could be leveraged to increase access to critically needed HIV prevention education. This studypresents an exciting opportunity to examine the use of Facebook as a technique to expand the reach of evidence-based preventions interventions for high-risk drug users who are not likely to engage in formal treatment.Findings from this study will inform development of the larger R01 which would allow examination of theeffectiveness and sustainability of this HIV prevention intervention in understudied high risk populations.

project_terms:
AIDS prevention;Address;Affect;Alcohol or Other Drugs use;Appalachian Region;Area;Attention;Cessation of life;Communicable Diseases;Consent;Country;County;Coupled;Development;Disease Outbreaks;Documentation;Drug user;Education;Effectiveness;Effectiveness of Interventions;Epidemic;Evidence based intervention;Feedback;Focus Groups;Frequencies;Funding;HIV;Health;Hepatitis C;Human immunodeficiency virus test;Impairment;Imprisonment;Indiana;Infection;Injections;Intervention;Interview;Jail;Kentucky;Knowledge;Link;Media Intervention;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Needle Sharing;Participant;Pharmaceutical Preparations;Pilot Projects;Prevalence;Prevention;Prevention education;Preventive Intervention;Public Health;Publications;Quality of life;Randomized;Reporting;Research;Resources;Risk;Risk Behaviors;Rural;Rural Community;Science;Services;Techniques;Testing;Time;Underserved Population;United States National Institutes of Health;Virus Diseases;Vulnerable Populations;Woman;Work;behavioral health;community reentry;control trial;cost efficient;disability;disease transmission;drug use behavior;evidence base;health disparity;high risk;high risk behavior;high risk population;improved;injection drug use;innovation;men;opioid epidemic;pilot trial;prevention service;primary outcome;public health research;recruit;rural area;rural underserved;social media;testing services;transmission process;trend

public_health_relevance:
PROJECT NARRATIVEThe overall aim of this R34 application is to adapt and feasibility test an evidence-based HIV preventioneducation for high-risk underserved rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase access to prevention interventions using social media as well asadvance knowledge about the high-risk drug use behaviors among vulnerable populations.


application_id: 9558096
project_number: 1R41HL142489-01
project_title: Technology for Non-invasive High-throughput Breath Tracking in Rodents
administering_ic: NHLBI
award_notice_date: 2018-05-23
opportunity_number: PA-17-303
application_type: 1
activity_code: R41
ic: HL
serial_number: 142489
program_official: LAPOSKY, AARON D
project_start_date: 2018-06-01
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
contact_pi_person_id: 1883852
contact_pi: O'HARA, BRUCE FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT: Signal Solutions has developed a novel noninvasive and automated piezoelectric-based sleepdetection system for high-throughput studies of sleep in mice and has recently expanded to rat studies as well.The respiratory signal detected by the piezo sensor during sleep can be applied to investigate important healthconditions including respiratory depression due to disease or drug use and other sleep disordered breathingconditions such as Central Sleep Apnea (CSA) which contributes to approximately 20% of all sleep apnea inhumans. Rodent models are essential to better understand respiratory control of breathing and to investigaterespiratory abnormalities that present with disease. CSA is increasingly recognized as an importantcontributing factor to the morbidity and mortality in a number of cardiovascular diseases. Respiratorydepression can cause immediate death in diseases such as epilepsy and cases such as opiate overdose ormany other drugs. Preclinical studies of such drugs in rodents would be greatly improved if there was an easierway to monitor breathing.The current methods used to monitor breathing in rodents are laborious expensive and technicallychallenging. Plethysmography is used to study breathing in rodents and measures small breath volumes whilethe animal is confined to a small chamber This technology is expensive and stressful to the animal and canonly be used over short periods. Sleep disordered breathing is difficult to examine due to time required for theanimal to adapt to the chamber and the limited time for keeping the animal confined. Signal Solutions sleep system is ideally suited to improve methods for assessing a variety of breathingvariables. During sleep or quiet wake breathing is the primary movement and our technology thus providesaccurate respiratory traces. In addition to breath rates apneas are easily detected and should be amenableto automatic scoring. The advantages over current technology for detection of altered breathing includes cost-effective noninvasive stress-free continuous monitoring that is high-throughput and requires no surgery tomonitor sleep. Adapting our system for breathing applications will be made by meeting the followingobjectives: 1) Optimize compatibility of our piezo sensor system with standard plethysmography; 2) Collectsimultaneous piezo and plethysmography data in both rats and mice under multiple conditions. 3) Scoreassess and quantify signals from the piezo system vs. plethysmography for several respiratory variables. 4)Develop and optimize algorithms for automatic scoring and optimize performance. The outcome of this projectwill be to provide researchers with a simple to use cost effective technology for basic and pre-clinical studiesin rodents investigating respiratory depression sleep apnea and other disordered breathing during sleep thatcontribute to extensive morbidity and mortality in people.

project_terms:
Adoption;Adverse effects;Air Pressure;Algorithmic Analysis;Algorithms;Amplifiers;Animals;Apnea;Breath Tests;Breathing;Calibration;Cardiovascular Diseases;Cause of Death;Central Sleep Apnea;Cessation of life;Collection;Computer software;Conscious;Dangerousness;Data;Data Collection;Data Set;Detection;Development;Disease;Disease model;Drug usage;Environmental air flow;Epilepsy;Event;Exhalation;Frequencies;Goals;Gold;Health;Heart failure;Housing;Human;Inhalation;Knock-in;Knockout Mice;Location;Measures;Metabolism;Methods;Modeling;Monitor;Morbidity - disease rate;Mouse Strains;Movement;Mus;Neurodegenerative Disorders;Noise;Operative Surgical Procedures;Outcome;Output;Oxygen;Pattern;Performance;Pharmaceutical Preparations;Phase;Physiological;Plethysmography;Polysomnography;Predictive Value;Protocols documentation;Publishing;Rat Strains;Rattus;Recovery;Research Personnel;Respiration;Respiration Disorders;Rodent;Rodent Model;Safety;Signal Transduction;Sleep;Sleep Apnea Syndromes;Spinal cord injury;Stress;Stroke;System;Technology;Testing;Tidal Volume;Time;Ventilatory Depression;base;cost effective;drug efficacy;human disease;improved;knockout gene;meetings;mortality;neurotransmission;new technology;novel;opioid overdose;preclinical study;pressure;respiratory;sensor;sleep abnormalities;success;tool

public_health_relevance:
Project Narrative: Our goal is to develop simpler less expensive and less stressfulnoninvasive technology to monitor breathing parameters in rodents. This tool willprovide wider access to monitor respiratory output in rodents to study breathingdisorders associated with neurodegenerative diseases central sleep apnea heartfailure spinal cord injury and drugs with dangerous respiratory related side effects.


application_id: 9557948
project_number: 1R41NS107148-01
project_title: Noninvasive Seizure Screening in Preclinical Models of Epilepsy
administering_ic: NINDS
award_notice_date: 2018-04-03
opportunity_number: PA-17-303
application_type: 1
activity_code: R41
ic: NS
serial_number: 107148
program_official: CAPORELLO, EMILY LAURA
project_start_date: 2018-04-15
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Noninvasive Seizure Screening in Preclinical Models of EpilepsyThere is an urgent need for research into treatment options for epilepsy and other seizure disorders. Animalmodels are increasingly used to understand disease mechanisms and to screen promising therapeuticapproaches. Animal epilepsy model use typically requires expensive and labor-intensive experimentation withinvasive EEG measurements being the preferred method of validation. This severely limits the pace and scale ofinvestigation. In models of acquired epilepsy animals usually undergo treatment to induce status epilepticusa period of unremitting seizurefollowed by a latent period during which the brain rewires itself to generatespontaneously recurring seizures evidence of chronic epilepsy. The duration of the latent period and thelikelihood that an animal will develop epilepsy are both uncertain. Animals must be observed for weeks toconfirm epilepsy before they are ready for experimentation. During this latent period seizures are commonlydocumented by visual observation or video review which are tedious and prone to error. A commercial systemfor automated noninvasive seizure detection would therefore be attractive to epilepsy researchers.Signal Solutions LLC has developed technology based on piezoelectric sensors for noninvasive high-throughput behavioral monitoring of rodents that is currently used by research groups around the world toidentify genes related to sleep and circadian rhythms. The system discriminates sleep from wakefulness withover 90% accuracy. The Sunderam Lab at the University of Kentucky has further demonstrated using EEGanalysis that these piezo sensors can be used to label REM and NREM stages of sleep in mice.In this STTR proposal PI Sunderam and co-investigator Bauer will work with Signal Solutions to developmethods based on the piezo technology for accurate noninvasive seizure screening in rodent models ofepilepsy. The result will be a validated system that minimizes the need for invasive and resource-intensive EEGanalysis or tedious video monitoring. The objectives of the project are the following: 1. Test the feasibility ofcoarse detection of epilepsy onset in rodents using a noninvasive piezo sensor; 2. Train a piezo classifier toaccurately detect and quantify seizures in rodents with confirmed epilepsy; and 3. Test the utility of a miniaturepiezo sensor for seizure screening and an infrared imager for seizure verification and severity assessment.The envisioned product is a turnkey system for convenient and noninvasive seizure screening in small animalmodels of epilepsy in custom or commercial cages. Potential customers include academic research labs as wellas labs in the pharmaceutical sector engaged in high-volume screening of antiepileptic drugs.

project_terms:
Aftercare;Algorithms;Alzheimer's Disease;Animal Experimentation;Animal Model;Animals;Antiepileptic Agents;Behavior;Behavior monitoring;Behavioral;Brain;Cataplexy;Chronic;Circadian Rhythms;Communities;Computer software;Convulsants;Custom;Detection;Development;Devices;Disease;Drug Screening;Electroencephalography;Environment;Epilepsy;Epileptogenesis;Evaluation;Floor;Frontal Lobe Epilepsy;Funding;Genes;Genetic Models;Government;Image;Implanted Electrodes;Industrialization;Investigation;Kentucky;Knock-out;Label;Laboratory Animals;Lafora Disease;Measurement;Measures;Methods;Modeling;Monitor;Mus;Narcolepsy;Operative Surgical Procedures;Outcome;Persons;Pharmacologic Substance;Phase;Post-Traumatic Epilepsy;Pre-Clinical Model;Research;Research Personnel;Resources;Rodent;Rodent Model;Seizures;Severities;Signal Transduction;Sleep;Sleep Stages;Small Business Technology Transfer Research;Status Epilepticus;System;Technology;Temporal Lobe Epilepsy;Testing;Therapeutic;Time;Training;United States National Institutes of Health;Universities;Validation;Video Recording;Visual;Wakefulness;Work;base;commercialization;dravet syndrome;imager;implantation;interest;natural hypothermia;neonatal stroke;new technology;perinatal stroke;pressure;respiratory;screening;sensor;therapy development;trait;treatment effect;voltage

public_health_relevance:
The development of treatments for epilepsy depends heavily on laboratory animal studies in which the effect oftreatment on seizures is measured. Seizures are rare and unpredictable and monitoring animals for seizuresrequires tedious observation or review of video recordings; the alternative is to record brain signals whichrequires invasive surgery to implant electrodes. A new technology is proposed here that would enablecompletely noninvasive detection of seizures in animals. The accuracy of this method will be compared withEEG analysis in an animal model of epilepsy.


application_id: 9557470
project_number: 5R01AG056998-02
project_title: Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease
administering_ic: NIA
award_notice_date: 2018-07-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 056998
program_official: REFOLO, LORENZO
project_start_date: 2017-09-15
project_end_date: 2019-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: NORRIS, CHRISTOPHER MARK
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:
7. Project Summary/AbstractThis project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN)inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneouslydevelop amyloid- (A) deposition with advanced age. Consequently the aging beagle model has shownexceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of ourtreatment strategy CN has recently emerged as a key mechanism for AD pathophysiology. Signs of CNhyperactivity are found during early stages of cognitive decline in humans and in mouse models of AD. Studiesacross numerous laboratories using a variety of experimental models suggest that CN activity is bothnecessary and sufficient for the progression of key AD biobehavioral markers including A depositionneurodegeneration neuroinflammation/glial activation synapse dysfunction and cognitive loss. To inhibit CNwe will use tacrolimus an FDA-approved drug for the prophylaxis of allograft rejection and a second linetreatment for numerous immune/inflammatory disorders. In animal models tacrolimus exhibits potent anti-inflammatory neuroprotective and perhaps lifespan extending properties. Moreover a recent epidemiologicalstudy found that the incidence of dementia was strikingly reduced in human kidney transplant patients takingtacrolimus relative to age-matched subjects in the general population. In this project 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7months-of age (prior to the development of significant amyloid pathology) dogs will be sorted into two groupsmatched for cognitive status. One group will received tacrolimus (.075mg/kg/day orally) continuously for thenext two years while the other group will receive placebo. Aim 1 will assess multidomain cognition andmeasure blood and CSF biomarkers (e.g. A and cytokines) at multiple time points across the tacrolimustreatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion brainmetabolism and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assaysto assess AD biomarkers (e.g. A deposition glial activation synapse loss and neurodegeneration) and CN-related signaling parameters (e.g. cell-type specific expression CN proteolysis and NFAT activation) inpostmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possiblypave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human ADclinical trials.

project_terms:
7 year old;9 year old;Adverse effects;Age;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animal Model;Animals;Anti-inflammatory;Atrophic;Attenuated;Autopsy;Behavioral;Biochemical;Biological Assay;Biological Markers;Blood;Brain;Calcineurin;Calcineurin inhibitor;Canis familiaris;Cerebrospinal Fluid;Cerebrovascular Disorders;Cerebrum;Clinical Trials;Cognition;Cognitive;Dementia;Development;Diffusion Magnetic Resonance Imaging;Disease;Dose;Elderly;Exhibits;Experimental Models;FDA approved;FK506;Freezing;Functional disorder;General Population;Genes;Genetic;Gold;Human;Hyperactive behavior;Image;Immune;Immunohistochemistry;Impaired cognition;Incidence;Individual;Inflammatory;Investigation;Kidney Transplantation;Label;Laboratories;Liquid substance;Literature;Longevity;Longitudinal Studies;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Maintenance;Matched Group;Measures;Metabolic;Metabolic dysfunction;Metabolism;Modeling;Molecular;Molecular Target;Mus;Nerve Degeneration;Neurons;Oral;Oral Administration;Organ Transplantation;PPP3CA gene;Pathologic;Pathology;Pathway interactions;Perfusion;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Placebos;Plant Roots;Pre-Clinical Model;Preclinical Testing;Predisposition;Property;Prophylactic treatment;Protein phosphatase;Proteolysis;Recovery;Rodent;Role;Safety;Sampling;Signal Transduction;Solid;Spin Labels;Synapses;Tacrolimus;Testing;Therapeutic;Time;Transgenic Mice;Transgenic Organisms;Translations;Transplant Recipients;Work;abeta deposition;allograft rejection;amyloid pathology;biobehavior;brain metabolism;brain tissue;calcineurin phosphatase;cell type;cerebrovascular;cerebrovascular imaging;cerebrovascular pathology;cognitive function;cytokine;druggable target;epidemiology study;familial Alzheimer disease;glial activation;improved;middle age;mouse model;mutant;neurogenesis;neuroimaging;neuroinflammation;neuron loss;neuropathology;neurotoxicity;overexpression;preclinical evaluation;prevent;relating to nervous system;screening;synaptic function;therapy design;treatment duration;treatment strategy;white matter

public_health_relevance:
8. Project NarrativeThis study will use an FDA approved drug (tacrolimus) to inhibit the protein phosphatase calcineurin in a highermammalian model of Alzheimer's disease (i.e. aging beagles). Studies will determine the mechanistic role ofcalcineurin in AD and lay the groundwork for the use of calcineurin inhibitors in anti-AD drug trials.


application_id: 9557081
project_number: 1R43CA228656-01
project_title: Clinical Validation of the Multiple Biopsy Device a Novel Endoscopic Biopsy Technology
administering_ic: NCI
award_notice_date: 2018-06-07
opportunity_number: PA-17-302
application_type: 1
activity_code: R43
ic: CA
serial_number: 228656
program_official: EVANS, GREGORY
project_start_date: 2018-06-07
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 DKUS-N (10)]
contact_pi_person_id: 11871743
contact_pi: APPLING, ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 832287838
primary_uei: QLTCVSA4S5E1
duns_number: 832287838
uei: QLTCVSA4S5E1
fips: US
organization_id: 10024846
organization_name: ENDOSCOPIC ASSIST DEVICES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402232171
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project AbstractThe objective of this proposal is to complete clinical validation of the Multiple Biopsy Device (MBD) anendoscopic device that will revolutionize endoscopic practice by improving the efficiency of endoscopic biopsyeliminating the loss of critical specimens and improving the safety of endoscopic biopsy for both practitionersand patients. Over 16 million endoscopic procedures will require endoscopic biopsy in the year 2017 and thenumber of diagnostic endoscopic procedures is expected to grow by 6-8% per year over the next decade.Currently marketed biopsy devices require a separate pass of the device every 1-2 bites. Clinical protocols forendoscopic biopsy require multiple passes to satisfy the total number of specimens needed to achieve diagnosticcertainty adding significant time pressures to already overburdened endoscopists. We have developed a devicethat will allow the acquisition of an unlimited number of biopsies from one pass of the biopsy device. The MBDoperates by mechanically harvesting a mucosal specimen taken for histologic analysis then transporting thespecimen to a collection device located outside of the endoscope. Biopsies from different lesions or locationscan be segregated in separate sample cups to avoid confusion about their site of origination. Furthermore theMBD collection container will greatly speed up transfer of specimens from the collection device to formalin cupswhile eliminating the risk of impalement by the central spike during the retrieval of samples from the cups of thebiopsy forceps. The following specific aims will complete MBD validation in preparation for regulatory submission.SA1. Specific Aim 1: (i) Design and implement a Design Trace Matrix (DTM) Risk Management Plan andassociated protocols for manufacturing and testing clinical-grade MBDs. (ii) Construct an adequate number ofmedical devices using contract manufacturers for supplying components for final assembly and packaging byEAD including a sterilization safety studySA 2: Conduct a phase I Feasibility Study to support a future pivotal trial. This will consist of a RBDPB cross-over trial as detailed in the Research Strategy section (n = 150).Successful completion of this SBIR funded development program will support the commercialization of aparadigm-shifting diagnostic device that will dramatically improve the process of endoscopic biopsy whilemaximizing patient and ancillary staff safety.

project_terms:
Address;Age;Anatomy;Animal Testing;Biopsy;Biopsy Specimen;Bite;Caliber;Clinical;Clinical Protocols;Clinical Trials;Collection;Confusion;Contracts;Coupled;Cross-Over Trials;Crowding;Device or Instrument Development;Devices;Diagnosis;Diagnostic;Endoscopes;Endoscopic Biopsy;Endoscopy;Equipment;Evolution;Feasibility Studies;Forcep;Formalin;Foundations;Funding;Future;Grant;Guidelines;Harvest;Histologic;Institution;Institutional Review Boards;Intellectual Property;Laceration;Lesion;Letters;Licensing;Location;Manufacturer Name;Mechanics;Medical Device;Modification;Mucous Membrane;Patients;Phase;Positioning Attribute;Preparation;Procedures;Process;Program Development;Property;Protocols documentation;Research;Research Personnel;Retrieval;Risk;Risk Management;Safety;Sample Size;Sampling;Secure;Site;Small Business Innovation Research Grant;Specimen;Speed;Sterilization;System;Techniques;Technology;Testing;Time;Tissues;Universities;Validation;Work;Workload;commercialization;design;experience;falls;first-in-human;improved;innovation;instrument;interest;new technology;novel;phase 1 study;pressure;prospective;research clinical testing;safety study;safety testing;sample collection

public_health_relevance:
Project NarrativeEndoscopy Assist Devices LLC will clinically validate the Multiple Biopsy Device (MBD) a noveltechnology that will enable endoscopists to take and retrieve an unlimited quantity of biopsy specimenswith one pass of the biopsy device. This feature will greatly expedite acquisition times when multiplesamples are required for diagnosis while eliminating lost specimens and the risk of lacerations fromthe spike found on current biopsy devices. In the present application we propose to clinically validatethe MBD in a first-in-human clinical trial. The work completed during the period of this grant will positionthe MBD for subsequent commercialization efforts and licensing opportunities.


application_id: 9556975
project_number: 5R21AA026129-02
project_title: A Human Laboratory Study of n-Acetylcysteine for Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2018-08-10
opportunity_number: PA-15-254
application_type: 5
activity_code: R21
ic: AA
serial_number: 026129
program_official: FALK, DANIEL EVAN
project_start_date: 2017-09-05
project_end_date: 2020-08-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
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_abstract:
ABSTRACTAlcohol (ALC) use disorder (AUD) is an unrelenting public health concern. Several medications have beenapproved for treating AUD but these pharmacotherapies are not widely used nor are they universally effectiveor appropriate to use in all AUD patients due to contraindications. To address the continued need to improveAUD treatment identifying novel AUD pharmacotherapies is a high NIAAA priority. Preclinical studies showthat chronic or binge-like ALC administration decreases extracellular glutamate levels which are thenincreased during ALC withdrawal. These elevated glutamate levels observed during ALC withdrawal can bereduced with further ALC administration driving a cycle of heavy ALC use and withdrawal periods thatcharacterize AUD. The changes in glutamate homeostasis that occur during the cycle of chronic ALCintoxication and withdrawal have been attributed to altered glutamate transport (e.g. changes in cystine-glutamate exchanger [xCT] and glial glutamate transporter [GLT-1] expression and function). Normalization ofextracellular glutamate levels (i.e. restoration of glutamate homeostasis) through administration of compoundslike n-acetylcysteine (NAC) which increase expression of the xCT and GLT-1 following drug exposureattenuates maladaptive brain changes produced by ALC as well as ALC self-administration and behavioralsensitization in preclinical models. Preclinical data provide a strong scientific premise for the hypothesis thatrestoration of glutamate homeostasis is a promising pharmacotherapeutic approach for AUD yet this researcharea remains unexamined in prospective clinical studies. The overarching goal of this application is todemonstrate that restoration of glutamate homeostasis with NAC is a viable strategy for treating AUD. Thisgoal will be achieved through the conduct of a rigorous within-subject placebo-controlled study that has beenmodeled from previous successfully reverse-engineered human laboratory approaches. This research willdemonstrate the initial efficacy safety and tolerability of NAC for treating AUD. This work will directly translatefindings from preclinical research and provide basic science information about the glutamatergic mechanismsunderlying the pharmacodynamic effects of ALC in humans. The proposed research will also expand the scopeof current AUD treatment research by focusing on glutamate homeostasis which has strong preclinicalevidence supporting its critical role in AUD but remains unstudied in clinical research.

project_terms:
Acetylcysteine;Address;Adverse effects;Adverse event;Alcohol consumption;Alcohol withdrawal syndrome;Alcoholic Intoxication;Alcohols;American;Antibiotic Resistance;Area;Attenuated;Automobile Driving;Basic Science;Behavioral;Brain;Ceftriaxone;Cessation of life;Chronic;Clinical;Clinical Research;Clinical Trials;Clostridium difficile;Cognitive;Cystine;Data;Development;Disease;Disulfiram;Dose;Drug Exposure;Economic Burden;Environment;Glutamate Transporter;Glutamates;Goals;Heart Rate;Heavy Drinking;Homeostasis;Human;Human Engineering;Impulsivity;Incidence;Infection;Information Sciences;Intravenous;Laboratories;Laboratory Study;Lead;Link;Maintenance;Measures;Modeling;Naltrexone;National Institute on Alcohol Abuse and Alcoholism;Oral;Outcome;Outcome Measure;Patient Self-Report;Patients;Personality;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Physiological;Placebos;Pre-Clinical Model;Public Health;Questionnaires;Research;Research Design;Role;Safety;Self Administration;Study Subject;Substance Use Disorder;System;Testing;Translating;Work;acamprosate;alcohol craving;alcohol effect;alcohol measurement;alcohol use disorder;behavioral sensitization;chronic alcohol ingestion;discount;discounting;extracellular;improved;novel;placebo controlled study;pre-clinical;pre-clinical research;preclinical study;prospective;prospective test;reduced alcohol use;response;restoration;trait

public_health_relevance:
PROJECT NARRATIVEChronic alcohol use disrupts glutamate function. The goal of this project is to demonstrate that maintenance ona drug that ameliorates disrupted glutamate function n-acetylcysteine reduces alcohol use and craving in asophisticated human laboratory model. This research will advance n-acetylcysteine along the alcohol usedisorder medications development continuum from current preclinical studies into clinical laboratory studiesand eventually clinical trials.


application_id: 9555799
project_number: 5R01CA194409-05
project_title: sEcad as a novel target and therapy for IGF-1R expressing tumors
administering_ic: NCI
award_notice_date: 2018-08-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 194409
program_official: SALOMON, RACHELLE
project_start_date: 2015-09-01
project_end_date: 2021-08-31
study_section: Cancer Immunopathology and Immunotherapy Study Section[CII]
contact_pi_person_id: 7799129
contact_pi: BROUXHON, SABINE M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Over the last decade the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy drugs such as trastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses and increased disease-free survival in patients with metastatic disease. However despite an initial positive response the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) and its associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in this de novo and acquired resistance. Therefore identification of novel targets and antineoplastic agents that modulate IGF-1R signaling is paramount.  We have recently identified soluble E-cadherin termed sEcad as a novel oncogenic target that is selectively increased in human breast cancers. Additionally we have discovered that sEcad imparts its tumorigenic effects (enhances proliferation migration and invasion) by activating many of these resistance pathways including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly using a purified IGF-1R holoreceptor we are the first to discover that sEcad acts as a true ligand for IGF-1R and in the presence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore we have evidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands IGF1 and EGF to promote cancer cell proliferation migration and invasion in vitro and act as an oncogenic driver in xenograft tumors in vivo. Therefore we propose that sEcad is a valid and innovative therapeutic target for breast cancer.  Additionally we have recently tested region-specific antibodies against sEcad that successfully suppressed HER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis and necrosis) via down-regulating the IGF-1R HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumab-resistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice our studies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibiting proliferation and inducing cell death. Consistent with the in vivo findings this targeted therapy inhibited proliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumab-resistant breast cancer cells without showing any off-target cytotoxic effects in normal cells.  In this translational study we have assembled an outstanding research team to: 1) biochemically and biophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcad suppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how the antibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy PK/PD studies and evaluation of off-target effects.  Of note although monoclonal antibodies against IGF-1R have given mixed results in clinical trials these anti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors with a very unique and innovative targeting mechanism.

project_terms:
Address;Adjuvant Chemotherapy;Affinity;Antibodies;Antigens;Antineoplastic Agents;Apoptosis;Binding;Biochemical;Biophysics;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Carcinogenesis;Breast Oncology;Breast cancer metastasis;Cell Death;Cell Proliferation;Cell model;Cells;Cetuximab;Clinical Trials;Development;Disease;Disease-Free Survival;Drug Kinetics;E-Cadherin;EGF gene;ERBB2 gene;Effectiveness;Endocytosis;Epidermal Growth Factor Receptor;Evaluation;Exhibits;FRAP1 gene;Grant;Growth;Growth Factor;Human;IGF1 gene;IGF1R gene;In Vitro;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Ligands;MAP Kinase Gene;Malignant Neoplasms;Mediating;Modeling;Monoclonal Antibodies;Mouse Mammary Tumor Virus;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Oncogenic;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phosphorylation;Proteins;Receptor Inhibition;Receptor Signaling;Relapse;Research;Resistance;Rodent;Signal Transduction;Tamoxifen;Testing;Trastuzumab;Tumor Burden;Woman;Xenograft procedure;biophysical properties;cancer cell;crosslink;cytotoxic;hormone receptor-positive;hormone therapy;in vivo;ineffective therapies;inhibitor/antagonist;innovation;insight;malignant breast neoplasm;migration;mouse model;neoplastic cell;novel;novel anticancer drug;novel therapeutics;overexpression;public health relevance;response;safety testing;targeted agent;targeted treatment;therapeutic target;therapy development;translational study;tumor;tumor growth;tumor xenograft;tumorigenic

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Breast cancer is the most common cancer in women with 1.7 million new cases in 2012 worldwide. Soluble E-cadherin a small protein produced by cancer cells in large quantities appears to enhance cancer growth and expansion. In this R01 grant we will study the function of soluble E-cadherin in breast cancer development and how it binds to a cancer growth promoting receptor IGF-1R. Additionally we will test the effectiveness of a new therapy we developed against this soluble fragment in human cells and mouse models of breast cancer so as to understand whether IGF-1R is involved. We believe that our discovery will lead to a new therapy for human breast cancer.


application_id: 9555400
project_number: 7K01TW010271-02
project_title: Metabolic Syndrome and Epigenetic Markers of Breast Cancer in Nigerian Women
administering_ic: FIC
award_notice_date: 2017-09-15
opportunity_number: PA-16-285
application_type: 7
activity_code: K01
ic: TW
serial_number: 010271
program_official: MICHELS, KATHLEEN M
project_start_date: 2016-09-28
project_end_date: 2021-08-31
study_section: International and Cooperative Projects - 1 Study Section[ICP1]
contact_pi_person_id: 9235849
contact_pi: AKINYEMIJU, TOMI F
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTDeveloping countries accounted for 45% of new breast cancer cases globally in 2009 and 57% in 2012 withthese proportions projected to increase to 70% by 2030. Nigeria has experienced a three-fold increase inbreast cancer incidence between 1973 and 2012 coinciding with an increase in the prevalence of so-called`diseases of affluence' including obesity hypertension and diabetes a cluster of biochemical abnormalitiesthat constitute Metabolic Syndrome (MetS). Recent studies in the US and Europe have shown a consistentpositive association between MetS and breast cancer risk suggesting that rising breast cancer rates in Nigeriamay be a biological consequence of increasing rates of MetS. Once diagnosed with breast cancer Nigerianwomen similar to other women of African descent are also more likely to present at younger ages with highlyaggressive hormone-receptor negative tumors associated with higher mortality. The reason for a higherprevalence of these tumor types in women of African descent is unclear. Epigenetic changes through DNAmethylation histone modification and micro RNA changes are critical aspects of breast cancer tumorigenesisand are influenced by both genetic background and environmental exposures. Multiple US studies haveobserved significant differences in DNA methylation levels of critical breast cancer genes between African-Americans and whites including BRCA1 and BRCA2 CYP1A1 H-ras-1 and Cyclin D1. DNA methylationlevels in critical breast cancer genes among Nigerian women have never been examined and this may be thekey to understanding racial differences in breast cancer phenotypes. Identification of race-specific epigeneticpatterns could potentially be used as an intermediary marker of the association between exposures such asMetS and breast cancer incidence or as prognostic markers for clinical management and therapeuticinterventions. Using a sample of newly diagnosed breast cancer cases and age-matched healthy controls thisstudy aims to examine the association between MetS and breast cancer overall and by sub-type in Nigeria. Inaddition we plan to identify genome-wide DNA methylation differences between breast cancer tumor andadjacent normal tissue among women with and without MetS. These findings will provide critical information onthe influence of MetS on breast cancer in Nigeria and improve our understanding of the specific epigeneticchanges that occur with breast cancer in Nigerian women; this is likely to be different from epigenetic changesobserved among African American women with significantly different environmental exposures.

project_terms:
Address;Africa;African;African American;Age;Alcohol consumption;Applications Grants;BRCA1 gene;BRCA2 gene;Biochemical;Biological;Blood;Blood Glucose;Blood specimen;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer gene;CYP1A1 gene;Cancer Prognosis;Case-Control Studies;Cause of Death;Clinical Management;Communicable Diseases;Controlled Study;Country;Cyclin D1;DNA;DNA Methylation;Data;Developing Countries;Diabetes Mellitus;Diagnosis;Disease;Economic Development;Employee Strikes;Environmental Exposure;Epidemic;Epidemiology;Epigenetic Process;Europe;Foundations;Freezing;Genes;Genetic;Goals;HRAS gene;Health Planning;High Density Lipoproteins;High Prevalence;Hormone Receptor;Hospitals;Hypertension;Incidence;International;Kidney Diseases;Laboratories;Lasers;Life Style;Link;Mammary Gland Parenchyma;Mentors;Metabolic syndrome;MicroRNAs;Molecular;Molecular Epidemiology;Newly Diagnosed;Nigeria;Nigerian;Normal tissue morphology;Obesity;Pathway interactions;Pattern;Phenotype;Population;Positioning Attribute;Prevalence;Prognostic Marker;Questionnaires;Race;Recruitment Activity;Research;Residual state;Risk Factors;Role;Sampling;Sampling Studies;Ships;Smoking;Therapeutic Intervention;Tissue Sample;Tissues;Training;Triglycerides;Tumor Suppression;Waist-Hip Ratio;Woman;Women's Group;World Bank;breast cancer diagnosis;cancer risk;cancer subtypes;early onset;epigenetic marker;experience;genome-wide;global health;histone modification;improved;low and middle-income countries;malignant breast neoplasm;metabolic rate;methylation pattern;mortality;outcome forecast;racial difference;triple-negative invasive breast carcinoma;tumor;tumor DNA;tumorigenesis;urban area

public_health_relevance:
NARRATIVEBreast cancer rates in Nigeria are increasing very rapidly and are predominantly of aggressive sub-types withpoor prognosis. However few studies have determined the factors associated with the increasing rates. Thisstudy provides critical information on the influence of metabolic syndrome as a risk factor for breast cancer inthis population and examines potential biological mechanisms through which it influences breast cancer.


application_id: 9555108
project_number: 1R43HL142337-01
administering_ic: NHLBI
award_notice_date: 2018-09-21
opportunity_number: PA-17-302
application_type: 1
activity_code: R43
ic: HL
serial_number: 142337
program_official: LEE, ALBERT
project_start_date: 2018-09-24
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1 CVRS-A (12)]
contact_pi_person_id: 10540197
contact_pi: JIMENEZ, JORGE HERNAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 079588486
primary_uei: JXNDFBMEL195
duns_number: 079588486
uei: JXNDFBMEL195
fips: US
organization_id: 10037752
organization_name: COR HABERE CORPORATION
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021208
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-24
project_title:
Left atrial appendage closure device with catheter-based delivery for patients with non-valvular atrial fibrillation

project_abstract:
In the US there are 2.3 million patients with nonvalvular atrial fibrillation (NVAF) which is expected to increaseto 12 million by 2050. The treatment of NVAF is estimated to cost $6.65 billion including $2.93 billion (44%) forhospitalizations alone. The most significant morbidity and mortality associated with NVAF is embolic strokewith 90% of thrombus originating from the left atrial appendage (LAA). Anticoagulation is the preferredtreatment for NVAF patients but clinical studies have demonstrated high levels of non-compliance andincreased risk of bleeding or ineligibility for anticoagulation therapy especially in the elderly population wherethe incidence of NVAF is highest. Currently there are multiple clinically approved surgical and catheter-basedLAA devices but they continue to be plagued by peri-device leaks and thrombus formation because of residualvolume subsequently they have failed to eliminate the risk of stroke. To overcome these limitations CorHabere (Louisville KY) and the University of Louisville are developing a LAA closure device with catheter-based delivery (StrokeShield system) that completely occludes and collapses the LAA to minimize the risk ofstroke. The StrokeShield device is a collapsible occluder (nitinol reinforced membrane) that completely coversthe LAA orifice with an expandable conical coil anchor that attaches to the outer wall of the LAA. The device isdelivered using a catheter-based approach and expands to completely occlude the LAA orifice and collapsethe LAA. The primary advantages of the StrokeShield system are a completely sealed LAA (no peri-device flowor residual space) and smooth endothelialized connection to the left atrial wall with minimal risk of cardiacbleeding and tamponade. In this SBIR phase I proposal we will complete testing of the StrokeShield systemto achieve required sample size to demonstrate feasibility. Upon successful demonstration of feasibility weplan to submit a phase II proposal to complete engineering development and achieve a design freeze of theStrokeShield system by testing in human and canine models to demonstrate functional performance; reliabilityand hemocompatibility by completing Verification and Validation (V&V) testing in compliance with GoodManufacturing Practices (GMP); and safety and biocompatibility by completing a 60-day chronic study in acanine model in compliance with Good Laboratory Practices (GLP). The phase II experimental data will beused to support an Investigational Device Exemption (IDE) application to the Food and Drug Administration(FDA) for clinical trials in NVAF patients at risk for stroke.

project_terms:
Acute;Anatomy;Animal Model;Anticoagulation;Area;Atrial Fibrillation;Biomedical Engineering;Cadaver;Canis familiaris;Cardiac;Cardiac Tamponade;Cardiovascular system;Catheters;Chronic;Clinical;Clinical Engineering;Clinical Research;Clinical Trials;Data;Development;Devices;Elderly;Engineering;Foundations;Freezing;Funding;Geometry;Goals;Heart Atrium;Hemorrhage;Hospitalization;Human;Incidence;Institutes;International;Investigation;Left;Legal patent;Length;Membrane;Mitral Valve;Modeling;Morbidity - disease rate;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Performance;Pharmacology;Phase;Population;Pulmonary veins;Quality of life;Research Personnel;Residual state;Residual volume;Risk;Safety;Sample Size;Small Business Innovation Research Grant;Stretching;Stroke;Stroke prevention;Surface;Surgical sutures;System;Testing;Thick;Thrombus;Translating;United States Food and Drug Administration;Universities;auricular appendage;base;biomaterial compatibility;clinical practice;cost;design;embolic stroke;experimental study;good laboratory practice;implantable device;implantation;improved;innovation;minimal risk;mortality;nitinol;non-compliance;novel;prevent;product development;risk minimization;seal;stroke risk;tool;verification and validation

public_health_relevance:
Cor Habere (Louisville KY) and the University of Louisville are developing a left atrial appendage (LAA) deviceand catheter-based delivery system designed to completely occlude the LAA orifice and collapse the LAA toprevent stroke in patients with nonvalvular atrial fibrillation (NVAF). The StrokeShield system is designed toovercome many of the limitations associated with current pharmacological (non-compliance bleeding) andimplanted devices (thrombus) to improve patient outcomes and restore quality of life.


application_id: 9555104
project_number: 1R43HL142385-01
project_title: Development of a sutureless LVAD outflow graft anastomotic quick-connect system
administering_ic: NHLBI
award_notice_date: 2018-09-21
opportunity_number: PA-17-302
application_type: 1
activity_code: R43
ic: HL
serial_number: 142385
program_official: LEE, ALBERT
project_start_date: 2018-09-25
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1 SBIB-Y (12)]
contact_pi_person_id: 11183980
contact_pi: TOMPKINS, LANDON HEATH
other_pis: DASSE, KURT A
congressional_district: 03
department: Unavailable
primary_duns: 838779366
primary_uei: FM8XH18NYPC7
duns_number: 838779366
uei: FM8XH18NYPC7
fips: US
organization_id: 10038616
organization_name: MYOCARDIAL ASSIST SYSTEMS AND TECHNOLOGY
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021208
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Heart failure (HF) is the leading cause of death in the United States affecting nearly six million people at a costover $31 billion. Clinically-approved mechanical circulatory support (MCS) therapy such as left ventricularassist devices (LVADs) continue to improve as a viable treatment option for patients with advanced heartfailure as evidenced by over 13000 implants over the past five years. However MCS device therapy can besurgically invasive time consuming prone to adverse events and often requires a median sternotomycardiopulmonary bypass (CPB) and partial clamping (cross-clamping) of the aorta to facilitate anastomosis ofthe outflow graft. These procedures are associated with adverse events including risk of post-operativeinfection bleeding pulmonary complications post-operative neurological complications and potential aorticdissection. Conventional manual suturing techniques are currently used to attach a MCS device outflow graft tothe ascending aorta and for which CPB support and aortic clamping time may increase risk of post-operativeadverse events. To improve clinical outcomes MAST (Louisville KY) is developing a sutureless anastomoticgraft connection device (sG2A) to eliminate the need for manual suturing and CPB during MCS device surgery.Several sutureless vascular connection devices have been proposed and/or developed; however most ofthese devices were designed for smaller graft and vessel sizes (< 5mm diameter) that are primarily used forcoronary artery bypass graft (CABG) procedures. Many surgical adhesives have also been proposed and/ordeveloped as an alternative to suturing techniques for achieving vascular connection and hemostatic sealingbut have not achieved clinical acceptance due to poor strength and toxicity concerns. The MAST sG2A systemis unique in that it is designed to attach large diameter grafts (10-15mm diameter) to large vessels (18-28 mmdiameter) using a hybrid polymer-mechanical seal to achieve hemostasis. The sG2A device is a nitinol wingedconnector attached to the distal end of an outflow graft and an external polymer-flanged cuff that covers theend-to-side intersection of the aortotomy and outflow graft. The super-elastic properties of annealed nitinolallow for the winged connector to be deformed and compressed for loading into the delivery-aortotomy tooland restored to its functional shape when deployed potentially enabling distal graft anastomosis via a less-invasive surgical approach. In this SBIR phase I proposal we will demonstrate feasibility of the sG2A systemand then plan to submit a phase II proposal to complete engineering development to achieve a design freezeof the sG2A system and complete pre-clinical testing to demonstrate efficacy safety and reliability. The phaseII experimental data will be used to support an Investigational Device Exemption (IDE) application to the Foodand Drug Administration (FDA) for clinical trials.

project_terms:
Achievement;Acute;Adhesives;Adverse event;Affect;Anastomosis - action;Aorta;Apical;Blood Vessels;Cadaver;Caliber;Cannulas;Cardiopulmonary Bypass;Cardiovascular system;Cattle;Cause of Death;Chronic;Clinical;Clinical Trials;Closure by clamp;Coronary Artery Bypass;Data;Development;Device or Instrument Development;Devices;Disclosure;Dissection;Distal;Drosophila chb protein;Embolism;Engineering;Freezing;Goals;Greater curvature of stomach;Heart failure;Hemorrhage;Hemostatic Agents;Hemostatic function;Human;Hybrids;Hypotension;Hypovolemia;Imagery;Implant;Implantation procedure;Incidence;Infection;Institutes;Investigation;Length of Stay;Lung;Manuals;Mechanics;Medical;Medical Device;Modeling;Neurologic;Operative Surgical Procedures;Organ Transplantation;Outcome;Pain;Partner in relationship;Patient-Focused Outcomes;Patients;Phase;Physiological;Polymers;Positioning Attribute;Postoperative Period;Preclinical Testing;Procedures;Property;Pump;Quality of life;Recovery;Research Personnel;Risk;Safety;Saint Jude Children's Research Hospital;Scientist;Secure;Shapes;Side;Small Business Innovation Research Grant;Sternotomy;Stroke;Surface;Surgeon;Surgical incisions;Surgical sutures;Surveys;Suture Techniques;System;Techniques;Testing;Time;Toxic effect;Translating;United States;United States Food and Drug Administration;United States National Institutes of Health;Universities;Vision;Wing;Work;ascending aorta;axillary artery;base;calcification;clinical practice;clinical risk;cost;dacron;design;dexterity;early experience;experience;experimental study;good laboratory practice;implantation;improved;innovation;invention;left ventricular assist device;minimally invasive;nitinol;pressure;prototype;seal;tool;verification and validation;wound

public_health_relevance:
Investigators at MAST (Louisville KY) and the University of Louisville (UofL) are developing a sutureless graftto aorta (sG2A) anastomotic device to facilitate minimally-invasive surgery for implant of mechanical circulatorysupport (MCS) devices. The sG2A system will enable surgeons to connect the MCS device outflow graft moreefficiently which should result in shorter procedures with improved patient outcomes and better quality of life.


application_id: 9554905
project_number: 5P42ES023716-02
project_title: Development of Novel Ultrasensitive Devices for the Measurement of VOCs
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5122
contact_pi_person_id: 9972311
contact_pi: NANTZ, MICHAEL H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
13-Butadiene;Acrolein;Acute;Adsorption;Air;Benzene;Biomedical Research;Butadiene;Chemicals;Chronic;Complex;Coupled;Custom;Detection;Development;Devices;Disease;Ecology;Electrodes;Engineering;Environmental Exposure;Environmental Monitoring;Environmental Pollutants;Exposure to;Face;Gas Chromatography;Gases;Goals;Gold;Health;High Pressure Liquid Chromatography;Human;Insulin Resistance;Ions;Liquid substance;Mass Spectrum Analysis;Measurement;Measures;Methods;Modification;Normal Range;Oxidants;Pattern;Process;Research;Research Project Grants;Security;Signal Transduction;Silicon;Site;Sulfhydryl Compounds;Superfund;Surface;System;Techniques;Technology;Temperature;Tube;Vinyl Chloride;Work;adduct;air sampling;base;carbonyl compound;cardiometabolism;cost;design;functional group;glycolaldehyde;improved;liquid chromatography mass spectrometry;mass spectrometer;metal oxide;microsensor;miniaturize;nanoGold;new technology;novel;sensor;simulation;superfund site;vascular inflammation;volatile organic compound


application_id: 9554904
project_number: 5P42ES023716-02
project_title: Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5121
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
ATF6 gene;Acids;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Apoptosis;Atherosclerosis;Attenuated;Benzene;Biochemical Pathway;Biological;Biological Markers;Blood Vessels;Body Burden;Butyric Acids;Cardiovascular Diseases;Cardiovascular system;Carnosine;Cell Respiration;Chemical Exposure;Chemical Injury;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Disease Resistance;Dyslipidemias;Endoplasmic Reticulum;Endothelial Cells;Environmental Exposure;Environmental Impact;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Goals;Hazardous Chemicals;Hazardous Substances;Health;Hepatic;High Prevalence;Individual;Inflammatory;Injury;Insulin Resistance;Investigation;Lead;Link;Lipids;Measures;Mediator of activation protein;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Organic Chemicals;Oxidative Stress;Parents;Particulate;Particulate Matter;Pathway interactions;Pharmacology;Phase;Plants;Plasma;Poisons;Polyvinyl Chloride;Process;Production;Proteins;Protocols documentation;Reporting;Risk;Role;Series;Signal Transduction;Stress;Stroke;Superfund;Surveys;Symptoms;Testing;Therapeutic;Tissues;Tobacco smoke;Toxic effect;Vinyl Chloride;Work;aldehyde dehydrogenases;ambient air pollution;cardiometabolism;cardiovascular disorder risk;cardiovascular health;design;endoplasmic reticulum stress;global health;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;oxidized lipid;prevent;protein folding;response;superfund site;tauroursodeoxycholic acid;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;volatile organic compound;western diet


application_id: 9554903
project_number: 5P42ES023716-02
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5120
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Air;Area;Arsenic;Attention;Benzene;Biochemical Pathway;Biological Markers;Blood;Blood Coagulation Factor;Blood Platelets;Cardiac Death;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cessation of life;Chronic;Clinical;Collaborations;Communities;Controlled Study;Cross-Sectional Studies;Cytokeratin 18;Data;Databases;Death Certificates;Development;Disease;Disease Progression;Dyslipidemias;Endocrine Disruptors;Endothelial Cells;Enrollment;Environment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Event;Exposure to;Fatty Liver;Geography;Glucose Intolerance;Goals;Heart;Heart Diseases;Hot Spot;Human;Impact evaluation;Individual;Industrialization;Industry;Inflammation;Injury;Insulin;Insulin Resistance;Lipids;Liver diseases;Longitudinal prospective study;Measures;Medical;Medical History;Metabolic;Metabolic Marker;Metabolism;Modeling;Monitor;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Occupational;Occupational Exposure;Outcome Measure;Participant;Particulate;Pathogenicity;Pathway interactions;Plants;Plasma;Population;Prevalence;Process;Prospective Studies;Publishing;Research;Resources;Retrospective Studies;Risk;Rodent;Role;Sampling;Serum;Severities;Specimen;Stem cells;Superfund;Testing;Time;Toxicology;Toxin;Urine;Vinyl Chloride;Work;adipokines;animal data;atherogenesis;base;biobank;blood glucose regulation;cardiometabolism;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;data management;data warehouse;endoplasmic reticulum stress;endothelial dysfunction;exposed human population;insulin signaling;monocyte;novel;novel marker;nutrition;obesity development;pollutant;primary outcome;prospective;superfund chemical;superfund site;translational study;urinary;volatile organic compound


application_id: 9554902
project_number: 5P42ES023716-02
project_title: Sample and Data Management Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5119
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
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_terms:
Animals;Annual Reports;Archives;Basic Science;Bioinformatics;Biological;Biometry;Biostatistical Methods;Cataloging;Catalogs;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Consultations;Continuing Education;Data;Data Analyses;Development;Dimensions;Disease;Educational workshop;Elements;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;Faculty;Fostering;Future;Goals;Hazardous Chemicals;Hazardous Substances;Health;Human Resources;Individual;Journals;Metabolism;Methods;Modeling;Outcome;Population Analysis;Postdoctoral Fellow;Preparation;Prevention;Procedures;Productivity;Protocols documentation;Publications;Records;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Sampling;Scientist;Services;Signal Recognition Particle;Source;Specimen;Statistical Data Interpretation;Statistical Methods;Students;Superfund;System;Technology;Testing;Tissues;Toxic effect;Training;Translational Research;Universities;Work;base;biobank;cardiometabolism;career development;cohesion;cohort;data archive;data management;design;disorder risk;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;innovation;meetings;member;novel;operation;pollutant;preclinical study;programs;quality assurance;radio frequency;repository;statistical service;tool;usability


application_id: 9554901
project_number: 5P42ES023716-02
project_title: Metabolism and Toxicity Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5118
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Address;Analytical Chemistry;Animals;Biochemistry;Biological Assay;Biological Markers;Biology;Cells;Charge;Chemical Exposure;Clinical;Communities;Complex;Continuing Education;Data;Detection;Development;Disease;Ensure;Environmental Exposure;Equipment;Extramural Activities;Faculty;Felis catus;Flow Cytometry;Future;Goals;Histologic;Human;Human Resources;Informatics;Measurement;Metabolic;Metabolism;Mission;Mus;Pathologic;Pathology;Physiological;Population;Postdoctoral Fellow;Procedures;Property;Proteomics;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Sampling;Services;Signal Transduction;Superfund;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;Toxicology;Toxin;Training;Universities;Validation;cardiometabolism;career development;flexibility;graduate student;interest;investigator training;meetings;member;metabolomics;novel;operation;response;success;superfund chemical;systemic toxicity;volatile organic compound


application_id: 9554900
project_number: 5P42ES023716-02
project_title: Research Translation Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5117
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Administrator;Affect;Area;Awareness;Basic Science;Cardiovascular Diseases;Chemical Exposure;Chemicals;Collaborations;Communication;Communities;Consequentialism;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Education;Educational Activities;Educational Materials;Educational Technology;Effectiveness;Emergency response;Engineering;Ensure;Environment;Environmental Exposure;Environmental Health;Evaluation;Exposure to;Federal Government;General Population;Goals;Government;Government Agencies;Government Officials;Health;Health Policy;Health Professional;Human;Human Resources;Information Dissemination;Institution;Intellectual Property;Kentucky;Knowledge;Learning;Link;Liver diseases;Local Government;Medical emergency;Methods;National Institute of Environmental Health Sciences;Newsletter;Organic Chemicals;Participant;Pathway interactions;Policies;Policy Maker;Population;Process;Public Health;Regulation;Research;Research Activity;Research Personnel;Risk Estimate;Science;Scientist;State Government;Students;Superfund;Technology;Technology Transfer;Time;Training;Translating;Translational Research;Work;base;cardiometabolism;effectiveness research;experience;federal policy;health organization;innovation;interest;meetings;member;news;novel;programs;public health relevance;social media;superfund chemical;superfund site;symposium;tailored messaging;tool;web site;webinar


application_id: 9554899
project_number: 5P42ES023716-02
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5116
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
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_terms:
Address;Adult;Affect;African American;Age;Air;Air Pollution;Area;Awareness;Back;Belief;Centers for Disease Control and Prevention (U.S.);Child;Chronic;Chronic Disease;Code;Communities;Dangerousness;Data;Death Rate;Development;Diabetes Mellitus;Disease;Elements;Ensure;Environment;Environmental Exposure;Environmental Health;Equipment;Evaluation;Exposure to;Fatty Liver;Feedback;Future;Goals;Government;Grant;Green space;Growth;Health;Health Food;Health Sciences;Heart Diseases;Hepatic;Home environment;Hospitals;Hot Spot;Housing;Hypertension;Industrialization;Industry;Intervention;Kentucky;Knowledge;Liver diseases;Love;Malignant Neoplasms;Marines;Measures;Medical;Monitor;Natural Sciences;Neighborhoods;Obesity;Participant;Patient Recruitments;Perception;Plants;Play;Policy Maker;Population;Poverty;Prevention;Preventive Intervention;Process;Public Health;Recording of previous events;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Scientist;Social Sciences;Source;Superfund;Surveillance Program;Syndrome;Testing;Toxic effect;Training;Transcend;Translational Research;Transportation;Trees;Vinyl Chloride;Work;attributable mortality;biological systems;cardiometabolism;community center;fighting;health care delivery;health disparity;landfill;meetings;member;pollutant;public health relevance;racial disparity;social;superfund site;therapy design;toxicant


application_id: 9554896
project_number: 5P42ES023716-02
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2022-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Action Research;Acute;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Attenuated;Awareness;Biological;Biological Markers;Cardiovascular Diseases;Cause of Death;Chemical Exposure;Chemicals;Chemistry;Chronic;Communities;Community Outreach;Complement;Cost Measures;Critical Pathways;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Disease Pathway;Ecology;Education and Outreach;Ensure;Environment;Environmental Exposure;Epidemic;Epidemiology;Etiology;Evaluation;Exposure to;Fatty Liver;Foundations;Future;Goals;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Human;Incidence;Industrialization;Injury;Investigation;Knowledge;Liver diseases;Mass Spectrum Analysis;Measures;Medical;Metabolism;Methods;Molecular;Monitor;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Organic Chemicals;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Techniques;Technology;Testing;Therapeutic Intervention;Time;Tissue Sample;Toxic effect;Toxicity Tests;Toxicology;Training;Training Programs;Translational Research;Universities;Validation;Work;animal tissue;base;biobank;cardiometabolism;computer code;data archive;data management;experience;exposed human population;graduate student;human population study;human tissue;innovation;interest;member;metabolomics;multidisciplinary;new technology;novel marker;obesity development;outreach program;planetary Atmosphere;pollutant;programs;remediation;repository;resilience;response;sharing data;superfund chemical;superfund site;tool;translational medicine


application_id: 9554871
project_number: 5R01DA043938-02
project_title: Cardiovascular Immune and Psychosocial Benefits of Reduced Cocaine Use
administering_ic: NIDA
award_notice_date: 2018-04-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043938
program_official: MANDLER, RAUL N
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: 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:
Abnormal Cell;Abstinence;Adopted;Adoption;Aftercare;Alcohol dependence;Atherosclerosis;Behavioral;Biochemical;Biological Markers;Blood Platelets;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Cellular Immunity;Chronic;Clinical;Clinical Trials;Cocaine;Cognitive;Comorbidity;Contracts;Control Groups;Counseling;Data;Delayed Hypersensitivity;Diagnosis;Disease;Dose;Drug Use Disorder;Drug usage;Eating;Endothelin-1;Fatty acid glycerol esters;Foundations;Frequencies;Health;Heart Rate;Heavy Drinking;Hypertension;Immune;Immunologic Markers;Incentives;Individual;Infection;Inflammatory;Intervention;Knowledge;Life Style;Measures;Mediating;Medical;Mental Health;Myocardial Infarction;Outcome;Patient Self-Report;Physiological;Problem behavior;Randomized;Research;Risk;Risk Behaviors;Standardization;Stress Tests;Stroke;TNF gene;TNFSF5 gene;Toxic effect;Treatment Efficacy;Unemployment;Vasospasm;active method;alcohol use disorder;behavioral pharmacology;biopsychosocial;cardiovascular fitness;clinical practice;cocaine use;drug use behavior;expectation;experience;financial incentive;fitness;follow-up;immune function;improved;innovation;prevent;prospective;psychosocial;response;success;therapy development;treadmill;vasoconstriction;week trial


application_id: 9554760
project_number: 5R01AG055359-02
project_title: Mechanisms mediating severity of acute pancreatitis in the aged
administering_ic: NIA
award_notice_date: 2018-07-23
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 055359
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2017-09-01
project_end_date: 2022-05-31
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:
Adipocytes;Adipose tissue;Affect;Age;Agonist;Animal Model;Animals;Antibodies;Area;Biological;Blood Circulation;Cells;Cessation of life;Characteristics;Clinical;Coagulation Process;Creatinine;Cytokine Gene;Development;Diagnostic;Disease;Elderly;Enzymes;Excision;Exhibits;Extravasation;Fatty acid glycerol esters;Foundations;Gene Expression;Immune;Incidence;Infiltration;Inflammation;Inflammatory;Injury;Interleukin-6;Intraperitoneal Injections;Kidney;Life;Link;Lipase;Lipolysis;Lung;Mediating;Mediator of activation protein;Modeling;Multiple Organ Failure;Mus;Mutant Strains Mice;Necrosis;Nonesterified Fatty Acids;Organ;PPAR alpha;Pancreas;Pathologic;Peritoneal;Peritoneal Fluid;Peritoneum;Phase;Plasminogen Activator Inhibitor 1;Prevention strategy;Production;Public Health;Research;Risk;Severities;Source;Testing;Therapeutic;Thrombosis;Tissues;Visceral;acute pancreatitis;age related;aged;cytokine;effective therapy;experimental study;inhibitor/antagonist;mortality;mouse model;older patient;prevent;release factor;therapeutic development;treatment strategy


application_id: 9554639
project_number: 5U18FD006237-02
administering_ic: FDA
award_notice_date: 2018-06-13
opportunity_number: RFA-FD-17-010
application_type: 5
activity_code: U18
ic: FD
serial_number: 006237
program_official: WOODOM-COLEMAN, ERIN
project_start_date: 2017-09-05
project_end_date: 2019-06-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15012788
contact_pi: HART, JEREMY
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_title:
Maintenance and Enhancement of ISO/IEC 17025 Accreditation and Whole Genome Sequencing for State Food Testing Laboratories.

project_abstract:
Project Summary:The main objective of the Division of Laboratory Services (DLS) at the Kentucky Department forPublic Health is to maintain ISO/IEC 17025 accreditation (achieved in September 2016for food chemistry and microbiology testing) and enhance testing capabilities by expanding the scopeof current accreditation for additional testing to include food microbiology whole genome sequencinganalyses. ISO/IEC 17025 accreditation is one of the most important standards for testing laboratoriesand attests to the competency and technical capability of a laboratory to perform specific tasks. Theresults generated are defensible to a recognized standard. In addition accreditation supports thetraceability of technical results generated by a laboratory. In the event of a large-scale terrorist activityor other large-scale events affecting foods or food products States and Federal authorities can uselaboratory test results from accredited laboratories to respond rapidly with streamlined analyticalreview and enforce regulatory compliance to protect the safety of the nation's food supply. DLS is theprimary servicing laboratory for conducting microbiological and chemical food analyses on behalf ofthe KY State manufactured food regulatory program (MFRPS) in the Department for Public Health /Food Safety Branch which has a current food safety inspection contract with FDA and is enrolled inthe MFRPS. DLS has a quality management system that is in compliance with the managerial andtechnical requirements of the ISO/IEC 17025:2005 standard. DLS is a Food Emergency ResponseNetwork (FERN) Laboratory and participates in Food proficiency testing and submits laboratoryresults through electronic laboratory exchange network (eLEXNET) as requested. The Division ofLaboratory Servicess goal is to enhance laboratory activities by bringing in new testing capabilities.DLS will implement whole genome sequencing tests for environmental micro food samples tocomplement progressive testing performed on clinical samples in outbreak situations. This wouldresult in faster identification of the food/pathogens implicated in the outbreak and matching clinical toenvironmental samples.Funding of this proposal will assist the KY State MFRPS in achieving conformance with Standard 10Laboratory Support of the MFRPS and will contribute to production of accurate and reliable testdata a quicker acceptance of analytical results by FDA and other regulatory agencies forenforcement actions surveillance purposes and response to foodborne outbreaks. In addition DLSwill provide insight into the origin of the contaminated food by the genomic information provided by theGenomeTrackr network which will point investigators to specific food products potentially related to anoutbreak. This will lead to develop a stronger international rapid surveillance system for pathogentraceback by further enhancing the GenomeTrackr network and growing the database.

public_health_relevance:
Project Narrative:This proposal will increase the analytical capacity for FDA through the Kentucky Division ofLaboratory Services (DLS) and enhance efforts to protect the nations food supply. In addition DLSwill implement whole genome sequencing tests for environmental micro food samples to complementprogressive testing performed on clinical samples in outbreak situations. This would result in fasteridentification of the food/pathogens implicated in the outbreak and matching clinical to environmentalsamples. In the event of nefarious-type activity or other large-scale events affecting foods or foodproducts States and Federal authorities can use DLS test results for rapid response and surveillance;and these response efforts will enable enforcement of regulatory compliance to protect the safety ofthe nations food supply. By funding this proposal DLS will assist in achieving conformance withstandard 10 Laboratory Support of the MFRPS (see-attached letter of support from Food SafetyBranch/KY State MFRPS).


application_id: 9552461
project_number: 3P20GM103527-10S1
project_title: Center of Research on Obesity and Cardiovascular Diseases
administering_ic: NIGMS
award_notice_date: 2017-09-11
opportunity_number: PAR-12-224
application_type: 3
activity_code: P20
ic: GM
serial_number: 103527
suffix: S1
program_official: GAO, HONGWEI
project_start_date: 2008-09-08
project_end_date: 2019-07-31
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of the Center of Biomedical Research Excellence (COBRE) on Obesity and Cardiovascular Diseases (COCVD). Kentucky ranks within the top 10 states for the prevalence of obesity and cardiovascular diseases and the epidemic is not abating. Thus it is imperative that mechanisms linking obesity to cardiovascular diseases are identified. During the 4 years of support the COCVD has made significant strides advancing knowledge on obesity-associated cardiovascular diseases through support of junior investigators and the development of research cores. As a result we have experienced outstanding success with graduation of 75% of 12 supported junior investigators to independent R01 support including 15 new NIH R01s. The program has graduated 2 junior faculty/year to NIH R01 level support with 125 publications from junior investigators and an additional 318 publications from mentors. In addition we have supported 7 pilot projects that have contributed to 58 publications. New research cores to quantify obesity phenotypes and to provide analytical services in lipidomics have markedly increased the research infrastructure. As a direct result of COCVD activities the institution competed successfully for a CTSA to establish the Center for Clinical and Translational Sciences. In the second phase of the COCVD we propose to create a nationally recognized Center of Research Excellence to define mechanisms linking the epidemic of obesity to cardiovascular diseases the primary cause of death in the obese population. To accomplish this goal we will (1) develop a critical mass of funded investigators including basic and physician scientists with research programs directly related to the Center's unifying theme (2) provide strong mentoring programs (2) recruit new investigators to the Center through pilot project grant support which will be leveraged by the institution and the CTSA (4) expand and further develop an Analytical Core (with a focus on lipidomics) a Physiologic Core to quantify obesity and cardiovascular phenotypes and a Pathology Core to assess tissue histology.

project_terms:
Adipose tissue;Area;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical Sciences;Core Facility;Development;Epidemic;Exhibits;Faculty;Funding;Goals;Grant;Histology;Inflammation;Institution;Kentucky;Knowledge;Link;Mentors;Obesity;Obesity associated cardiovascular disease;Pathology;Phase;Phenotype;Physicians;Physiological;Pilot Projects;Positioning Attribute;Prevalence;Publications;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Scientist;Services;Testing;Tissues;Translational Research;United States National Institutes of Health;bench to bedside;clinically significant;experience;multidisciplinary;programs;public health relevance;research and development;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The Center of Biomedical Research Excellence on Obesity and Cardiovascular Diseases seeks to define mechanisms for the rampant prevalence of cardiovascular diseases in the obese population. We will enhance the competitiveness of junior faculty with research programs in this highly significant area through research support mentoring and through development and access to cutting-edge research cores.


application_id: 9551409
project_number: 5P01HL078825-12
project_title: Project 4 - Metabolic Regulation of Myocardial Repair
administering_ic: NHLBI
award_notice_date: 2018-08-23
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6153
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-01
project_abstract:
ABSTRACTResults of several preclinical studies and clinical trials suggest that cell therapy improves cardiac function aftermyocardial infarction; however high variability marginal efficacy and our poor understanding of themechanisms by which cell therapy works have precluded its clinical translation. One major knowledge gap is alack of understanding of how host metabolism impinges on the efficacy of cell therapy. This is importantbecause a pervasive feature of heart failure is insulin resistance a condition known to affect glucose transportin the myocardium as well as the function of circulating and tissue-resident stem cells. This dysfunction isfurther exacerbated by frank diabetes a condition inordinately common in HF patients. Therefore identificationof the metabolic factors that determine the efficacy of cell therapy is required to optimize cell therapy for HFpatients. In this project we will examine how diabetes affects cardiac repair induced by transplantation ofcardiac mesenchymal cells (CMCs) or paracrine factors derived therefrom. Our preliminary data indicate thatin contrast to CMCs isolated from non-diabetic mice CMCs isolated from diabetic mice fail to improve thefunction of the infarcted heart. The diabetic CMCs show elevated rates of glycolysis associated with expressionof Pfkfb3 which in cardiac progenitor cells increases glycolysis by augmenting phosphofructokinase activityand appears to diminish their proliferation and survival. In addition we find that these changes involve not onlyglycolytic mediators such as PFKFB3 but mitochondrial effectors such as sirtuin 1 (Sirt1) as well. Building onthese observations we propose to test the hypothesis that diabetes compromises the therapeutic efficacy ofCMCs by chronically increasing glycolysis which alters paracrine mechanisms that mediate cardiac repair andthat Sirt1 improves the repair capacity of CMCs by augmenting mitochondrial activity and thereby decreasingglycolysis. To test this hypothesis we will i) determine how diabetes affects CMC-mediated myocardial repairii) elucidate how glycolysis affects CMC repair competence and iii) develop strategies to improve CMC therapyin diabetes. This project will provide fundamental knowledge regarding how metabolic disease affects celltherapy and how mesenchymal cells adapt to nutrient stress. In addition these studies will illuminatemechanisms by which metabolism regulates paracrine factor secretion thereby generating novel biologicalunderstanding of cell-cell communication. Collectively the knowledge garnered from this project will facilitatethe optimization of cell therapy protocols and provide critical direction to ongoing clinical trials.

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

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


application_id: 9551408
project_number: 5P01HL078825-12
project_title: Project 3 - Cell Therapy and Remodeling
administering_ic: NHLBI
award_notice_date: 2018-08-23
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6152
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-01
project_abstract:
Despite the dearth of mechanistic insights into precisely how cell therapy works preclinical studies commonlyreport a reduction in fibrosis. Thus to understand how cell therapy limits remodeling we must first appreciatehow reparative cells interact with the stromal compartment. In the normal heart fibroblasts are essential inmaintaining the extracellular matrix. Following infarction fibroblasts assume an active role in acute woundhealing. Although this phenotypic activation is necessary for the acute post-ischemic injury responsefibroblasts become chronically activated which contributes to post-ischemic pathology. Project 3 will elucidatewhether and how cardiac mesenchymal cells (CMCs) interact with the recipient heart and will identify CMC-mediated changes in fibroblast activation. Because the post-MI heart is characterized by a shift in the balanceof hyaluronan (HA) metabolism in which more HA is produced than is degraded HA accumulation maycontribute to persistent fibroblast activation and support unresolved inflammation. Furthermore we reason thatcell therapy effects myocardial repair by restoring balance to dysregulated HA metabolism which is largelypropagated by activated fibroblasts. We will perform proof-of-concept studies to show whether and how HAmetabolizing enzymes in reparative cells may regulate their competence in in vivo models of post-ischemicmyocardial repair. We will identify specific receptor-ligand interactions that confer reparative competence totherapeutic cells. Although the aforementioned goals are worthy of pursuit on their own we argue they shouldbe examined further through a translational lens because preclinical studies of reparative cells use healthyanimals as cell donors; however clinical trials of autologous cells use heart failure (HF) patients as bothdonors and recipients. This preclinical/clinical dichotomy creates a sizeable translational barrier. Becausesignificant changes occur in the stromal compartment following infarction reparative cells derived therefromlikely differ from nave reparative cells. Indeed our preliminary data indicate that heart failure-derived CMCslack reparative competence which may stem from their inability to properly metabolize post-MI stromalcomponents such as HA. We will identify and correct defects in incompetent heart failure-derived CMCs.Thus our central hypothesis holds that reparative cells attenuate ventricular remodeling through recognition ofand response to specific stromal components which are lost in CMCs derived from failing hearts. We will testthis hypothesis through these synergistic aims: 1) Elucidate the impact of CMCs on fibroblast activation; 2)Determine how CMCs interact with the recipient heart to limit maladaptive remodeling; 3) Identify and rescuedefective mechanisms in heart failure-derived reparative cells. Thus we will show for the first time how CMCsshape the post-MI stroma to limit fibroblast activation. We will also identify reasons for reparativeincompetence in heart failure-derived CMCs and restore their competence by rescuing their capacity tometabolize HA. Collective insights from Project 3 will fundamentally change future cell therapy studies.

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

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


application_id: 9551406
project_number: 5P01HL078825-12
project_title: Project 1 - Repeated Cell Therapy for Heart Failure: A New Paradigm
administering_ic: NHLBI
award_notice_date: 2018-08-23
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6150
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-01
project_abstract:
The therapeutic benefits of cell-based treatments have often been regarded as modest borderline or nil. As aresult clinical translation has not occurred and considerable uncertainty and skepticism surround the conceptof cell therapy. A major factor limiting the benefits of cell therapy (regardless of cell type) is the poorengraftment of the cells which disappear rapidly after transplantation; because of this we propose thatadministering one dose of cells cannot be considered an adequate test of efficacy. However almost allpreclinical and clinical studies of cell therapy performed heretofore have based their assessment of efficacy onthe outcome of one cell administration. Our work in the current PPG has shown that 3 doses of c-kitPOScardiac progenitor cells (CPCs) are strikingly (~3 times) more effective than 1 dose in improving LV function.Building on this prior work we will test the idea that the problem of poor engraftment can be overcome byrepeated cell administrations. We have recently discovered a new population of cells cardiac mesenchymalcells (CMCs) that appear to be more suitable for widespread use and to have greater therapeutic potentialthan CPCs. Consequently we will focus this proposal on CMCs. The overall goal of Project 1 is tothoroughly evaluate the therapeutic effectiveness and mechanism of action of repeated doses ofCMCs. Our central hypothesis is that repeated administrations of CMCs dramatically increase the beneficialeffects of cell therapy not only in mice but also in large preclinical animal models (pigs) and in the presence ofmajor co-morbidities (diabetes) via mechanisms that involve the cumulative effects elicited by repetitive burstsof extracellular vesicle (EV) release resulting in cumulative favorable modulation of the inflammatory andfibrotic response to CMC transplantation. The specific Aims are: 1) To establish the most effective protocols foradministering repeated doses of CMCs or CMC-derived EVs. We will determine how the effects of repeateddoses can be maximized by varying the number of doses and the interval between doses and the impact ofdiabetes. 2) To generate data necessary for Phase I clinical trials of repeated CMC or EV therapy in patientswith heart failure. Using a preclinical porcine model we will assess the effects of repeated administrations ofCMCs or EVs and identify the optimal doses. 3) To elucidate the mechanism of action of repeated doses ofCMCs and EVs including their effect on the inflammatory and fibroblast response to infarction. Throughoutthese studies the effects of EVs will be compared with those of CMCs to determine whether cell-free EVtherapy recapitulates the benefits of CMC therapy. This Project will test two potentially disruptive ideas: i) theconcept that the full effects of cell or EV therapy require repeated doses would constitute a major paradigmshift with potentially vast implications for the entire field of reparative medicine; ii) the concept that theeffects of cell therapy can be reproduced with cell-free administration of EVs would revolutionize the field.These studies will lay the groundwork necessary for first-in-human trials of repeated CMC/EV administration.

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

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


application_id: 9551402
project_number: 5P01HL078825-12
project_title: Administrative Core
administering_ic: NHLBI
award_notice_date: 2018-08-23
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6146
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-01
project_abstract:
Core A will provide scientific budgetary administrative logistic and biostatistical oversight to all aspects ofthe Program Project. The Core will facilitate communication among investigators and sharing of reagentstools specimens and data; will ensure appropriate allocation of funds to each Project and appropriate use ofthese funds; will provide clerical support; will coordinate the Projects with subcontracted institutions; willorganize regular investigator meetings; and will provide biostatistical assistance. Dr. Bolli Core Leader will beresponsible for the overall coordination integration and administration of the Program Project for theappropriate utilization of the funds for compliance with institutional and federal regulations for the scientificproductivity of the Program and for any issues related to the Program. The Principal Investigator will beassisted by the other members of the Executive Committee which will be composed of the four ProjectLeaders and the four Core Leaders. The Principal Investigator and the executive Committee will meet on amonthly basis to discuss the scientific progress data problems and future directions for the four Projects.Scientific responsibilities include (1) providing leadership in maintaining the focus of the investigators (2)providing statistical assistance and (3) weekly meetings of all Program Project Investigators. Administrativeand financial responsibilities include (1) implementing guidelines for PPG support (2) administering thebudget according to NIH guidelines (3) monitoring budgets for each Project and Core and (4) ensuringcompliance with the institutional and NIH regulations. The Biostatistician working in the Core will be Dr. MaiyingKong. She will attend the monthly meetings of the Executive Committee review the experimental dataanalyze them calculate group sizes and ensure that all studies are performed with rigor. Indeed an importantaspect of this Program Project is that in all in vivo studies proposed in this Project we will adhere strictly to theprocedures that we used in the CAESAR Consortium. Specifically: i) all animals will be allocated to treatmentgroup randomly (randomization will be performed by Dr. Kong); ii) all investigators will be blinded to treatmentallocation until the final data analysis is released by Dr. Kong; iii) exclusion criteria will be established a prioribefore the experiments are started not during or after the experiments; iv) group sizes will be determined apriori before the experiments are started (based upon power analysis by Dr. Kong) and will not be changedduring or after the experiment; v) the experiments will be carried out until the predetermined sample sizes areachieved without any knowledge of interim results. After the predetermined sample sizes are achieved alldata will be given to Dr. Kong where they will be unblinded and analyzed by appropriate statistical methods.These are the same procedures that we have used successfully in CAESAR for the past six years. Use ofthese methods will ensure rigor and greatly reduce the chance of spurious or misleading results.

project_terms:
Animals;Basic Science;Biography;Biological Markers;Biometry;Biostatistics Core;Blinded;Budgets;Cardiac;Cardiology;Cardiotonic Agents;Cardiovascular system;Cell Therapy;Cells;Clinical Trials;Communication;Data;Data Analyses;Effectiveness;Ensure;Environment;Exclusion Criteria;Faculty;Family suidae;Funding;Future;Goals;Grant;Growth;Guidelines;Human Resources;Individual;Institutes;Institution;Knowledge;Laboratories;Laboratory mice;Leadership;Logistics;Medicine;Mesenchymal;Methods;Mission;Molecular;Monitor;Myocardial Ischemia;National Heart Lung and Blood Institute;Personality;Principal Investigator;Procedures;Productivity;Protocols documentation;Randomized;Reagent;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Sample Size;Scientist;Services;Specimen;Standardization;Statistical Methods;Therapeutic Studies;Time;United States National Institutes of Health;Work;base;cardioprotection;experience;experimental study;in vivo;meetings;member;multidisciplinary;next generation;power analysis;pre-clinical;preclinical study;programs;student training;tool;treatment group


application_id: 9551097
project_number: 5R01NS089515-05
project_title: The Role of Perlecan Domain V in Vascular Dementia
administering_ic: NINDS
award_notice_date: 2018-08-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089515
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-01
project_end_date: 2019-07-31
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: 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): Despite its prevalence VaD remains woefully understudied and poorly understood in part due to its diverse etiology. The outcome of these multiple causes of VaD however remains the same- disruption of the complex coupling between endothelial cells astrocytes pericytes neurons and the extracellular matrix the components of the neurovascular unit. We hypothesize that the extracellular matrix plays a critical role in the neurovascular disruption of VaD. In particular we have identified a biologicaly active fragment of one prominent matrix component the heparan sulfate proteoglycan perlecan to play a major role in regulating endothelial cell function after experimental ischemic stroke. This fragment termed domain V (DV) is actively generated in the stroked brain and appears to be important to the brain's response to injury inasmuch as its absence results in more significant stroke injury and worse outcome. Furthermore DV stroke treatment after stroke enhances peri-infarct new blood growth (angiogenesis) and important component of neurorepair. As extracellular matrix remodeling is likely to occur in the vascular pathology leading to VaD we hypothesize that DV is actively generated plays a key role in regulating brain endothelial cell function and may improve endothelial cell function and neurovascular coupling when administered in two experimental mouse models of VaD the BCAS and the DB/AD models which differentially impact white matter and gray matter respectively. This will allow us to determine both the impact of white and gray matter endothelial cell dysfunction on VaD and DV's potential impact on it. To investigate these hypotheses we propose three aims: Aim 1. Determine the extent and significance of DV generation in the BCAS and DB/AD mouse models. Aim 2. Determine the therapeutic potential of DV in the BCAS and DB/AD mouse models. Aim 3. Determine the extent and significance of DV generation in human autopsy brain from subjects with VaD. Successful completion of these studies will increase our understanding of the role of the extracellular matrix and angiogenesis in VaD and support the therapeutic potential for DV.

project_terms:
APP-PS1;Acute;Aftercare;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Arteriovenous malformation;Astrocytes;Autopsy;Bilateral;Biochemical;Biological;Blood;Blood Vessels;Brain;Brain region;Carotid Stenosis;Cell Communication;Cell physiology;Cerebral Amyloid Angiopathy;Cerebrovascular Disorders;Cerebrovascular system;Cognitive;Complex;Coupling;Dementia;Development;Endothelial Cells;Etiology;Experimental Animal Model;Extracellular Matrix;Failure;Functional disorder;Gene Expression;Generations;Growth;Growth Factor;Heparan Sulfate Proteoglycan;Histologic;Homo;Human;Immunohistochemistry;Impaired cognition;Infarction;Injury;Integrin alpha5beta1;Ischemic Stroke;Knock-in Mouse;Methods;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Pericytes;Phenotype;Play;Prevalence;Process;Protein Fragment;Proteins;Replacement Therapy;Role;Stroke;Therapeutic;Time;Vascular Dementia;angiogenesis;blood vessel development;brain abnormalities;brain endothelial cell;cerebrovascular;cerebrovascular pathology;cognitive function;combat;diabetic;gray matter;hypoperfusion;improved;mouse model;neurovascular;neurovascular coupling;neurovascular unit;novel;perlecan;post stroke;prevent;public health relevance;receptor;response;response to injury;stroke treatment;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although vascular dementia is the second leading cause of dementia behind Alzheimer's disease it remains woefully understudied and poorly understood in part due to its diverse etiology. The gradual failure of compensatory new brain blood vessel formation (angiogenesis) in the face of ongoing cerebrovascular insult appears to contribute to vascular dementia regardless of the etiology. We propose to determine the role and therapeutic potential of an angiogenic extracellular matrix fragment in human and novel animal models of vascular dementia.


application_id: 9549047
project_number: 5R01DK104653-04
project_title: Hydrogen sulfide mechanism of renal hypertension
administering_ic: NIDDK
award_notice_date: 2018-06-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 104653
program_official: NIHALANI, DEEPAK
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): For decades hydrogen sulfide (H2S) was known only for its neurotoxicity and as an environmental hazard. Recent findings however suggest that endogenous H2S has a variety of physiological functions and a decrease in production can lead to vascular dysfunction atherosclerosis and hypertension. This discovery has stimulated further research into its development as a potential therapeutic agent in diseases attributed to diminished H2S synthesis. In chronic kidney disease low levels of plasma H2S is often associated with a concomitant increase in homocysteine (Hcy) known as hyperhomocysteinemia (HHcy). HHcy is well known to cause vascular dysfunction. The cause and effect relationship of HHcy in renal disease can therefore adversely affect the final outcome. Because Hcy is a precursor of H2S changes in the H2S metabolism can have a significant impact on HHcy-induced pathology. However the mechanism by which HHcy causes vascular dysfunction and the role of H2S in renal protection is incompletely understood. In the body Hcy is metabolized by three enzymes cystathionine -synthase (CBS) cystathionine y-lyase (CSE) and 3- mercaptopyruvate sulfurtransferase (3MST) and produce H2S. During HHcy an impairment in these enzymes leads to deficient H2S production. Our preliminary studies suggest that HHcy results in upregulation of caveolin-1 and homocysteinylation of eNOS thus decreasing NO production. The resulting imbalance in matrix metalloproteinases and their tissue inhibitors of metalloproteinases causes accumulation of extracellular matrix proteins leading to microvascular remodeling renal dysfunction and hypertension. In this proposal we hypothesize that H2S offers renal protection from HHcy-induced renal damage by inhibition of caveolin-1 and modulation of eNOS. We will test this hypothesis in vivo and in vitro. Wild type (C57BL/6J) and genetic model of HHcy (CBS+/-) mice will be supplemented without or with H2S. To determine whether HHcy effects are caveolin-1 dependent we will use caveolin-1-/- mice supplemented with high Hcy diet. To ameliorate the HHcy- induced injury single double or triple gene delivery system employing CBS CSE and 3MST enzymes will be used to enhance conversion of Hcy to H2S. In addition to confirming the preliminary findings further studies will be performed for a deeper understanding into H2S-mediated improvement in renovascular dysfunction caused by pro-fibrotic and pro-inflammatory effects of HHcy. This research is novel because it evaluates gene delivery as a therapeutic option to ameliorate HHcy-induced microvascular remodeling renal dysfunction and hypertension.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Affect;Amino Acids;Angiography;Antihypertensive Agents;Antioxidants;Atherosclerosis;Blood Pressure;Blood Vessels;Blood capillaries;Cells;Chemicals;Chronic Kidney Failure;Co-Immunoprecipitations;Collagen;Connexins;Cystathionine;Cystathionine beta-Synthase;Development;Diet;Disease;Endothelial Cells;Environmental Hazards;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Functional disorder;Future;Gap Junctions;Gelatinase A;Gelatinases;Gene Delivery;Genes;Genetic Models;Glomerular Filtration Rate;Goals;Histologic;Homocysteine;Hydrogen Sulfide;Hyperhomocysteinemia;Hypertension;Impairment;In Vitro;Inflammatory;Injury;Intercellular Junctions;Interstitial Collagenase;Investigation;Kidney;Kidney Diseases;Knowledge;Lead;Lyase;Mass Spectrum Analysis;Matrilysin;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metabolism;Methods;Molecular;Mus;NOS3 gene;Nitric Oxide;Outcome;Outcomes Research;Oxidative Stress;Pathology;Perfusion;Physiological;Plasma;Process;Production;Renal Hypertension;Renal function;Renovascular Hypertension;Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Role;Structure;Sulfhydryl Compounds;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Tissues;Up-Regulation;Vascular Diseases;Vascular remodeling;Western Blotting;blood pressure regulation;caveolin 1;collagenase;connexin 37;density;gene delivery system;histological stains;in vivo;insight;kidney vascular structure;neurotoxicity;novel;prevent;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A non-protein amino acid homocysteine at elevated levels cause vascular remodeling and dysfunction. Homocysteine however in the body metabolizes and produces hydrogen sulfide. Although high levels of hydrogen sulfide are toxic low levels are protective against varieties of vascular diseases. This study proposes to mitigate high homocysteine effects on renal vascular tissues either by hydrogen sulfide supplementation or through conversion of bad homocysteine to good hydrogen sulfide by gene manipulation. The research outcome will further our knowledge for future investigations of therapeutic potential of hydrogen sulfide in high homocysteine-associated renovascular diseases.


application_id: 9548968
project_number: 5U44AA026126-02
administering_ic: NIAAA
award_notice_date: 2018-08-02
opportunity_number: PAR-15-154
application_type: 5
activity_code: U44
ic: AA
serial_number: 026126
program_official: FERTIG, JOANNE
project_start_date: 2017-08-25
project_end_date: 2021-08-31
study_section: ZAA1-DD(44)
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
budget_start_date: 2018-08-01
project_abstract:
Abstract Alcohol dependence affects at least 4% of the US population with a financial cost in excess of $100Bn. Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target but current treatments are ineffective and there is an urgent need for new medications. Major factors in causing relapse include the protracted symptoms of withdrawal from alcohol which are relieved by returning to drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence. There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol withdrawal and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B subunit as a specific target in alcohol withdrawal and molecular screening identified several lead compounds. JR220 was the most active novel compound from an aryliminoguanidine series and its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of rodent screens relevant to alcohol dependence withdrawal and neurotoxicity including several screens in other laboratories. The drug was highly active in all of these screens with a potency 5-200x that of acamprosate which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher doses but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitoneal subcutaneous and oral administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days JR220 did not accumulate in plasma or brain and no overt toxicity was observed. The only concern is that the plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as an anti-relapse medication and the current proposal is to develop the drug further for this use. The aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drug (IND). Thus in the proposed studies we will complete investigation of metabolism and metabolite identification in vitro and Absorption Distribution Metabolism and Excretion in vivo. The studies will also include a screen for off target actions and studies on safety and toxicology in two species. These studies will include escalating acute dose studies and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). JR220 will be produced under GMP conditions and production scaled up to meet requirements for future human trials. If an IND designation is obtained the objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trial and then in clinical trials in alcohol dependent volunteers. The objective is to develop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available.

project_terms:
Acute;Address;Adverse effects;Affect;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcohols;Autopsy;Binding;Biological Availability;Blood - brain barrier anatomy;Brain;Canis familiaris;Cardiovascular system;Chemicals;Chronic;Clinical;Clinical Trials;Complex;Data;Dependence;Development;Dose;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Excretory function;FDA approved;Financial cost;Formulation;Future;Gastritis;Glutamates;Guanidines;Half-Life;Hepatic;Hepatocyte;Human;In Vitro;Intellectual Property;Investigation;Investigational Drugs;Kilogram;Label;Laboratories;Lead;Liver Microsomes;Lung;Macaca fascicularis;Maintenance;Maximum Tolerated Dose;Medical;Metabolism;Methods;Modeling;Molecular;Molecular Target;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Nerve Degeneration;Neurons;Oral;Oral Administration;Pathologic;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Physiological;Plasma;Plasma Proteins;Play;Polyamines;Population;Production;Rattus;Receptor Inhibition;Recovery;Relapse;Research;Rodent;Role;Route;Safety;Schedule;Sedation procedure;Series;Site;Symptoms;System;Testing;Therapeutic Uses;Toxic effect;Toxicokinetics;Toxicology;Treatment Efficacy;Up-Regulation;Validation;Withdrawal;Withdrawal Symptom;absorption;acamprosate;alcohol abuse therapy;alcohol exposure;alcohol use disorder;aminoguanidine;chemical synthesis;design;disorder later incidence prevention;drinking;drug testing;genotoxicity;high throughput screening;human subject;in vivo;ineffective therapies;intraperitoneal;meetings;neuroprotection;neurotoxicity;nonhuman primate;novel;novel therapeutics;phase 1 study;preclinical development;preclinical study;receptor;receptor function;reduce symptoms;scale up;screening;subcutaneous;therapeutic target;translational model;uptake;volunteer


application_id: 9548908
project_number: 5F31MH114551-02
project_title: Do Bulimic Behaviors Increase Shame? Toward an Understanding of Transdiagnostic Risk
administering_ic: NIMH
award_notice_date: 2018-08-06
opportunity_number: PA-16-308
application_type: 5
activity_code: F31
ic: MH
serial_number: 114551
program_official: CHAVEZ, MARK RAY
project_start_date: 2017-08-06
project_end_date: 2019-08-05
study_section: Special Emphasis Panel[ZRG1-F16-M(09)F]
contact_pi_person_id: 14505464
contact_pi: DAVIS BORCHETTA, HEATHER A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
There is abundant evidence documenting the comorbidity of bulimia nervosa (BN) internalizing disorders suchas anxiety and depression and externalizing disorders such as substance misuse. One important line ofresearch is to move beyond descriptions of comorbidity to determine underlying mechanisms that may accountfor it. The intent of the proposed research is to begin to test the possibility that engagement in one behavior ina specified set of comorbid dysfunctional behaviors increases the experience of shame and that theincreased shame contributes to risk for others of the comorbid behaviors. The scientific basis for investigatingthis possibility is that (a) estimates of comorbidity between BN internalizing and externalizing disorders are ashigh as 74.4% (Ulfvebrand et al 2015); (b) prior research on comorbidity has often been descriptivehighlighting the need to investigate mechanisms to explain it; (c) the experience of shame is associated witheach of these disorders; and (d) in recent longitudinal work my colleagues and I demonstrated that bingeeating in elementary school predicts increased levels of depression alcohol use and tobacco smoking fouryears later in high school. The research component of this proposal is a study designed to begin to test thisidea using bulimic behaviors by women with BN as an entry point for studying this comorbidity model.Specifically I propose to test in the laboratory whether eating while in a negative mood increases stateshame in women with BN as compared to healthy controls. After an ad lib eating session following negativemood induction women with BN will experience an increase in state shame that is greater than any increase instate shame for the healthy control group and these increases will predict subsequent increases in stateanxiety and depression as well as increased urges to use substances. Demonstration of increased stateshame and transdiagnostic risk following a distress-based eating session for women with BN is a crucial stepin a program of research I hope to conduct using both experimental and longitudinal designs. The trainingcomponent of this proposal includes the following: (1) training in the design and execution of laboratoryexperimental studies; (2) training in the construct of shame its distinction from related constructs such as guiltthe role of shame transdiagnostically methods of measuring shame and the possibility of reducing shame; (3)training in multilevel modeling: my planned program of research will involve studies of observations nestedwithin people nested within groups; (4) further advanced training in research ethics including a secondgraduate course on ethical research with clinical populations attendance at the University's clinical ethicsgrand rounds and research ethics lecture series; (5) preparation of research reports for publication includinglearning how to respond effectively to revise and resubmit decisions; (6) presenting original research atleading international scientific meetings; and (7) training in the mentoring of junior graduate students andundergraduate research assistants including those assisting with the proposed research.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;American Indians;Anxiety;Behavior;Binge Eating;Bulimia;Clinical;Clinical Ethics;Comorbidity;Conscious;Control Groups;Disease;Distress;Eating;Emotions;Ethics;Experimental Designs;First Generation College Students;Functional disorder;Future;Goals;Guilt;Hyperphagia;Impulsive Behavior;Individual;International;Intervention;Laboratories;Laboratory Study;Lead;Learning;Measures;Mental Depression;Mentors;Methods;Modeling;Negative Valence;Observational Study;Pharmaceutical Preparations;Population;Preparation;Process;Proxy;Public Health;Publications;Reporting;Research;Research Assistant;Research Design;Research Ethics;Risk;Role;Series;Shame;Specific qualifier value;Symptoms;Testing;Tobacco smoking behavior;Training;Universities;Woman;Work;anxiety states;anxiety symptoms;base;binge type behavior;cigarette smoking;depressive symptoms;design;elementary school;experience;experimental study;graduate student;high school;lectures;longitudinal design;meetings;multilevel analysis;negative affect;negative mood;programs;purge;response;substance misuse;therapy design;undergraduate research

public_health_relevance:
Bulimia nervosa (BN) internalizing disorders such as depression and anxiety and externalizing disorders suchas substance use tend to co-occur in people. The proposed project is part of a program of research designedto test the experience of shame as one mechanism explaining this co-occurrence. The project will support thePI a first generation college student of American Indian background in her goal to develop a cutting edgeresearch program to understand risk processes that contribute to multiple forms of dysfunction.


application_id: 9548456
project_number: 5R01AR068313-04
project_title: MYD88 Signaling in Mammalian Myoblast Fusion
administering_ic: NIAMS
award_notice_date: 2018-08-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 068313
program_official: BOYCE, AMANDA T
project_start_date: 2015-09-14
project_end_date: 2019-08-12
study_section: Special Emphasis Panel[ZRG1-MOSS-V(03)S]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
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 PI):  Myoblast fusion is a critical event that is required not only for the development of skeletal muscle during embryogenesis but also for the regeneration of adult myofibers upon injury and for load-induced skeletal muscle hypertrophy. Augmenting the natural process of muscle cell fusion in existing or introduced myogenic cells has enormous therapeutic potential to treat degenerative muscle diseases. However the mechanisms of myoblast fusion in vertebrates remain less understood. Accumulating evidence suggests that myoblast fusion in mammalian system involves the activation of specific cell signaling pathways such as MAPK non-canonical NF-B canonical Wnt signaling. However the upstream signaling mechanisms leading to their activation and how the activation of these pathways promotes myoblast fusion during myogenesis remain poorly understood. Our preliminary studies have identified that myeloid differentiation primary response gene 88 (Myd88) is a critical regulator of myoblast fusion both in vitro and in vivo. Our results show that the levels of Myd88 are increased during myogenesis. Genetic ablation of Myd88 impairs myoblast fusion whereas overexpression of Myd88 enhances the formation of myotubes in cultured myoblasts. Furthermore we have obtained initial evidence that Myd88 regulates the activation of specific profusion signaling pathways during myogenesis. Based on our preliminary studies we have proposed to establish the role and delineate the signaling and molecular mechanisms by which Myd88 mediates skeletal muscle formation in vitro and in vivo. Our working hypotheses are: (I) Myd88 promotes myoblast fusion in multiple conditions through augmenting the gene expression of specific profusion molecules; (II) Myd88 coordinates the activation of canonical Wnt and non-canonical NF-B signaling to promote myoblast fusion during myogenesis; (III) Both transcriptional and post-transcriptional mechanisms regulate the levels of Myd88 in differentiating myoblasts. We will test these hypotheses by addressing the following three specific aims. Aim I: Establish the role and investigate molecular mechanisms by which Myd88 mediates myoblast fusion; Aim II: Investigate the signaling networks through which Myd88 promotes myoblast fusion; and Aim III: Investigate the mechanisms by which levels of Myd88 are increased during myogenesis. Successful completion of this project will provide critical insights into the mechanisms of myoblast fusion and will lead to the identification of novel drug targets for treatment of muscle disorders.

project_terms:
3' Untranslated Regions;Ablation;Adaptor Signaling Protein;Address;Adult;Age;Attenuated;Binding;Bioinformatics;Caliber;Cell fusion;Cells;Consensus;DNA Sequence;Defect;Development;Drosophila genus;Drosophila melanogaster;Embryonic Development;Event;Family;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Growth;Hypertrophy;Impairment;In Vitro;Injury;Innate Immune Response;Interleukin-1;Knock-out;Knockout Mice;Knowledge;MAP Kinase Gene;Mediating;MicroRNAs;Molecular;Molecular and Cellular Biology;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;MyD88 protein;Myelogenous;MyoD Protein;Myoblasts;Myogenic Regulatory Factors;Myogenin;Myopathy;Natural regeneration;Neonatal;Pathway interactions;Pattern;Play;Process;Promoter Regions;Research;Role;Seminal;Signal Pathway;Signal Transduction;Skeletal Development;Skeletal Muscle;Small Interfering RNA;System;TLR3 gene;Testing;Therapeutic;Toll-like receptors;Transcript;Vertebrates;WNT Signaling Pathway;Wild Type Mouse;base;experimental study;improved;in vivo;insight;interleukin-18 receptor;knock-down;mouse model;muscle form;muscle hypertrophy;myogenesis;new therapeutic target;novel therapeutics;overexpression;promoter;public health relevance;receptor;recruit;repaired;response;response to injury;skeletal muscle growth;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Myoblast fusion is a fundamental process that is crucial for the repair and growth of skeletal muscle upon injury. Understanding of the mechanisms of myoblast fusion has enormous potential for the development of novel therapeutics aimed at treating various genetic and acquired degenerative muscle disorders. The primary goal of the proposed research is to understand the signaling mechanisms of myoblast fusion and thereby providing fundamental knowledge required to enhance the therapeutic potential of myogenic cells to treat muscle wasting in various muscle disorders.


application_id: 9547788
project_number: 5R01CA195573-04
project_title: Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
administering_ic: NCI
award_notice_date: 2018-07-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 195573
program_official: FU, YALI
project_start_date: 2015-09-25
project_end_date: 2020-08-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GUO, PEIXUAN ;THORSON, JON SCOTT
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Although progress has been made in survival of patients with earlier stage colorectal cancer (CRC) only minimal improvement has been noted in patients with systemic metastases (Stage IV disease). Current chemotherapeutic agents while highly effective at killing CRC cells are limited by their systemic toxicity. If advances ar to be made in the survival of cancer patients highly innovative strategies are required for more targeted delivery of anti-cancer agents directly to CRC metastases. Our ultimate translational goal is to develop a highly effective and less toxic approach to specifically deliver anti-cancer agents to CRC metastases. To achieve this goal we have assembled a multidisciplinary and highly collaborative team who are at the forefront of molecular signaling pathways in CRC CRC treatment modalities medicinal chemistry novel nanoparticle synthesis and delivery systems. Over the last two years we have made significant progress to achieve our goals: (i) using a novel three-way junction (3WJ) motif we have constructed thermodynamically and chemically stable three-branched RNA nanoparticles with an aptamer against receptors that can deliver a small molecule inhibitor or chemotherapeutic agent specifically to CRC metastases in the liver (ii) we have constructed a variety of RNA nanoparticles using the pRNA-3WJ motif as a scaffold and have demonstrated in critical experiments that the resulting RNA constructs retained their folding and independent functionalities for specific cell binding cell entry and cancer targetingboth in vitro and in vivo (iii) we have shown that the RNA nanoparticles remain intact after systemic injection into mice and strongly bind to tumors with little accumulation in normal organs or tissues; these RNA constructs are non- toxic non-immunogenic and display favorable pharmacological profiles in mice and (iv) we have demonstrated localized in vivo delivery of pRNA-3WJ to CRC xenografts and liver metastases. Thus the central hypothesis of our proposal is that CRC receptor-specific delivery of chemotherapeutic agents using our pRNA-3WJ nanoparticles will provide a safe effective strategy to selectively target and inhibit CRC metastasis. To address our hypothesis we have designed experiments with the following Specific Aims: 1) to construct pRNA-3WJ nanoparticles coupled with anti-cancer agents and analyze their stability cellular uptake and anti-proliferative effects in vitro; 2) to determine te pharmacokinetics stability safety and drug delivery of pRNA-drug conjugates in vivo; and 3) to evaluate the selective delivery and in vivo anti-tumor effect of pRNA- 3WJ nanoparticles coupled with anti-cancer agents. In summary our enthusiasm for our current proposal is driven not only by its inherent scientific importance but also by its translational potential clinical impact and the possibility to provide a more effective and less toxic delivery system targeting CRC metastases.

project_terms:
Address;Antineoplastic Agents;Binding;Biodistribution;Biological Models;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Cessation of life;Chemicals;Clinical;Colorectal Cancer;Coupled;Disease;Distant;Drug Delivery Systems;Drug Kinetics;Early treatment;Epithelial Cells;Excision;FOLR1 gene;Goals;Growth;Human;In Vitro;Injections;Intestines;Kentucky;Laboratories;Liver;Malignant Neoplasms;Metastatic Neoplasm to the Liver;Modality;Molecular;Motor;Mucous Membrane;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Process;RNA;Research;Resistance;Safety;Signal Pathway;Submucosa;System;Technology;Thermodynamics;Tissues;Tumor Tissue;Universities;Xenograft procedure;antitumor effect;aptamer;base;cancer cell;cancer survival;chemotherapeutic agent;colorectal cancer metastasis;colorectal cancer treatment;design;experimental study;improved;in vivo;innovation;metastatic colorectal;mortality;multidisciplinary;nanoparticle;nanoparticle delivery;novel;overexpression;public health relevance;receptor;scaffold;small molecule inhibitor;systemic toxicity;targeted delivery;targeted treatment;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Colorectal cancer is the second leading cause of cancer death in the U.S. When localized to the mucosa and submucosa of the bowel wall (Stage I) the five-year survival approaches 100% after resection; however systemic metastasis (Stage IV) usually to the liver is associated with a five-year survival that is less than 12%. Therefore mor selective highly innovative and better targeted therapies are required if we are to achieve an improved patient survival.


application_id: 9547375
project_number: 5R01DE026963-02
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2018-08-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DE
serial_number: 026963
program_official: MELILLO, AMANDA A
project_start_date: 2017-09-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Periodontitis a microbial-driven destructive disease of the tissues surrounding the teeth occurs in approximately50% of the population and is associated with several debilitating systemic conditions (including vascular and lung diseasesdiabetes mellitus and pre-term birth). Patients who smoke have increased susceptibility to periodontitis and are more likelythan non-smokers to display severe disease and to be refractory to treatment. Indeed the most recent epidemiological evidencesuggests that tobacco smoking accounts for the majority of destructive periodontal disease cases in developed nations. Smoking enhances infectionrates and enriches numbers of the keystone periodontal pathogen Porphyromonas gingivalis. However the mechanisms underlyingthis phenomenon are in need of elucidation. We plan to generate whole genome transposon sequencing (TnSeq) libraries for two P. gingivalis strains (ATCC 33277and W83) to be employed in order to (i) identify genes that are putatively essential for P. gingivalis to survive cigarette smokeexposure in vitro; (ii) to validate that TnSeq-identified genes are indeed essential by generating single gene deletion mutants andmonitoring their ability to grow planktonically and in biofilms under cigarette-induced stress; (iii) to determine the in vivorelevance of such mutations in a murine model of smoke-exacerbated periodontitis; (iv) to establish the distribution of essentialgenes in multiple low-passage clinical P. gingivalis isolates; (v) to characterize the function of those genes confirmed to be requisitefor survival of tobacco-induced stress both in vitro and in vivo and (vi) to identify in silico essential gene orthologues in otherbacteria whose virulence is also enhanced in tobacco smokers. There are several potential translational benefits to a successful R01 which include a better understanding of how P.gingivalis thrives in a tobacco-toxin rich environment; future therapeutic targeting of essential genes to control P. gingivalis infectionin smokers; potential identification of novel vaccine targets for prevention or control of P. gingivalis infection; alternate treatmentregimens for smokers based on mechanistic insight into smoke-induced and/or exacerbated periodontal diseases; and theestablishment of an essential gene database for tobacco-enhanced pathogens that will facilitate the identification of commonbacterial strategies for surviving tobacco smoke exposure thus broadening the significance of the research beyond the oralcavity.

project_terms:
Adult;Anaerobic Bacteria;Bacteria;Bacterial Model;Biochemical;Biological Assay;Chronic;Cigarette;Clinical;Collection;Communicable Diseases;Complex;Computer Simulation;Crystallography;Data;Databases;Deposition;Developed Countries;Developing Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Ensure;Environment;Epidemiology;Essential Genes;Exhibits;Exposure to;Future;Gene Deletion;Generations;Genes;Genome;Growth;Homologous Gene;Immune;In Vitro;Individual;Infection;Inflammation;Investigation;Laboratories;Libraries;Lung diseases;Microbial Biofilms;Modeling;Monitor;Mus;Mutation;New Zealand;Nicotine;Oral;Oral cavity;Output;Pathogenicity;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Periodontium;Persons;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevalence;Prevention;Preventive;Process;Refractory;Research;Resistance;Scandinavia;Smoke;Smoker;Smoking;Stress;Structural Models;Techniques;Testing;Time;Tissues;Tobacco;Tobacco smoke;Tobacco smoking behavior;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;base;cigarette smoke;enzyme activity;exposure to cigarette smoke;fitness;in vivo;insight;microbial;mouse model;mutant;non-smoker;novel;novel vaccines;pathogen;periodontopathogen;prediction algorithm;screening;therapeutic target;whole genome

public_health_relevance:
PROJECT NARRATIVETobacco smoking is the leading environmental cause of chronic periodontal diseases. Many periodontal pathogens are highlyresistant to the plethora of toxic insults contained in cigarette smoke. One such important pathogen is Porphyromonas gingivalis.We will identify the P. gingivalis genes that are required for surviving smoke exposure; ensure in vivo relevance in a mouse modelof bacterial-induced periodontitis; and compare the presence or absence of confirmed essential genes in multiple strains of P.gingivalis as well as other oral and non-oral pathogens whose infectivity is known to be enhanced in tobacco smokers.


application_id: 9546508
project_number: 5K07CA181351-05
project_title: The Dynamics of Smoking Cessation After Cancer Diagnosis: A Naturalisitic Study
administering_ic: NCI
award_notice_date: 2018-08-03
opportunity_number: PAR-12-067
application_type: 5
activity_code: K07
ic: CA
serial_number: 181351
program_official: BIAN, YANSONG
project_start_date: 2014-09-01
project_end_date: 2020-08-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA L
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): The activities proposed in this NCI K07 application are designed to advance the career development of Dr. Jessica Burris whose long-term career goal is to sustain an independent innovative and meaningful clinical research program that focuses on tobacco use and cessation in cancer patients. Most clinicians view cancer diagnosis as a teachable moment and thus urge immediate smoking cessation after delivery of cancer diagnosis. However most quit attempts end in relapse and extant interventions for smoking cessation in cancer patients have limited success. A cancer diagnosis brings about many intra- and inter-personal changes (e.g. increase in emotional distress greater need for social support increase in saliency of personal risk) but there is very little understanding as to how such changes influence smoking cessation. With an eye toward intervention development the independent research proposed in this application will examine the naturalistic course of smoking cessation after cancer diagnosis as well as the dynamics that underlie changes in smoking behavior. Specific aims are 1) to describe key events in the process of smoking cessation and 2) to uncover cognitive and affective variables that promote or undermine the occurrence of a quit attempt lapse and relapse among newly diagnosed cancer patients. After a baseline assessment (N=120 head and neck cancer patients) participants will initiate a 30-day period of daily assessment via interactive voice response technology with a final assessment to occur three months after the baseline assessment. Biochemical verification of abstinence at the end of the 30-day daily IVR assessment and final assessment will be achieved through use of saliva cotinine samples. Statistical analysis will allow novel tests of how and to what extent day-to-day changes in cognitive and affective variables influence smoking cessation outcomes in newly diagnosed cancer patients. Innovation is achieved by: 1) a focus on the process of smoking cessation as opposed to the treatment of abstinence as a discrete outcome 2) equal attention given to cognitive and affective predictors of smoking cessation outcomes 3) use of mobile technology as the primary means of data collection among cancer patients and 4) proper application of longitudinal data analysis techniques to rich within-subjects data. A training plan that complements the independent research includes coursework seminars workshops mentored research journal clubs and conferences the combination of which will cover these topics: nicotine dependence; individual-level and public health approaches to tobacco control; longitudinal research design coordination and execution; advanced statistical techniques; research dissemination; grantsmanship; and ethical conduct of research. The strong support of an excellent team of mentors and the vast resources and outstanding scientific environment of the Medical University of South Carolina create an optimal training environment. Collectively the integrated research and training plan proposed in this NCI K07 application are an ideal mechanism to promote the career development of Dr. Burris.

project_terms:
Abstinence;Affective;Alcohol consumption;Attention;Behavior;Belief;Biochemical;Cancer Control;Cancer Model;Cancer Patient;Cancer Survivor;Clinical;Clinical Investigator;Clinical Research;Cognitive;Complement;Complex;Cotinine;Data;Data Analyses;Data Collection;Distress;Educational workshop;Electronic cigarette;Ensure;Environment;Ethics;Event;Eye;Future;Goals;Grain;Head and Neck Cancer;Health;High-Risk Cancer;Home environment;Hour;Individual;Intention;Intervention;Journals;Knowledge;Lead;Life;Measures;Medical;Mentors;Motivation;Nature;Newly Diagnosed;Nicotine Dependence;Outcome;Outcome Study;Participant;Perception;Play;Prevention;Process;Public Health;Recurrence;Relapse;Research;Research Design;Research Training;Resources;Risk;Risk Behaviors;Risk Factors;Role;Saliva;Sampling;Second Primary Cancers;Self Concept;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Social Environment;Social support;South Carolina;Statistical Data Interpretation;Survival Rate;Techniques;Technology;Testing;Time;Tobacco;Tobacco Use Cessation;Training;Universities;Voice;Withdrawal;Work;behavioral outcome;cancer complication;cancer diagnosis;cancer prevention;cancer recurrence;cancer therapy;career;career development;cigarette smoking;craving;design;emotional distress;head and neck cancer patient;innovation;longitudinal design;mobile computing;novel;programs;protective factors;psychologic;public health relevance;research data dissemination;response;skills;smoking cessation;smoking restriction;success;symposium;therapy development;tobacco cessation intervention;tobacco control;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:Cigarette smoking after head and neck cancer diagnosis can lead to a number of significant health problems including a high risk of cancer recurrence and second primary cancer. The goal of this research is to uncover the process of smoking cessation in newly diagnosed head and neck cancer patients and to identify the dynamics of cognitive and affective variables that underlie quit attempts lapses and relapses. The results will inform the design of more effective smoking cessation treatments which has clear implications for the prevention of future threats to the health of cancer patients.


application_id: 9546459
project_number: 5R01AG026307-12
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults
administering_ic: NIA
award_notice_date: 2018-04-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2022-03-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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:
SummaryThe typical older adult experiences declines in brain structure and cognitive function but these mean declinesoccur in the context of what can be very different individual trajectories. The purpose of this project is tomeasure individual differences and changes in self-regulation (control of thoughts emotions behaviors andimpulses) over time in older adults and to link self-regulation to physical activity inflammation and trajectoriesof neurocognitive health. This is a competing renewal of this longitudinal study which began in 2001 andreceived R01 funding in 2006 submitted by a research team with expertise in aging self-regulation exercisescience neuropsychology neuroimaging and longitudinal design and analysis. The previous renewal periodfocused on relationships among facets of self-regulation and their relationship to immunological andcardiovascular health. The renewal continues assessment of these measures to provide continuity in thislongitudinal dataset and adds innovation in the inclusion of repeated neuroimaging and assessment ofinfectious disease burden. Specifically the aims of the study are: (1) to test the effects of facets of self-regulation (conscientiousness self-regulation executive cognitive function and heart rate variability) onmeasures of neurocognitive health associated with aging and risk for neurological disease; (2) to test thedegree to which the relationship between self-regulation and neurocognitive health is mediated by physicalactivity and inflammation; (3) to test whether neurocognitive health associated with executive cognitivefunctions (e.g. dorsolateral frontal lobe volume) contributes to better self-regulation higher physical activityand lower inflammation; and (4) to test effects of infectious disease burden (latent viruses Toxoplasma gondii)on self-regulation inflammation and neurocognitive health. At 6-month intervals older adults (N = 175) willcomplete measures of self-reported self-regulation; executive cognitive functions including inhibition shiftingand working memory; and resting HRV. Physical activity BMI and waist circumference will be measured ateach visit. Blood draws will be synchronized with these visits and assays performed on these samples willcapture serum proinflammatory cytokines and antibodies against latent infections. The sample has follow-backdata on many of these measures from 1-15 years and an eligible subset (N = 90) will already have baselineneuroimaging. Neuroimaging will be repeated twice at 2-year intervals. This renewal will be innovative in itslongitudinal assessment of a dynamic system that includes brain behavior and immunity; integration ofneuroimaging measures with other domains of healthy and unhealthy aging; and multimodal assessment ofneurocognitive health including subjective cognitive health cognitive function volumetric imaging measuresconnectivity fractional anisotropy and resting cerebral blood flow.

project_terms:
Adult;Affect;Age;Aging;Alzheimer's disease risk;Anisotropy;Antibodies;Back;Behavior;Biological Assay;Blood;Brain;Cerebrovascular Circulation;Cognition;Cognitive;Communicable Diseases;Cytomegalovirus;Data;Dementia;Elderly;Emotions;Episodic memory;Exercise;Failure;Funding;Goals;Health;Hippocampus (Brain);Image;Immunity;Immunologic Factors;Impaired cognition;Individual;Individual Differences;Infection;Inflammation;Informal Social Control;Knowledge;Latent Virus;Link;Longevity;Longitudinal Studies;Longitudinal cohort;Maintenance;Measures;Mediating;Mental Health;Motivation;Neurocognitive;Neuropsychology;Outcome;Parasites;Pathway interactions;Patient Self-Report;Physical activity;Prefrontal Cortex;Psychological Factors;Psychoneuroimmunology;Research;Rest;Risk;Risk Factors;Role;Sampling;Science;Serum;Short-Term Memory;Structure;Testing;Time;Toxoplasma gondii;Virus Latency;Visit;brain behavior;brain health;burden of illness;cardiovascular health;cognitive function;cohort;cytokine;dynamic system;executive function;experience;frontal lobe;heart rate variability;immune health;inflammatory marker;innovation;interest;latent infection;longitudinal analysis;longitudinal dataset;longitudinal design;multimodality;nervous system disorder;neuroimaging;physical conditioning;prospective;success;thought control;waist circumference


application_id: 9546198
project_number: 2R01ES019217-06
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: ES
serial_number: 019217
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1 CVRS-C (02)]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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:
Acute;Adult;Adverse effects;Affect;Age;Air Pollution;Angiogenesis Inhibition;Animal Model;Antioxidants;Arrhythmia;Arteries;Atherosclerosis;Attenuated;Automobile Exhaust;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell physiology;Cells;Characteristics;Chronic;Clinical Trials;Coal;Defect;Development;Dipeptides;Double-Blind Method;Enrollment;Ethnic Origin;Event;Exposure to;Fossil Fuels;Functional disorder;Grant;Growth Factor;Guidelines;Health;Heart Arrest;Heart failure;Hematopoiesis;Human;Impairment;Individual;Industrialization;Inflammation;Inflammatory Response;Injury;Insulin Resistance;Intervention;Lead;Link;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Mus;Myocardial Infarction;Myocardial Ischemia;Organic Chemicals;Oxidative Stress;Participant;Particulate;Particulate Matter;Peripheral;Placebos;Population;Populations at Risk;Predisposing Factor;Predisposition;Reactive Oxygen Species;Reporting;Risk;Risk Factors;Smoke;Socioeconomic Status;Stem cells;Stroke;Testing;Therapeutic Intervention;Thrombosis;Toxic effect;Vascular Diseases;Wood material;Work;adverse outcome;ambient particle;arterial stiffness;atherogenesis;base;biological adaptation to stress;burden of illness;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;design;epidemiology study;experimental study;fine particles;indexing;mortality;novel;oral supplementation;pollutant;prevent;randomized trial;repaired;sex;sudden cardiac death


application_id: 9546132
project_number: 1R01HL139047-01A1
project_title: Remote Hind Limb Ischemia Mechanism of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2018-02-05
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 139047
suffix: A1
program_official: SCHWARTZ, LISA
project_start_date: 2018-07-01
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-R (02)]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Anti-inflammatory;Antioxidants;Apoptotic;Area;Attenuated;Biogenesis;Biological Assay;Bone Marrow Stem Cell;Bone Marrow Transplantation;Cardiac;Coronary heart disease;Cystathionine;DNA;Data;Diabetes Mellitus;Endocrine;Enzymes;Epigenetic Process;Event;Female;Fibrosis;Fluorescence;Functional disorder;Gases;Genes;Goals;Heart;Hematopoietic Stem Cell Mobilization;Hindlimb;Histology;Homocysteine;Hormones;Hydrogen Sulfide;Hyperhomocysteinemia;Hypermethylation;Incidence;Injury;Ischemia;Label;Limb structure;Lyase;Measures;Methylation;Mitochondria;Modification;Mouse Protein;Mus;Muscle;Muscle function;Muscular Atrophy;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;PPAR gamma;Plasma;Procedures;Production;Proteins;Recovery;Risk;Sampling;Site;Skeletal Muscle;Supplementation;Testing;cardioprotection;conditioning;diabetic;effective therapy;exosome;gene induction;glucose metabolism;improved;male;mitochondrial metabolism;myocardial damage;response


application_id: 9545778
project_number: 5R01ES028321-02
project_title: ROS and Nrf2 in arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2018-07-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028321
program_official: REINLIB, LESLIE J
project_start_date: 2017-09-01
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-P(04)]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Arsenic-induced cancers of lung skin liver and bladder pose serious health threats given the global extentof environmental arsenic contamination. Although the mechanism by which arsenic drives carcinogenesis isstill poorly understood increasing evidence implicates reactive oxygen species (ROS) in transformation ofcells to a malignant phenotype. NF-E2-related factor-2 (Nrf2) is a key transcription factor that regulatesantioxidant proteins to neutralize ROS and restore cellular redox balance. Indeed many natural compoundswith anticancer properties exhibit protective effects by activating Nrf2. Conversely constitutive activation ofNrf2 which is prominent in several types of human cancer cell lines and tumors is known to be oncogenic asit protects cancer cells against oxidative stress and chemotherapeutics. Our preliminary studies have shownthat human lung bronchial epithelial (BEAS-2B) cells exposed to arsenic generate ROS leading to malignantcell transformation and a cascade of subsequent effects: sharply reduced level of ROS; increased levels ofantioxidants; constitutive activation of Nrf2; and resistance to apoptosis. These arsenic-transformed cells alsoexhibit autophagy impairment leading to accumulation of p62 protein and constitutive activation of Nrf2 highlevels of inflammatory agents COX-2 and TNF- and activation of transcription factor hypoxia-inducible factor(HIF)-1. Animals exposed to arsenic through drinking water showed both activated HIF-1 and Nrf2.Knockdown of Nrf2 down-regulates HIF-1 resulting in decreased angiogenesis of arsenic-transformed cells.The central hypothesis is that inducible Nrf2 is anti-oncogenic at the early stage of arsenic-inducedcarcinogenesis (cell transformation) via up-regulation of antioxidants to decrease ROS while constitutivelyexpressed Nrf2 is oncogenic in the later stages (tumorigenesis and metastasis) by inducing resistance toapoptosis creating an inflammatory microenvironment and activating angiogenesis. Aim 1 will elucidate aprotective role of inducible Nrf2 in arsenic-induced malignant cell transformation decrease of ROS by Nrf2induction of Nrf2 target antioxidant proteins by arsenic and protective role of Nrf2 in arsenic-induced oxidativedamage. Aim 2 will establish the oncogenic role of constitutively activated Nrf2 in development of resistance toapoptosis of arsenic-transformed cells. The study will determine whether p62 is a positive inducer of Nrf2establish a mechanism for Bcl-2 up-regulation and elucidate the roles of decreased ROS generation and Bcl-2up-regulation in apoptosis resistance. Aim 3 will establish the oncogenic role of constitutive Nrf2 intumorigenesis and metastasis of arsenic-transformed cells in vivo by deciphering the role of p62/Nrf2 increating an inflammatory microenvironment by studying activation of NF-B and expressions of COX-2 andTNF- in arsenic-transformed cells. The roles of p62 Nrf2 inflammatory proteins angiogenesis and apoptosisresistance in arsenic-induced tumorigenesis and metastasis will be investigated using animal models.

project_terms:
Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;Arsenic;Autophagocytosis;BCL2 gene;Biological;Bladder;Cancer cell line;Carcinogens;Cells;Curcumin;Data;Development;Environmental Exposure;Environmental Health;Epithelial;Equilibrium;Exhibits;Exposure to;GTF2H1 gene;Generations;Health;Human;Hypoxia Inducible Factor;Impairment;Individual;Inflammation;Inflammatory;Link;Liver;Lung;Malignant - descriptor;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;NF-E2-related factor 2;Nature;Neoplasm Metastasis;Normal Cell;Oncogenic;Oxidation-Reduction;Oxidative Stress;PTGS2 gene;Phenethyl Isothiocyanate;Premalignant;Privatization;Property;Proteins;Public Health;Publishing;Reactive Oxygen Species;Reporting;Resistance;Resistance development;Resveratrol;Role;Skin;Skin Cancer;Stress;Sulforaphane;TNF gene;Time;Transcriptional Activation;United States;Up-Regulation;Water;angiogenesis;anti-cancer;antioxidant enzyme;arsenic carcinogenesis;arsenic-induced carcinogenesis;cancer cell;carcinogenesis;cell transformation;chemotherapeutic agent;drinking water;epidemiology study;exposed human population;in vivo;inflammatory milieu;knock-down;malignant phenotype;malignant state;oxidative damage;protective effect;protein activation;transcription factor;tumor;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE Human environmental exposure to arsenic a Group 1 carcinogen is a world-wide public healthconcern. This proposal investigates the dual roles of Nrf2 in arsenic-induced carcinogenesis. Whileinduction of Nrf2 protects against arsenic-induced cell transformation by activating target antioxidantsagainst reactive oxygen species (ROS) in the early stage of carcinogenesis in the later stage(tumorigenesis and metastasis) constitutive activation of Nrf2 is oncogenic by causing apoptosis resistancein arsenic-transformed cells by creating an inflammatory environment and by activating angiogenesis.


application_id: 9545432
project_number: 2R01AG019223-12A1
project_title: Ceramide and acute phase proteins elevation during aging
administering_ic: NIA
award_notice_date: 2018-06-19
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: AG
serial_number: 019223
suffix: A1
program_official: GUO, MAX
project_start_date: 2002-08-01
project_end_date: 2023-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute-Phase Proteins;Adverse effects;Affinity;Aging;Aging-Related Process;Agonist;Alzheimer's Disease;Animals;Asses;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Play;Population;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;stressor;transcription factor;transcriptome sequencing


application_id: 9544724
project_number: 5P01HD071875-05
project_title: Administrative Core
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D
subproject_number: 7822
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The Administrative Core is the operational center behind the entire P01 program. The Core will facilitate the research goals of the program by:  * providing the organizational and administrative structure that insures maximally efficient use of resources among all investigators * providing a centralized location for the tracking of expenditures and compilation of budgets * insuring optimal dissemination of information among all investigators * overseeing usage of the Tissue Repository Core to insure efficient distribution of human  macaque and rat tissues to all investigators * directing usage of the Tissue Repository Core so that minimal numbers of animals are  utilized * funding new pilot projects in promising areas of research that complement the existing  P01 projects while also opening additional avenues of research collaboration or expertise arranging and coordinating the annual scientific retreat for the P01 program investigators * assisting with the preparation and submission of manuscripts reporting P01 program scientific advances and also providing for page charges to support publication of these manuscripts * interacting with NICHD and the Office of Sponsored Projects Administration at the University of Kentucky to ensure compliance with all federal regulations * insuring that each scientific project maintains regulatory compliance by coordinating and accounting for all aspects of personnel training protocol submission approval revision and continuing review (IACUC recombinant DNA biohazardous materials)

project_terms:
Accounting;Advisory Committees;Animals;Area;Budgets;Charge;Collaborations;Complement;Ensure;Expenditure;Faculty;Funding;Goals;Human;Human Resources;IACUC;Individual;Information Dissemination;Information Distribution;Institutional Review Boards;Instruction;Kentucky;Laboratories;Letters;Location;Macaca;Manuscripts;Monitor;Monkeys;National Institute of Child Health and Human Development;Organization administrative structures;Ovulation;Pilot Projects;Preparation;Program Research Project Grants;Protocols documentation;Publications;Rattus;Recombinant DNA;Regulation;Reporting;Research;Research Personnel;Resources;Retreatment;Rodent;Scientific Advances and Accomplishments;Secondary to;Services;Structure;Tissues;Training;Universities;Visit;Woman;Work;meetings;member;operation;programs;repository;success;synergism;web page

public_health_relevance:
RELEVANCE (See instructions): The Administrative core is responsible for carefully and closely monitoring the entire operation of the P01 program which is a multi-institutional program with 6 investigators at 3 different Universities. This core is the "command central" that deals with the day to day problems as well as insures that the long term research goals of the program are achieved.


application_id: 9544723
project_number: 5P01HD071875-05
project_title: CIPAR1 A Novel Modulator of Progesterone Accumulation in Periovulatory Follicle
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D
subproject_number: 7820
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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: 2018-07-01
project_abstract:
PROJECT SUMMARY (See instructions): In response to the preovulatory LH surge the preovulatory follicle rapidly increases progesterone production which is essential for ovulation and/or corpus luteum formation. Although this rise in progesterone level has been mainly linked to a few LH-induced genes involved in steroidogenesis (e.g. StAR Cypi 1 a l  and HSD3b) but there are many gaps in our understanding of periovulatory accumulation of progesterone. In this proposal we put forward a novel protein CIPAR1 (castration-induced prostatic apoptosis-related protein 1) as a vital mediator of progesterone accumulation in the periovulatory follicle. We have recently demonstrated the LH surge increases the expression of Ciparl in periovulatory follicles of rodent ovaries. More importantly our preliminary study using granulosa cell cultures showed that knockdown of Ciparl expression resulted in significant reduction of progesterone levels. Based on these novel findings we hypothesize that induction of CIPAR1 by the LH surge is crucial for progesterone accumulation in periovulatory follicles thus ovulation and luteinization. In specific Aim#1 we will demonstrate that the alteration of Ciparl expression by silencing or over-expression affects progesterone production in rat periovulatory follicles using both in vivo and in vitro models. As the first approach to pinpoint the functional contribution of C1PAR1 in periovulatory follicles we will identify the genes and proteins that are differentially expressed when Ciparl expression is silenced or over-expressed in periovulatory follicles. Because littie is known about cellular function of CIPAR1 Specific Aim #2 focuses on first determining the cellular location of CIPAR1 in periovulatory granulosa cells using confocal co-localization and/or subcellular fractionated protein analyses and then identifying CIPAR1 interacting proteins in periovulatory granulosa cells using immunoprecipitation followed by a proteomic approach. Other than our preliminary data detecting Ciparl expression in human granulosa cells nothing is known about CIPAR1 in human tissues. In collaboration with Drs. Brannstrum and Duffy specific Aim #3 will determine whether Ciparl expression is hormonally regulated during the periovulatory period and critical for LH-induced progesterone production in humans and/or macaques. Data obtain from the proposed studies will unravel the role of C1PAR1 as a novel and critical mediator of progesterone accumulation in periovulatory follicles of primates as well as rodents.

project_terms:
Affect;Antibodies;Apoptosis;Castration;Cell Culture Techniques;Cell Differentiation process;Cell physiology;Cells;Collaborations;Cytoprotection;Data;Development;Enzymes;Experimental Models;Female;Future;Gene Proteins;Genes;Goals;Gonadotropins;Hormonal;Hormones;Human;Immunoprecipitation;In Vitro;Instruction;Link;Location;Luteinization;Macaca;Mediator of activation protein;Molecular;Monkeys;Ovary;Ovulation;Physiological;Play;Primates;Production;Progesterone;Prostaglandins;Prostate;Prostatic;Protein Analysis;Proteins;Proteomics;Rattus;Reproduction;Rodent;Role;Steroid biosynthesis;Testing;Tissues;Woman;base;corpus luteum;differential expression;experimental study;female fertility;granulosa cell;hormone regulation;human tissue;improved;in vitro Model;in vivo;knock-down;novel;overexpression;response

public_health_relevance:
RELEVANCE (See instructions): Progesterone plays a vital role in many aspects of reproduction including ovulation and corpus function therefore female fertility. Identifying the cellular function of CIPAR1 will improve our understanding of mechanisms controlling progesterone production and may suggest a novel target for managing female fertility.


application_id: 9544722
project_number: 5P01HD071875-05
project_title: Mechanism of Periovulatory Leukocyte Infiltration into the Ovary
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D
subproject_number: 7819
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
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: 2018-07-01
project_abstract:
PROJECT SUMMARY (See instructions): Crosstalk between the immune and reproductive systems dramatically impacts fertility. In particular studies have shown that a tight spatiotemporal control of leukocyte infiltration into the ovary is pivotal for successful ovulation. Once infiltrated the leukocytes differentiate into a cohort of pro- or anti-infiammatory cells in the preovulatory ovary and play critical roles in ovulation and luteal formation. In this study we will test the hypothesis that progesterone (P4) and prostaglandins (PG) play pivotal roles in recruiting leukocytes into the preovulatory ovary. Aim 1. To determine the mechanism(s) by which P4 and PG regulate WBC infiltration. We will first determine the roles of P4 and PG on WBC infiltration by treating cycling adult rats with RU486 indomethacin and vehicle and measuring the effect on the numbers populations and localization of infiltrating WBC by flow cytometry and immunohistochemistry together with a functional analysis of the expression of chemokines cytokines their receptors and cell adhesion molecules (CAMs) in serum on ovarian cells and WBC by ELISA and qPCR. Aim 2. To determine whether P4 and PG regulate WBC infiltration in primate ovary. In this Aim we will investigate P4 and PG regulated WBC infiltration in primates. Similar to rodents primates including humans also require P4 and PG for normal ovulation. Therefore we hypothesize that P4 and PG will regulate WBC infiltration in the primate ovary. The actions of P4 and PG will be inhibited by treating primates (Cynomolgous monkeys) with trilostane (3|3HSD inhibitor; inhibits progesterone synthesis) celecoxib (selective COX-2 inhibitor) or vehicle under ovarian stimulation. The effects on the numbers populations and localization of WBC together with the expression of infiammatory mediators will be determined. Upon the identification of the P4- and PG-regulated WBC subtypes and infiammatory mediators in the monkey the localization and expression patterns of their homologs will be determined in the human ovary. Aim 3. To determine the regulatory mechanism of preovulatory splenic WBC release. We will identify the trigger(s) and the mechanism of action of splenic WBC release from spleen. We hypothesize that either LH decreased concentration of circulating WBC or angiotensin-ll (the only known trigger of splenic leukocyte release) act as the trigger. To identify the trigger(s) ovariectomized rats will be treated with candidate triggers (LH and angiotensin-ll) or artificially reduce the concentration of circulating WBC by perfusing rats with plasma. The effects on splenic WBC release will be measured by counting WBC numbers in spleen and peripheral blood.

project_terms:
Adhesions;Adult;Affect;Age;Angiotensins;Animals;Anovulation;Biological Assay;Biological Process;Blood Circulation;Cell Adhesion Molecules;Cells;Chronic;Clinical Treatment;Cytokine Receptors;Cytometry;Data;Defect;Diagnosis;Disease;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Failure;Female;Fertility;Flow Cytometry;Human;Immune system;Immunohistochemistry;In Vitro;Indomethacin;Infiltration;Inflammation;Inflammation Mediators;Instruction;Knockout Mice;Leukocyte Trafficking;Leukocytes;Measures;Mediator of activation protein;Mifepristone;Migration Assay;Monitor;Monkeys;Ovarian;Ovarian Stimulations;Ovary;Ovulation;PTGS2 gene;Pathway interactions;Pattern;Plasma;Play;Population;Primates;Procedures;Progesterone;Prostaglandins;Rattus;Receptor Cell;Reproductive system;Rodent;Role;Serum;Signal Pathway;Spleen;Testing;Woman;celecoxib;chemokine;cohort;cytokine;inhibitor/antagonist;nonhuman primate;novel;novel strategies;peripheral blood;receptor;recruit;reproductive;spatiotemporal

public_health_relevance:
RELEVANCE (See instructions): Chronic anovulation affects up to 15% of the female US population many of the causes not being accounted for. This study will identify a novel cause of anovulation resulting from defective ovarian inflammation which will lead to develop a better treatment option for an ovulatory disorder.


application_id: 9544721
project_number: 5P01HD071875-05
project_title: Angiogenesis in the Primate Ovulatory Follicle
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D
subproject_number: 7818
contact_pi_person_id: 1919355
contact_pi: DUFFY, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone (LH) surge stimulates periovulatory follicles to produce prostaglandin E2 (PGE2). Blockade of PGE2 production causes ovulation failure. LH-stimulated neovascularization of the follicle is also essential for ovulation as inhibition of follicular angiogenesis prevents ovulation. This proposal puts for the overall hypothesis that PGE2 mediates the ability of the ovulatory LH surge to regulate angiogenesis within the ovulatory follicle. Angiogenesis is regulated via vascular growth factors. In Aim 1 we will determine if LH acts at follicular granulosa cells to regulate production of vascular growth factors in a PGE2-dependent manner. Monkey ovaries with multiple follicles will be obtained before and after administration of an ovulatory dose of the LH-like hormone hCG; some monkeys will also receive concomitant administration of a prostaglandin (PG) synthesis inhibitor. Granulosa cells follicular fluid and whole ovaries will be assessed for vascular growth factor mRNAs by qPCR and proteins by western blotting ELISA and immunofiuorescent detection on tissue sections. In vitro studies will be performed to determine if PGE2 acts directiy at granulosa cells to regulate vascular growth factor mRNA and proteins. Vascular growth factors act at endothelial cells to promote the formation of new blood vessels. In Aim 2 we will determine if PGE2 and vascular growth factors act at endothelial cells of the follicle to stimulate angiogenesis. Using a novel proliferating population of monkey ovarian endothelial cells we will determine if PGE2 stimulates endothelial cell proliferation migration and formation of new capillaries. Similarly vascular growth factors produced by granulosa cells granulosa cell-conditioned media and coculture with granulosa cells will be used to determine if vascular growth factors stimulate endothelial cell functions necessary for angiogenesis. Finally monkey ovaries obtained after treatment in vivo with hCG hCG+PG synthesis inhibitor or hCG+PG synthesis inhibitor+PGE2 will be assessed histologically for neovascularization of the ovulatory follicle. The proposed studies will likely demonstrate that PGE2 and vascular growth factors act directly at endothelial cells to promote the neovascularization of the primate ovulatory follicle. Modulation of follicular PGE2 levels or PGE2 receptor activity may provide effective treatments for infertility or suggest targets for the development of novel contraceptives.

project_terms:
Aftercare;Antibodies;Area;Biopsy;Blood Vessels;Blood capillaries;Cell Count;Cell Proliferation;Cell physiology;Cells;Coculture Techniques;Contraceptive Agents;Data;Detection;Development;Diagnosis;Dinoprostone;Dose;Endothelial Cells;Endothelial Growth Factors Receptor;Enzyme-Linked Immunosorbent Assay;Exposure to;Failure;Fertility;Follicular Fluid;Gonadotropins;Growth Factor;Histologic;Hormones;Human Chorionic Gonadotropin;In Vitro;Infertility;Instruction;Laboratories;Lead;Luteinization;Luteinizing Hormone;Macaca;Mediating;Mediator of activation protein;Messenger RNA;Monkeys;Ovarian;Ovarian Follicle;Ovarian Hyperstimulation Syndrome;Ovary;Ovulation;Population;Pregnancy;Primates;Production;Proliferating;Prostaglandin Antagonists;Prostaglandin Inhibition;Prostaglandins;Proteins;Reproduction;Rodent;Structure;Testing;Time;Tissues;Vascular Endothelial Growth Factors;Western Blotting;Woman;angiogenesis;effective therapy;experimental study;granulosa cell;human model;in vivo;infertility treatment;inhibitor/antagonist;migration;neovascularization;novel;prevent;receptor;response

public_health_relevance:
RELEVANCE (See instructions): Formation of new blood vessels In the ovarian follicle is essential for ovulation and therefore fertility. Understanding how prostaglandins regulate angiogenesis in the ovarian follicle may identify new treatments for infertility or suggest targets for the development of novel contraceptives.


application_id: 9544720
project_number: 5P01HD071875-05
project_title: EMMPRIN: A Regulator of Angiogenesis and Leukocyte Trafficking During Ovulation
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D
subproject_number: 7817
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The preovulatory LH surge stimulates an increase in ovarian extracellular matrix metalloproteinase inducer (EMMPRIN) which is known as a classic regulator o fthe matrix metalloproteinases (MMPs). The paramount role of EMMPRIN in ovulation is evident from experiments in mice lacking EMMPRIN that display a decrease in oocyte release and fertilization. Yet other than our preliminary data nothing is known as to temporal expression patterns the regulation and potential function of EMMPRIN in the ovulatory process in the human. This question will be addressed in the proposed POI program through a collaborative approach utilizing the exceptional backgrounds technical expertise and models ofthe PIs. We will make use of a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG (early late and postovulatory). The expression patterns of EMMPRIN in the human will be illuminated in Aim #1. Specific Aim #2 will build upon these findings to elucidate the role of EMMPRIN in ovarian angiogenesis in the human macaque and rat. The ability of EMMPRIN to stimulate proliferation migration and spouting of new vessels will be determined. To further characterize EMMPRIN's action. Specific Aim #3 will investigate the role of EMMPRIN in immune cell trafficking' Specifically studies will explore the impact of EMMPRIN on leukocyte expression of the MMP system and EMMPRIN's ability to regulate the invasive capacity of leukocytes. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the expression and function of EMMPRIN in the process of human ovulation which has never been accomplished. Another major strength of this proposal is the collaborative interactions between different investigators to address the function of EMMPRIN in periovulatory events across multiple species. As such the proposed studies are extremely timely to elucidate the role that this exquisite proteolytic system plays in the coordinated processes of follicular rupture and oocyte release which are key aspects of normal human ovarian physiology.

project_terms:
Address;Blood Vessels;Cells;Data;Defect;Dinoprostone;EGF gene;Endothelial Cells;Event;Expression Profiling;Extracellular Matrix;Fertilization;Foundations;Gene Expression Profile;Genes;Glycoproteins;Human;Human Chorionic Gonadotropin;Immune;In Vitro;Infertility;Inflammatory;Instruction;Leukocyte Chemotaxis;Leukocyte Trafficking;Leukocytes;Macaca;Matrix Metalloproteinases;Mediator of activation protein;Modeling;Monkeys;Motion;Mus;Oocytes;Ovarian;Ovarian Tissue;Ovary;Ovulation;Pattern;Peptide Hydrolases;Physiology;Play;Primates;Process;Production;Progesterone;Prostaglandins;Rattus;Regulation;Reporting;Research Personnel;Rodent;Rodent Model;Role;Rupture;Signal Pathway;Stimulus;System;Technical Expertise;Time;Tissue Model;Tissues;Vascular Endothelial Growth Factors;Woman;angiogenesis;collaborative approach;experimental study;granulosa cell;human tissue;implantation;in vitro Model;in vivo;migration;neoplastic cell;neovascularization;novel;programs;reproductive function;trafficking;tumor

public_health_relevance:
The proposed studies will use human tissues collected at carefully defined times prior to and immediately after ovulation to investigate the changes in gene expression patterns that may impact oocyte release. The changes in these genes and their regulation will be studied using both human tissues and rodent models to mimic the human. These studies will expand our understanding of ovulation in the human.


application_id: 9544719
project_number: 5P01HD071875-05
project_title: Ovulation and Luteal Formation in Rodents Monkeys and Women
administering_ic: NICHD
award_notice_date: 2018-07-04
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
program_official: TAYMANS, SUSAN
project_start_date: 2014-09-19
project_end_date: 2021-06-30
study_section: ZHD1-DRG-D(41)
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The unifying theme of this P01 proposal is to investigate one of the cornerstones of female fertility ovulation. Through this P01 project we will address key questions of the mechanisms associated with follicular rupture and the subsequent early changes in the postovulatory follicle. This will be accomplished through the scientific integration both experimentally and technically of 4 separate projects involving 5 investigators that will utilize ovarian tissues from women macaques and rodents. Project 1 (Curry/Brannstrom) will make use of an extremely novel model where human follicles are collected across the periovulatory period to examine the changes in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN). Project #2 (Duffy) will take advantage of Dr. Duffy's extensive experience with macaques to investigate the role of PGE2 in angiogenesis of the nonhuman primate periovulatory follicle. Project #3 (Ko) will study the mechanisms by which progesterone regulates leukocyte infiltration in the preovulatory ovary. Project #4 (Jo) will elucidate the cellular action of CIPAR1 in regulating the LH mediated induction of progesterone production. Translational interactions across the projects are readily evident as tissues from women (Project #1) and macaques (Project #2) will be available to extrapolate to rodent models (Projects 1 3 4). An Administrative core provides support for the research teams by overseeing the overall functioning of the program as well as coordinating shared tissues from women macaques and rodents across the different projects. A pilot project will also be supported to open additional avenues of research collaboration and expertise. The significance of this proposal lies in its truly unique translational potential to further our understanding of the pathways that are critical for ovulation and early luteal formation in the human. There can be no stronger translational potential than to use human follicles collected at defined times after hCG to truly comprehend the mechanisms of ovulation and luteinization. The proposed studies in both the human and macaque will make significant strides towards advancing our understanding and treatment of ovulatory associated infertility as well as providing therapeutic modalities to manipulate the ovulatory process in the human thereby providing an important relevance to human health.

project_terms:
Address;Collaborations;Contraceptive methods;Critical Pathways;Dinoprostone;Extracellular Matrix;Health;Human;Human Chorionic Gonadotropin;Infertility;Infiltration;Leukocytes;Luteinization;Macaca;Matrix Metalloproteinases;Mediating;Methods;Modality;Modeling;Monkeys;Oocytes;Ovarian Tissue;Ovary;Ovulation;Pilot Projects;Process;Production;Progesterone;Research;Research Personnel;Research Support;Rodent;Rodent Model;Role;Rupture;Therapeutic;Time;Tissues;Woman;angiogenesis;experience;female fertility;human model;nonhuman primate;novel;programs

public_health_relevance:
RELEVANCE: The proposed studies will examine the process of oocyte release using unique models and tissues from women monkeys and rodents. This will be accomplished by the integration of 4 synergistic and interactive research programs that will together provide a broader more comprehensive picture of the interrelated mechanisms of ovulation and luteal formation. This information can be used to treat infertility or conversely to explore novel methods of contraception.


application_id: 9544331
project_number: 5R34MH111783-02
project_title: Validation of an Implementation Strategy of COMPASS for School Trainers of Children with Autism
administering_ic: NIMH
award_notice_date: 2018-05-23
opportunity_number: RFA-MH-16-410
application_type: 5
activity_code: R34
ic: MH
serial_number: 111783
program_official: PINTELLO, DENISE
project_start_date: 2017-08-15
project_end_date: 2020-05-31
study_section: ZMH1-ERB-K(03)
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractWe seek to conduct a pilot effectiveness trial within an implementation trial for improving educational outcomesof children with autism spectrum disorder (ASD). Modeled after a Hybrid Trial Type 2 design [1] our study aimsto (a) to create a valid and locally adapted implementation training strategy leveraging the mechanismsunderlying the intervention effects and delivered in priority educational settings located in urban andunderserved rural contexts while also (b) considering implementation and maintenance factors impactingtraining sensitivity to mechanisms and adoption/uptake of COMPASS. The study addresses a significantresearch-to-practice gap that less than 10% of educational strategies for children with ASD are based onevidence [2 3]. Importantly consultation methods have a multiplier effect in the efficient and broaddissemination of best practices. This proposal responds to recommendations from the Interagency AutismCoordinating Committee for studies that utilize implementation science to test methods to improveimplementation of evidence-based treatments (p.41) and develop and evaluate quality measures to helpmonitor progress in improving care and outcomes for people with ASD (p.41) [4]. Our approach aligns withrecommendations from the Institute of Medicine framework for establishing evidence based standards [5] andthe goals of this RFA for effectiveness research on therapeutic interventions with previously demonstratedefficacy for use in community settings. The proposed study builds on two completed NIH funded randomizedcontrolled studies (RCTs) [6 7] a recently published treatment manual [8] and a monograph-length scientificreview [9]. The RCTs provided strong support for the efficacy of consulting delivered by the research team toassist public school special educators and parents via face-to-face interactions and through videoconferencingtechnology [10]. High quality ecological assessments research-informed goal development and guideddecision-making for individualizing evidence-based interventions for children with ASD are accomplished usingthe consultation intervention the Collaborative Model for Promoting Competence and Success (COMPASS)[8]. COMPASS consists of an initial parent-teacher session (3 hours) occurring near the start of the schoolyear followed by four 1-hour teacher coaching sessions evenly spaced through the rest of the school year.COMPASS assists in creating (1) individualized educationally appropriate well-constructed psychometrically-sensitive goals and (2) effective educational plans to meet the goals. Goals and teaching plans take intoaccount the personalized context within which the evidence based interventions will be delivered. Theobjectives of the current proposal are to evaluate the effectiveness of training local consultants/trainersincluding how well the training engages the mechanisms of change (e.g. fidelity) that have been identified andreplicated in two RCTs [67]. The long-term goal is to improve the quality of services and overall functional andsocial outcomes of children with ASD when COMPASS is delivered by practitioners. Our aims are framed withthe Replicating Effective Programs (REP) [11] Framework for implementation in community settings.

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

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


application_id: 9544205
project_number: 5R01DK112282-03
project_title: The activation of brown and beige fat and role in insulin sensitivity
administering_ic: NIDDK
award_notice_date: 2018-08-17
opportunity_number: RFA-DK-15-031
application_type: 5
activity_code: R01
ic: DK
serial_number: 112282
program_official: LAUGHLIN, MAREN R
project_start_date: 2016-09-15
project_end_date: 2021-08-31
study_section: ZDK1-GRB-7(O2)S
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
There has been much interest in exploiting brown adipose tissue (BAT) and beige adiposetissue for the treatment of obesity and related complications. Although brown and beigeadipocytes are derived from different precursors and display unique patterns of gene expressionmarkers both cells have increased mitochondrial content and express UCP1 which uncouplesoxidative respiration to generate heat. In addition both brown and beige adipocytes requirePPAR for their development and both cell types are induced through the -adrenergic receptor(AR)/PKA pathway. BAT and beige fat are activated through the sympathetic nervous systemor by the use of AR agonist drugs. Adipose tissue contains 3AR and there have beenattempts to treat obesity with 3 agonists. Currently mirabegron (Myrbetriq Astellas) is ahighly specific 3 agonist marketed for overactive bladder with minimal side effects at therecommended dose. In addition the diabetes drug pioglitazone is a PPAR agonist whichreduces inflammation and improves insulin sensitivity. We hypothesize that the combination ofpioglitazone and mirabegron will be more effective than either drug alone at activating both BATand beige adipose tissue and in improving insulin sensitivity. We hypothesize that themechanism of this improvement in insulin sensitivity will result from an increased partitioning oflipid into oxidative pathways improved metabolic flexibility and decreased adiposeinflammation.Hypothesis 1. Chronic treatment of insulin resistant subjects with a 3 agonist will result inincreased mass and activity of BAT and beige adipose tissue along with increased restingmetabolic rate.Hypothesis 2. The combined treatment with both a TZD (PPAR agonist) and a 3 agonist willresult in an additional stimulation of BAT and beige adipose mass and activity.Hypothesis 3. The activation of BAT and beige adipose tissue will be associated with reducedskeletal muscle lipotoxicity and improvements in adipose tissue inflammation.Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and 3agonists will result in a greater improvement in insulin sensitivity than by monotherapy alone.These studies are important because the repurposing of these common drugs couldsynergistically improve many of the metabolic dysfunctions in obese individuals.

project_terms:
Adipocytes;Adipose tissue;Adverse effects;Agonist;Basal metabolic rate;Biogenesis;Brown Fat;CREB1 gene;Cells;Chronic;Combined Modality Therapy;Cyclic AMP-Dependent Protein Kinases;Development;Diabetes Mellitus;Dose;Energy Metabolism;Fatty acid glycerol esters;Gene Expression Profile;Genetic Transcription;Heart Diseases;Human;Individual;Inflammation;Insulin Resistance;Lead;Link;Lipids;Lipolysis;Mammals;Metabolic;Metabolic dysfunction;Metabolism;Mitochondria;Mus;Obesity;Overactive Bladder;Oxidative Phosphorylation;PET/CT scan;PPAR gamma;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Pioglitazone;Respiration;Role;Skeletal Muscle;Sympathetic Nervous System;Thermogenesis;Tissues;beta-adrenergic receptor;cell type;flexibility;improved;insulin sensitivity;interest;natural hypothermia;obesity treatment;prevent;therapeutic target;transcription factor;transdifferentiation;uncoupling protein 1

public_health_relevance:
Obesity is closely linked with insulin resistance diabetes and heart disease. Brown and beigeadipose tissue can increase energy expenditure and help prevent obesity complications. Thisproposal examines two common drugs which may synergistically increase brown/beige fatwhich could lead to improvement the metabolic dysfunction in adipose tissue and improveinsulin sensitivity.


application_id: 9544184
project_number: 5UG3DA044798-02
project_title: Kentucky Communities and Researchers Engaging to Halt the Opioid Epidemic (CARE2HOPE)
administering_ic: NIDA
award_notice_date: 2018-08-08
opportunity_number: RFA-DA-17-014
application_type: 5
activity_code: UG3
ic: DA
serial_number: 044798
program_official: LEE-WINN, ANGELA EUNJI
project_start_date: 2017-08-15
project_end_date: 2019-07-31
study_section: ZDA1-HXO-H(18)R
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Appalachian Region;Area;Behavioral;Caring;Centers for Disease Control and Prevention (U.S.);Cities;Coal;Collaborations;Communities;Community Trial;Country;County;Disease Outbreaks;Drug usage;Effectiveness;Elements;Ensure;Environment;Epidemic;Epidemiologic Methods;Epidemiology;Evidence based intervention;General Population;HIV;HIV/HCV;Harm Reduction;Health;Health Services;Hepatitis C virus;Heroin;Incidence;Injecting drug user;Injections;Intervention;Kentucky;Knowledge;Laws;Letters;Methods;Modeling;Naloxone;National Institute of Drug Abuse;Needle-Exchange Programs;Outcome;Overdose;Pathway Analysis;Pharmaceutical Preparations;Phylogenetic Analysis;Plant Roots;Policies;Prescription opioid overdose;Provider;Public Health;Qualitative Research;Readiness;Research Infrastructure;Research Personnel;Resources;Risk;Risk Assessment;Rivers;Rural;Services;Site;Substance Use Disorder;Testing;United States Substance Abuse and Mental Health Services Administration;Work;base;combat;community based participatory research;cost effectiveness;data exchange;design;evidence base;implementation science;improved;infectious disease treatment;injection drug use;innovation;mathematical model;member;opioid epidemic;opioid injection;prescription opioid;randomized trial;response;rural counties;sex;social stigma;theories;virtual


application_id: 9543818
project_number: 5U48DP005014-05
project_title: Prevention Research Centers
administering_ic: NCCDPHP
award_notice_date: 2018-08-31
opportunity_number: RFA-DP-14-001
application_type: 5
activity_code: U48
ic: DP
serial_number: 005014
project_start_date: 2014-09-30
project_end_date: 2019-09-29
study_section: ZDP1-EEO(01)
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-30
project_abstract:
DESCRIPTION (provided by applicant): This renewal application proposes to continue the cancer prevention programs of the University of Kentucky PRC the only PRC dedicated to cancer prevention in rural Appalachia. Known locally as the Rural Cancer Prevention Center (RCPC) our past focus has been on the prevention (through vaccination) and early detection of cervical cancer. Through social marketing and planned outreach the RCPC has successfully leveraged the trust of rural people residing in the most economically depressed area of Appalachia (southeastern KY). The proposed renewal offers plans to continue our community-based cancer prevention research and to extend our programs to other regions of Appalachia using sustainable models. Moreover the previous research pertaining to cervical cancer prevention created a strong basis for testing a novel approach to community-based screening for colorectal cancer (CRC). Based on new screening technology this approach will be effective and accessible to medically disenfranchised and under-served rural residents. The proposed plan has 5 general aims (A-E) and a specific research aim (F): A) Provide infrastructure and administrative services that support cancer prevention; B) Build community capacity and actively engage the community in partnerships for cancer prevention; C) Provide an efficient and effective communications network that ties cancer prevention activities together and disseminates health communication; D) Offer training and technical support to state and local agencies; E) Evaluate (process and outcome) all planned activities related to aims A-D; and F) Conduct an applied prevention research project that demonstrates the value of using community change agents to foster widespread adoption of annual colorectal cancer (CRC) screening with Fecal Immunochemical Test (FIT) followed by navigation to colonoscopy for those screening FIT-positive and by an intervention program that promote annual repeat use of FIT. All six aims are inter-related; however the final aim is a highly focused set of activities that occur in two phases: 1) the programs supporting this aim will be tested in Years 1-3 and 2) to benefit other rural Appalachian states dissemination and implementation activities will be conducted in Years 4-5. Programs to be tested in Years 1-3 include 1) a community-based intervention featuring a Diffusion of Innovations model standard RCPC outreach methods and academic detailing for health care providers tested using a non-equivalent comparison design; this trial will end when 500 FIT specimens have been returned in the intervention health district 2) a social network analysis (N = 64) used to provide interim feedback regarding key characteristics of effective change agents used in the diffusion model 3) a navigation program (based on current RCPC practices for cervical cancer) that will be applied to people testing FIT-positive (N = 60) and 4)an internet-based program designed to foster annual repeat FIT screening tested using a randomized controlled trial design (N = 220). Programs will be designed for optimal sustainability and dissemination/implementation potential.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This renewal application proposes to continue the cancer prevention programs of the University of Kentucky PRC the only PRC dedicated to cancer prevention in rural Appalachia. The proposed renewal offers plans to continue our community-based cancer prevention research and to extend our programs to other regions of Appalachia using sustainable dissemination and implementation models.


application_id: 9543808
project_number: 5R01AR059810-07
project_title: TAK1 signaling in skeletal muscle
administering_ic: NIAMS
award_notice_date: 2018-07-06
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 059810
program_official: BOYCE, AMANDA T
project_start_date: 2011-08-07
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)S]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
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:
AbstractLoss of skeletal muscle mass is a devastating complication of a wide range of diseases andconditions. However there is still no approved therapy to prevent muscle wasting partly because themechanisms that regulate skeletal muscle mass remain enigmatic. Accumulating evidence suggeststhat an array of signaling pathways regulates skeletal muscle mass mainly through modulating therate of protein synthesis and degradation. However upstream signaling mechanisms that are involvedin the regulation of muscle mass remain poorly understood. During the current funding of this projectwe showed TRAF6 mediates muscle atrophy and inhibits muscle regeneration in a variety of catabolicconditions. We also demonstrated that TRAF6 and TAK1 are important regulators of satellite cellhomeostasis in adult skeletal muscle. In contrast to TRAF6 of which activation causes musclewasting we have discovered that TAK1 is essential for skeletal muscle growth and maintenance ofmuscle mass in adults. Inducible myofiber-specific inactivation of TAK1 in mice (henceforth TAK1mko)leads to severe muscle wasting and development of kyphosis. The positive role of TAK1 in musclegrowth is also supported by our findings that the activation of TAK1 is dramatically increased inskeletal muscle undergoing hypertrophy. Our experiments also suggest that TAK1 is required for theactivation of specific intracellular pathways which promote skeletal muscle growth. Moreover ourstudies indicate that TAK1 may be required for the activation of autophagy/mitophagy regulation ofmitochondrial structure and function and maintenance of redox balance in skeletal muscle of adults.Based on our preliminary data we hypothesize that (I) TAK1 promotes skeletal muscle growth andinhibits atrophy through augmenting protein synthesis and preventing oxidative stress; (II) TAK1induces the activation of specific intracellular signaling pathways to augment skeletal muscle mass;and (III) TAK1 is required for the activation of autophagy/mitophagy and regulation of mitochondrialdynamics (i.e. biogenesis fusion and fission) and respiratory function in adult skeletal muscle. To testthese hypotheses in the next phase of the project we propose to address the following three specificaims: (1) Establish the role and investigate the molecular mechanisms by which TAK1 promotesskeletal muscle growth and prevents atrophy; (2) Investigate the signaling mechanisms by whichTAK1 regulates skeletal muscle mass; and (3) Investigate the role of TAK1 in regulation of autophagyand mitochondrial content and function in adult skeletal muscle.

project_terms:
Address;Adult;Aging;Atrophic;Autophagocytosis;Autophagosome;Biochemical;Biogenesis;Biological Assay;Birth;Chronic Disease;Communication;Complex;Complication;Data;Denervation;Disease;Equilibrium;Etiology;Funding;Genetic;Growth;Growth Factor;Health;Homeostasis;Human;Hypertrophy;Immobilization;Impairment;Inhibition of Apoptosis;Injury;Knockout Mice;Kyphosis deformity of spine;Lead;Life;LoxP-flanked allele;MAPK Signaling Pathway Pathway;Maintenance;Mediating;Mitochondria;Molecular;Molecular Biology;Mus;Muscle;Muscle Development;Muscle function;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Natural regeneration;Nature;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Pharmaceutical Preparations;Phase;Phosphorylation;Phosphotransferases;Population;Prevention;Production;Protein Biosynthesis;Proteins;Reactive Oxygen Species;Regulation;Reporting;Respiratory physiology;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeletal Muscle;Starvation;Stem cells;Stimulus;Structure;Syndrome;TNF receptor-associated factor 6;Tamoxifen;Testing;Transforming Growth Factors;base;cell type;experimental study;improved;mTOR Signaling Pathway;mitochondrial dysfunction;mouse model;muscle form;muscle hypertrophy;muscle regeneration;new therapeutic target;novel;prevent;protein degradation;response;satellite cell;self-renewal;skeletal muscle growth;skeletal muscle wasting;wasting

public_health_relevance:
Project NarrativeWhile the maintenance of skeletal muscle mass and function is prerequisite for whole bodyhealth throughout life loss of skeletal muscle mass is a debilitating consequence of manychronic disease states and conditions. Unfortunately there is still no approved therapy fortreatment of this syndrome. Our proposed studies will identify molecular and signalingmechanisms by which TAK1 improves skeletal muscle mass in adults. Successful completion ofthis project will enhance the basic understating of etiology of muscle growth and atrophy andmay lead to the identification of TAK1 as a novel drug target to improve muscle mass andfunction in human population.


application_id: 9543721
project_number: 7R01NS095215-03
project_title: Regulation of cilia by ceramide
administering_ic: NINDS
award_notice_date: 2017-09-13
opportunity_number: PA-16-285
application_type: 7
activity_code: R01
ic: NS
serial_number: 095215
program_official: LAVAUTE, TIMOTHY M
project_start_date: 2016-09-30
project_end_date: 2020-06-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cilia are protrusions of the cell membrane with sensory (primary cilia) or motor (motile cilia) function. Inastrocytes and ependymal cells primary and motile cilia regulate cell division and migration and propelcerebrospinal fluid (CSF) respectively. Ciliary dysfunction leads to astrocytic overgrowth (astrogliosis) orependymal cell malfunction and hydrocephalus. It is vital for the function of cilia in cell signaling and motilitythat cilium number length and intraciliary or intraflagellar transport (IFT) of cargo proteins are dynamicallyregulated. A critical barrier in understanding this regulation is the lack of knowledge on dynamically activatedfactors in ciliogenesis and cilium function. Although cilia are membrane structures research so far has focusedon the role of proteins in the regulation of cilia and little is known about the role of lipids in this process. Ourresearch goals are to determine how membrane lipids and proteins interact in the regulation of cilia and howmodulation of lipid metabolism can be utilized to support the function of cilia in astrocytes and ependymal cells.Our central hypothesis is that the sphingolipid ceramide regulates cilium length and IFT which is critical forthe function of cilia in astrocytes and ependymal cells. Our objectives are to 1) test that cilia are regulated byceramide-associated protein complexes; 2) define these complexes by using a novel technique to pull downceramide enriched- and cilium-derived membrane vesicles and covalently crosslink a bifunctional ceramideanalog to its interacting proteins to identify ceramide binding domains; 3) test that induction of receptors in ciliais regulated by ceramide; and 4) test that astroglial activation and ependymal cell function is regulated byceramide in vitro and in vivo. Our expected outcomes include 1) determining ceramide species that promoteciliogenesis and support cilium function and how the generation of ciliogenic ceramide is regulated; 2) defininga mechanism of cilium extension and IFT regulation by interaction of ceramide with atypical PKC GSK-3 andHDAC6; 3) defining SMase activation in vesicle transport pathways and their function for ceramide flux to thecilium; 4) identifying proteins and protein domains that associate with ceramide; 5) determining that transportand activation of signaling proteins in cilia in particular of the sonic hedgehog pathway are regulated byceramide; and 6) defining a mechanism by which ceramide regulates astrocyte activation and ependymal cell-driven CSF flow. The impact of this project is on defining a fundamental and novel mechanism in basicneuroscience and membrane biology which has broad implications for our understanding of the regulation ofcilia by lipid-protein interaction and the importance of this regulation for the function of astrocytes andependymal cells during brain development and aging. Aim 1 will test the hypothesis that ceramide stabilizescilia in astrocytes and ependymal cells. Aim 2 will test the hypothesis that ceramide regulates IFT andreceptor activation in cilia. Aim 3 will test the hypothesis that ciliogenic ceramide regulates astrocyte andependymal cell function.

project_terms:
AGFG1 gene;Aging;Apical;Astrocytes;Binding;Brain;Carrier Proteins;Cell Surface Extensions;Cell division;Cell physiology;Ceramides;Cerebrospinal Fluid;Cilia;Complex;Development;Enzyme Activation;Ependymal Cell;Fatty acid glycerol esters;Functional disorder;Generations;Glycogen (Starch) Synthase;Goals;Growth Factor;HDAC6 gene;Hydrocephalus;Impairment;In Vitro;Inflammatory;Kinesin;Knowledge;Laboratories;Length;Lipids;Liquid substance;Mediating;Membrane;Membrane Biology;Membrane Lipids;Membrane Proteins;Motor;Neuroglia;Neurons;Neurosciences;Outcome;Process;Proteins;Receptor Activation;Regulation;Research;Role;SHH gene;Sensory;Signal Pathway;Signal Transduction;Signaling Protein;Sonic Hedgehog Pathway;Sphingolipids;Sphingomyelinase;Techniques;Tertiary Protein Structure;Testing;Tubulin;Vesicle;Vesicle Transport Pathway;Work;aging brain;analog;astrogliosis;base;cell motility;cell type;cerebrospinal fluid flow;cilium biogenesis;cilium motility;crosslink;cytokine;glycogen synthase kinase 3 beta;in vivo;lipid metabolism;novel;prevent;protein complex;receptor;transcription factor

public_health_relevance:
Cilia are protrusions of the cell membrane that work like antenna or whips. Antenna-like primary cilia sensegrowth factors that regulate activation and proliferation of astrocytes and other neural cells in the brain. Whip-like motile cilia of ependymal cells move fluids that contain growth factors such as the cerebrospinal fluid.Therefore primary and motile cilia are vital for brain development and function. The P.I.'s laboratory has foundthat a fat-like substance (lipid) called ceramide is critical for cilia. In the present study the P.I. will determinehow ceramide regulates cilia in the brain a fundamental and novel mechanism in basic neuroscience andmembrane biology.


application_id: 9543189
project_number: 1R13HL142278-01
project_title: ATVB/PVD Scientific Sessions 2018
administering_ic: NHLBI
award_notice_date: 2018-02-16
opportunity_number: PA-16-294
application_type: 1
activity_code: R13
ic: HL
serial_number: 142278
program_official: TOLUNAY, ESER
project_start_date: 2018-03-01
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZHL1 CSR-C (F1)]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Councils on Arteriosclerosis Thrombosis and Vascular Biology (ATVB) and the Peripheral VascularDisease (PVD) of the American Heart Association (AHA) hold an annual Spring Meeting the most recentof which ATVB|PVD 2017 was held in Minneapolis MN May 4-6 2017. The meeting was a resoundingsuccess with ~750 registrants including more than 150 international attendees from 19 different countries.Five hundred and twenty-three abstracts were submitted well above the typical ~400 abstracts that hadbeen submitted in earlier years. These encouraging statistics provide tangible evidence of the broadinterest and commitment of the scientific community in the topic areas of ATVB PVD and vascularmedicine and the overwhelming enthusiasm for the format and atmosphere of this meeting. Basicscientists translational researchers and clinicians seasoned investigators and early career scientists enjoycoming to this AHA specialty conference. The next ATVB|PVD conference will be held May 10-12 2018 atthe Hilton Union Square in San Francisco CA. As with previous applications this proposal specificallyrequests support for our Young Investigator Travel Awards. Knowing that early stage investigators are thefuture of our scientific progress a major emphasis of our annual conference is to encourage the activeinvolvement of the younger cohort of investigators in the ATVB and PVD Councils of the AHA andrecognize their achievements. Young Investigator Travel Awards have been supported by the NIH-NHLBIfor 16 years. These awards are an integral part of our strategy to recruit retain and actively engage younginvestigators in the fields of arteriosclerosis thrombosis vascular biology and vascular medicine researchthat are of major importance to the NIH-NHLBI and the health of the U.S. population.

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

public_health_relevance:
This renewal application seeks support for Travel Awards for Young Investigators to attendthe 2018 ATVB|PVD Scientific Sessions of the Arteriosclerosis Thrombosis and VascularBiology (ATVB) and Peripheral Vascular Disease (PVD) Councils of the American HeartAssociation. The ATVB|PVD Scientific Sessions provide unique opportunities for early stageinvestigators to meet peers present their work and interact with senior colleagues acrossdistinct disciplines that have an interest in cardiovascular disease as a unifying theme.


application_id: 9543064
project_number: 4UH3NS100606-03
project_title: Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort
administering_ic: NINDS
award_notice_date: 2018-08-21
opportunity_number: RFA-NS-16-020
application_type: 4
activity_code: UH3
ic: NS
serial_number: 100606
program_official: MCGAVERN, LINDA
project_start_date: 2016-09-30
project_end_date: 2021-07-31
study_section: ZNS1-SRB-T(19)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Vascular contributions to cognitive impairment and dementia (VCID) describes cognitive impairmentresulting from cerebrovascular disease or dysfunction. VCID is a frequent co-morbidity with Alzheimer'sdisease (AD) as well as a single dementia-causing entity. The most common vasculopathy associated withcognitive impairment is cerebral small vessel disease (SVD). It is highly likely that SVD significantly contributesto the clinical manifestation of dementia and therefore is a viable target for disease-modifying therapieswhether alone or in combination with AD-targeting therapies. One major obstacle for therapeutic developmentis the lack of biomarkers that are predictive of the presence and course of SVD-VCID. In this proposal wepresent candidate biomarkers for SV-VCID that will contribute to the consortium. We have identified MRI imaging modalities of 3D FLAIR ASL and DTI as our imaging candidatebiomarkers. We have also identified IL-12 p70 TNF PIGF and VEGFD as our candidate fluid biomarkers thatdiscriminate SVD well in the subset of our cohort that we have analyzed. In this application we have a plan fordeveloping our candidate biomarkers and validating them through the UH2 phase an individual research groupand also through the UH3 part as a member of the consortium. In addition we bring significant strengths thatwill help synergize and move the consortium as a whole forward in our collective goal of developing biomarkersthat are ready for large scale clinical trials and FDA qualification in years 6-7 of the consortium. Thesestrengths include a well characterized longitudinal cohort supported through our ADC and other NIH initiativesour long history of active participation in consortia providing the experience and infrastructure needed toensure success in this UH2/UH3 mechanism our history of data sharing resource sharing including samplesrecruitment of research participants for longitudinal studies and our foundation in basic and translationalscience.

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

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


application_id: 9543036
project_number: 1R01ES029378-01
project_title: EGFR and angiogenesis in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2018-04-24
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: ES
serial_number: 029378
program_official: REINLIB, LESLIE J
project_start_date: 2018-05-01
project_end_date: 2023-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cr(VI)-containing compounds are well-established environmental carcinogens. Most mechanisticinvestigations of Cr(VI)-induced carcinogenesis focus on oxidative stress and various cellular responsesleading to malignant cell transformation the first stage of metal-induced carcinogenesis. The development ofmalignantly transformed cells into tumors in which angiogenesis is required is the second stage. Thisapplication focuses on this second stage in particular the role of epidermal growth factor receptor (EGFR)signaling in angiogenesis and tumorigenesis of Cr(VI)-transformed cells. Our previous studies have found thatchronic exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) causes malignant cell transformation.Our preliminary studies have shown that EGFR is constitutively activated in Cr(VI)-transformed cells in lungtissues from Cr(VI)-exposed animals and in lung tumor tissues from non-smoking workers exposed to Cr(VI).Our preliminary studies have also shown that EGFR phosphorylates p62 at serine349 (S349) that p62upregulates nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) and that Nrf2 upregulates bothNAD(P)H:quinone oxidoreductase 1 (NQO1) and hypoxia-inducible factor (HIF)-1 in those Cr(VI)-transformedcells leading to elevated level of vascular endothelial growth factor (VEGF). Inhibition of EGFR by its shRNAor kinase inhibitor AK1478 suppresses HIF-1 in Cr(VI)-transformed cells. Our findings indicate that EGFRfunctions as an initiator in angiogenesis and causes a chain of events through constitutive activation of Nrf2 inCr(VI)-transformed cells. The central hypothesis of this application is that in Cr(VI)-transformed cellsconstitutively activated EGFR phosphorylates p62 at S349 causing upregulations of Nrf2 and NQO1 which inturn activate HIF-1 and its target protein VEGF leading to angiogenesis and tumorigenesis. Aim 1 willdemonstrate that EGFR phosphorylates p62 at S349 causing increased binding affinity between p62 andKelch-like ECH-associated protein 1 (Keap1) a negative regulator of Nrf2 leading to reduced binding betweenKeap1 and Nrf2 and subsequently increased stabilization of Nrf2. Aim 2 will demonstrate that HIF-1 isupregulated by NQO1 due to its binding to HIF-1 in completion with prolyl hydroxylase domain protein 2(PHD2) and to cap-independent but internal ribose entry site (IRES)-independent translation. We will alsodemonstrate the elevated protein levels of p-EGFR p62 p-p62 Nrf2 NQO1 HIF-1 and VEGF in humanlung tumor tissues from Cr(VI)-exposed workers. Aim 3 will demonstrate that activation of EGFR/HIF-1/VEGFcauses angiogenesis and promotes tumorigenesis in vivo using animal models of intranasal exposure toCr(VI) Matrigel plug assay and orthotopic lung cancer.

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

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


application_id: 9542972
project_number: 3R01EY024173-04S1
project_title: Parallel Tectothalamic Pathways
administering_ic: NEI
award_notice_date: 2017-08-28
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: EY
serial_number: 024173
suffix: S1
program_official: FLANDERS, MARTHA C
project_start_date: 2014-09-02
project_end_date: 2019-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The superficial layers of the superior colliculus (SC) contain two cell types that both respond to the movement of visual stimuli but are morphologically and functionally distinct. A projection from the SC to the lateral posterior nucleus (LPN) originates from wide-field vertical (WFV) cells while a projection from the SC to the dorsal lateral geniculate nucleus (dLGN) originates from narrow-field vertical (NFV) cells. WFV cells have been described as motion detectors based on their responses to small stimuli moving in any direction within a very large receptive field. In contrast NFV cells may be specialized to code more detailed motion parameters based on their small receptive fields and strong direction selectivity. The parallel WFV and NFV pathways remain segregated in that the tectorecipient dLGN and LPN project differentially to the striate and extrastriate cortex. However little is known regarding the interaction between the SC the tectorecipient thalamus and the cortex. We propose to analyze the circuits that connect these structures in mice by using novel combinations of optogenetics in vitro whole cell recordings from neuronal populations identified by retrograde tracing techniques as well as quantitative electron microscopic investigation of synaptic connections. The Aim 1 experiments will use in vitro whole cell recording from identified cortical cell populations and optogenetic activation of terminals tht originate from the tectorecipient dLGN or LPN to determine which cell types are directly innervated and to characterize the electrophysiological properties of these synapses. Electron microscopy will quantify ultrastructural features of these synapses. The Aim 2 experiments will use in vitro whole cell recordings from NFV and WFV cells and optogenetic activation of corticotectal terminals to determine whether these cells receive direct or indirect input from V1 or the lateral extrastriate cortex and to characterize the electrophysiological properties of thes connections. Electron microscopy will quantify ultrastructural features of corticotectal synapses and the distribution inputs to NFV and WFV cells that do and do not contain gamma amino butyric acid (GABA). As comparisons of parallel geniculocortical pathways have led to insights regarding cortical processing streams a comparison of WFV and NFV tecto-thalamo-cortical pathways will help us to understand how different aspects of visual motion are utilized by the visual system. In addition our circuit analysis can help reveal whether corticotectal pathways are organized to enhance segregation or synthesis of motion signals

project_terms:
Address;Affect;Animals;Back;Butyric Acids;Cell Nucleus;Cells;Code;Detection;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Electrophysiology (science);Homologous Gene;In Vitro;Investigation;Lateral;Lateral Geniculate Body;Lateral posterior nucleus of thalamus;Literature;Microscopic;Morphology;Motion;Motion Perception;Movement;Mus;Neurons;Output;Pathway interactions;Perception;Population;Property;Pulvinar structure;Reaction;Research;Rodent;Schizophrenia;Signal Transduction;Site;Stimulus;Stream;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Vision;Visual;Visual Motion;Visual system structure;Whole-Cell Recordings;area striata;base;brain circuitry;cell type;detector;experimental study;extrastriate;extrastriate visual cortex;insight;magnocellular;motion sensitivity;novel;optogenetics;parvocellular;public health relevance;receptive field;response;segregation;superior colliculus Corpora quadrigemina;visual neuroscience;visual stimulus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The results of these experiments will significantly enhance our understanding of the brain circuitry underlying visual motion perception thus providing information relevant to the treatment of disorders in which visual motion processing is compromised such as dyslexia and schizophrenia.


application_id: 9542937
project_number: 2R56AG024377-09A1
project_title: Characterization of the Sch9 Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2017-08-28
opportunity_number: PA-13-302
application_type: 2
activity_code: R56
ic: AG
serial_number: 024377
suffix: A1
program_official: GUO, MAX
project_start_date: 2004-09-01
project_end_date: 2019-08-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT CARL
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
project_abstract:
Dietary restriction and drugs such as rapamycin are promising ways to reduce theincidence and severity of diseases including cancer neurodegeneration and diabetesthat diminish health in the elderly. These and other ways to slow aging work in part bylowering activity of the target of rapamycin complex 1 (TORC1) protein kinase thatsenses amino acids (AAs) and adjusts growth and metabolism to their availability.Protein and AA restriction show promise in controlling aging and improving humanhealth but current strategies require dietary changes that few humans are likely toadhere to. We have identified a novel way to lower free AA pools and increase lifespan.We showed previously that chronological lifespan (CLS) can be increased in buddingand fission yeasts by decreasing the rate of sphingolipid synthesis and a similarapproach has been shown to increase lifespan in the nematode Caenorhabditiselegans. Slower sphingolipid synthesis was achieved by genetic or pharmacological(myriocin Myr) approaches that target the conserved initial enzyme in sphingolipidbiosynthesis serine palmitoyltransferase. We now find that Myr treatment lowers thefree pool of at least 15 AAs at least partly by reducing AA uptake in budding yeast.We posit that the drug perturbs membrane functions creating a state of AA restrictionthat lowers TORC1 activity and increases activity of the other conserved AA-sensingpathway Gcn2 (general control nonrepressible 2). To test this hypothesis we willidentify the AA transporters whose activity is lowered by Myr treatment (Aim 1).Second we will determine how drug treatment lowers AA transport activity (Aim 2).Third the temporal effects of drug treatment that induce AA-restriction will be identified(Aim 3). Finally the sphingolipid(s) responsible for lowering AA pools and other lipidspecies if they are involved will be identified. We will accomplish these goals by usingmolecular biology biochemistry and yeast genetic techniques. Our results are likely tostimulate studies in model organisms such as worms and mice to identify novel drugtargets for lowering AA pools in ways that are more likely to be used by humans toimprove health than are currently available strategies.

project_terms:
Age;Age of Onset;Aging;Amino Acid Permease;Amino Acid Transporter;Amino Acids;Anabolism;Animal Model;Biochemistry;Caenorhabditis elegans;Cardiovascular system;Cause of Death;Cell Extracts;Cell membrane;Cells;Chronology;Complex;Data;Developed Countries;Developing Countries;Diabetes Mellitus;Diet;Disease;Effectiveness;Elderly;Endosomes;Enzymes;Ergosterol;Event;Fission Yeast;Genes;Genetic;Genetic Techniques;Genetic Transcription;Global Change;Glycerophospholipids;Goals;Growth;Health;Human;Immune System Diseases;Immune System and Related Disorders;Incidence;Lead;Learning;Lipids;Location;Longevity;Longevity Pathway;Malignant Neoplasms;Mass Spectrum Analysis;Membrane;Metabolism;Molecular Biology;Mus;Nematoda;Nerve Degeneration;Nitrogen;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Organelles;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phosphotransferases;Physiological;Process;Protein Biosynthesis;Protein Kinase;Proteins;Repression;Role;Saccharomyces cerevisiae;Saccharomycetales;Severities;Severity of illness;Shotguns;Signal Transduction;Signal Transduction Pathway;Sirolimus;Sphingolipids;System;Testing;Transcriptional Regulation;Transfer RNA;Vacuole;Work;Yeasts;age related;biological adaptation to stress;deprivation;dietary restriction;human disease;improved;in vitro Assay;insight;new therapeutic target;novel;novel strategies;overexpression;permease;proteoliposomes;reconstitution;response;sensor;serine palmitoyltransferase;thermozymocidin;trafficking;trans-Golgi Network;uptake;yeast genetics

public_health_relevance:
Project NarrativeThe primary causes of death in developed countries are type 2 diabetes cancercardiovascular and immunological dysfunctions and neurodegeneration the so calledage-related diseases. Our studies are the first to show that treating yeast cells(Saccharomyces cerevisiae) with the drug myriocin which targets the first step in theevolutionarily conserved sphingolipid synthesis pathway can be used to slow aging andincrease lifespan. This novel strategy has the potential to reduce the incidence andslow the onset of age-related diseases in humans and improve health span.


application_id: 9542889
project_number: 5R01HL130086-02
project_title: Calpains and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2018-07-02
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130086
program_official: REID, DIANE M
project_start_date: 2017-08-10
project_end_date: 2021-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10792635
contact_pi: SUBRAMANIAN, VENKATESWARAN
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:
Abdominal Aortic Aneurysm;Angiotensin II;Animal Model;Aorta;Aortic Rupture;Attenuated;Calcium;Calpain;Caspase;Cessation of life;Chronic;Cleaved cell;Clinical;Cytoskeletal Filaments;Cytoskeletal Proteins;Data;Development;Disease;Dissociation;Exhibits;Extracellular Matrix;Fibroblasts;Filament;Genetic;Human;In Vitro;Inflammation;Inflammatory;LTBP2 gene;Mechanics;Medial;Mediating;Membrane;Morbidity - disease rate;Mus;Myofibrils;NF-kappa B;Operative Surgical Procedures;Patients;Peptide Hydrolases;Pharmacology;Phenotype;Play;Population;Process;Protein Isoforms;Proteins;Proteolysis;Rho-associated kinase;Role;Rupture;Signal Transduction;Smooth Muscle Myocytes;Substrate Specificity;TXN gene;Talin;Testing;Therapeutic;Tissues;Transforming Growth Factor beta;Vascular remodeling;abdominal aorta;base;cytokine;filamin;inhibitor/antagonist;insight;latent TGF-beta binding protein;macrophage;migration;mortality;mouse model;new therapeutic target;novel;prevent;repaired;rho;rhoB p20 GDI;vascular inflammation


application_id: 9542758
project_number: 5R21CA218231-02
administering_ic: NCI
award_notice_date: 2018-07-19
opportunity_number: PAR-16-248
application_type: 5
activity_code: R21
ic: CA
serial_number: 218231
program_official: BLAKE, KELLY D
project_start_date: 2017-08-10
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-B(58)R]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
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
budget_start_date: 2018-08-01
project_title:
Toward fine-grained e-cigarette surveillance on social media: Evolving themes popularity predictors and demographic variations

project_abstract:
ABSTRACTElectronic cigarettes (or e-cigarettes) are currently a popular emerging tobacco product. Because e-cigarettes donot generate toxic tobacco combustion products produced when smoking regular cigarettes they are perceivedand sometimes promoted as a less harmful alternative to smoking and also as a means to quit smoking. Althoughthey may be less harmful the efcacy of using them for smoking cessation has not been demonstrated conclu-sively with studies indicating evidence both favoring and opposing such an application for them. Furthermoreowing to their recent introduction there are also safety concerns given reported adverse events. The US FederalDrug Administration (FDA) has introduced regulations that went into effect on 8/8/2016 requiring FDA review fore-cigarette products banning sales to minors and free samples and requiring warning labels on certain prod-ucts. In this context surveillance of evolving themes and factors contributing to message popularity for e-cigarettechatter on social media platforms is an important activity. Twitter has become the favorite network for teenagersand young adults owing to the short message size and associated ease of use on smart phones. For an emerg-ing product like e-cigarettes the asymmetric follower-friend connections and hashtag functionality in Twitter offera convenient way to propagate information and facilitate discussion. Among online forums Reddit allows forlonger messages from users inviting specic feedback from other users. Within Reddit the e-cigarette subredditfacilitates focused discussions on e-cigarette use and products. In this project we propose to computationallyanalyze the contents and user proles available in the dataset of all e-cigarette tweets generated during 7/20166/2017 and all e-cigarette subreddit posts/comments generated since 9/2016. We will continue such analyseswith data collected through free but rate limited API throughout the duration of the project. Our rst aim is to sur-face specic themes of interest directly from e-cigarette messages using phrase based online and binned topicmodels. We expect these themes to complement familiar broad themes that researchers currently consider whenanalyzing online messages. Next we will identify factors (involving message content and prole characteristics)that contribute to different notions of popularity (#retweets #replies #up-votes) of e-cigarette tweets/messages.We expect these results will help health agencies the FDA and researchers gain insights into observed viralnature of certain messages and designing effective strategies to maximize diffusion of their messages. Finallywe will conduct these analyses along the dimensions of gender race and age to grasp variations in themes andpopularity factors specic to different vulnerable demographic segments.

project_terms:
Adverse event;African American;Age;Cellular Phone;Centers for Disease Control and Prevention (U.S.);Characteristics;Cigarette;Communication;Complement;Data;Data Set;Data Sources;Diffusion;Dimensions;Electronic Nicotine Delivery Systems;Electronic cigarette;Evolution;Feedback;Frequencies;Friends;Gender;Goals;Grain;Harm Reduction;Health;High School Student;Influentials;Informatics;Label;Light;Liquid substance;Long-Term Effects;Measures;Methods;Minor;Modeling;National Health Services;Nature;Nicotine Dependence;Outcome;Pharmaceutical Preparations;Psychometrics;Published Comment;Race;Regulation;Reporting;Research Personnel;Safety;Sales;Sampling;Site;Smoke;Smoker;Smoking;Social Network;Surface;Teenagers;Time;Tobacco;United States Food and Drug Administration;Vaporizer;Variant;Viral;Visual;Voting;Work;base;combustible cigarette;combustion product;computerized tools;design;electronic cigarette use;exhaustion;grasp;insight;interest;junior high school;member;news;phrases;smoking cessation;social media;social networking website;tobacco-free;young adult

public_health_relevance:
NARRATIVEElectronic cigarettes (e-cigarettes) have emerged as the main smoke-free alternative to regular cigarettes overthe past few years. While the ongoing healthy scientic debate about their long term health effects and theirsuitability for smoking cessation are important in this project we propose computational approaches towardne-grained surveillance of specic themes factors inuencing message popularity and demographic variations.The overarching goal is to create new affordances for researchers and health agencies to leverage online socialmedia platforms for knowing and reaching their audience in effective ways.


application_id: 9542744
project_number: 5K22CA201036-03
project_title: Defining epigenetic vulnerabilities of subtype-specific lung cancers
administering_ic: NCI
award_notice_date: 2018-08-08
opportunity_number: PAR-15-056
application_type: 5
activity_code: K22
ic: CA
serial_number: 201036
program_official: JAKOWLEW, SONIA B
project_start_date: 2016-09-30
project_end_date: 2018-12-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Future Research Questions: As an independent investigator I will focus on answering two important questions: 1) What are the cells-of-origin orepigenetic programs that produce the two major types of lung tumors? and 2) How can epigenetic therapies be incorporated into useful cancer therapeutics? Background Lung cancer remains the leading cause of cancer related deaths world-wide. Precision medicine options for lung cancer patients may help to decrease the mortality of the disease by targeting the most vulnerable pathways in each specific cancer. However these efforts are complicated by both the genetic and epigenetic complexity of lung tumors. How epigenetic programs influence critical aspects of lung tumorigenesis and normal lung biology remains an uncharted area. Furthermore the lineage relationship and epigenetic differences between the two major subtypes of non-small cell lung cancer namely lung adenocarcinoma and lung squamous cell carcinoma are unclear. My main goal is to find methods to incorporate epigenetic drugs into effective cancer therapies. I will initially focus on lung stem cell biology as my platform to elucidate the cellular origins and epigenetic therapeutic vulnerabilities in lung cancer. Methodology The research proposed herein will allow for direct comparison of the transformation capacity of several lung stem/progenitor cell pools through FACS isolation lentiviral genetic modulation and 3D organotypic culture. The transformation potential and subtype acquisition of the cell pools will be tested by injection into the lungs of immunocompromised mice. This novel system will allow for careful dissection of what lung cells can serve as tumor cells-of-origin and in what contexts (i.e. genetic mutations and epigenetic modulation). These results can be linked back to the most permissible epigenetic states for transformation and allow understanding of how epigenetic programs are co-opted by tumor cells during malignant transformation. In parallel I will study the effects of different epigeneti therapeutics namely inhibition of BRD4 EZH2 or G9A on genetically defined murine lung tumors. I will again use the 3D organotypic culture assay which I have optimized for primary tumor cell growth. This approach will allow cost-effective but biologically relevant assessment of the effects of epigenetic therapies on varied subtypes and genotypes of lung cancer. Both of these approaches will be translated to human biology by using human cells in the 3D cultures. Career Potential I have had a very successful post-doctoral career in the laboratory of Carla Kim at Boston Children's Hospital and I have established a strong relationship with my collaborators for this award Drs. Leonard Zon and Kwok- Kin Wong. I have an outstanding environment and a comprehensive plan that will allow me to transition to an independent research role. My ultimate goal is to lead a research group exploring the relationships between stem cells and cancer with a specific focus on novel cancer therapeutics. I know that the K22 award would greatly aid me in realizing these goals.

project_terms:
AGTR2 gene;ATAC-seq;Adenocarcinoma;Area;Award;Back;Basal Cell;Biological;Biological Assay;Biology;Boston;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Complex;DNA Sequence Alteration;Disease;Dissection;Drug Combinations;EZH2 gene;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Genes;Genetic;Genomics;Genotype;Goals;Growth;Histology;Human;Human Biology;Immunocompromised Host;Infection;Injections;K22 Award;Knowledge;Laboratories;Lead;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Methods;Mus;Non-Small-Cell Lung Carcinoma;Organoids;Pathway interactions;Patients;Pediatric Hospitals;Pharmaceutical Preparations;Phenotype;Postdoctoral Fellow;Primary Neoplasm;Reader;Research;Research Methodology;Research Personnel;Role;Running;Sampling;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;Stem cells;Structure of parenchyma of lung;System;TP53 gene;Techniques;Testing;Therapeutic;Translating;Transplantation;Tumor Subtype;Vision;Xenograft procedure;cancer therapy;career;cell growth;cell transformation;clinical application;cost effective;disorder subtype;epigenetic drug;epigenetic therapy;experimental study;fitness test;in vivo;inhibitor/antagonist;lung tumorigenesis;mortality;mouse model;neoplastic cell;novel;pre-clinical;precision medicine;programs;public health relevance;response;stem;stem cell biology;three dimensional cell culture;transcriptome sequencing;tumor;tumor initiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Lung cancer is the leading cause of cancer-related deaths worldwide and is a highly complex disease with many possible cells-of-origin and genetic drivers. These studies will allow for a better understanding of which cells can serve as cells-of-origin of lung tumors and how differences in epigenetic programs can influence tumor initiation and subtype acquisition. In addition these experiments will help to determine the contexts in which epigenetic therapies which are widely believed to be game-changing in the field of cancer therapeutics will be viable strategies to treat lineage-specific lung cancers.


