# projects

application_id: 9084779
project_number: 3R44DK085810-04S1
project_title: Hollow Fiber Catheter for Drug Delivery into the Prostate
administering_ic: NIDDK
award_notice_date: 2015-06-10
opportunity_number: PA-12-088
application_type: 3
activity_code: R44
ic: DK
serial_number: 085810
suffix: S1
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-06-01
project_end_date: 2016-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 8714039
contact_pi: STICE, JIM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079228773
duns_number: 079228773
fips: US
organization_id: 10035571
organization_name: TWIN STAR TDS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071968
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-06-08
project_abstract:
DESCRIPTION (provided by applicant): The significance of the proposed research is based on the growing demand for healthcare resources to treat and manage prostatic disease particularly benign prostatic hyperplasia (BPH) and cancer. Both the incidence and cost of treatment for BPH and its complications are growing rapidly with the aging U.S. population; prostate cancer is the second-leading cause of cancer deaths among men in the U.S. There is a clear need for minimally invasive cost-effective therapies to match the outcomes of surgical treatment options which are associated with significant morbidity and complications. Prostate injections have not become standard of care due to inadequate drug distribution with needles. The Applicants have developed a microporous hollow fiber catheter (MiHFC) for improved injection distribution in the prostate. Phase II innovations focus on further developing MiHFC and combining existing treatment planning methods for drug delivery injections into human prostates with the objective to develop a system that is ready for human clinical use. The same MiHFC device with small changes would be adaptable for use in many other human clinical applications needing improved injection systems such as liver kidney and other solid organs. This would allow researchers to use MiHFC devices for other research projects involving human drug injections either with or without treatment planning. Hypothesis: The MiHFC injection system being developed in Phase II will give urologists and researchers a more reliable tool to plan and deliver injection therapies into the human prostate. Preliminary Data: In Phase I research the innovative use of applicant's MiHFC to improve injection drug delivery into the prostate was successful with MiHFC significantly improving ethanol distribution in canine prostates as compared to needle injections. Specific Aims: The objective of this Phase II proposal is to further develop the applicant's innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use. Aim 1: Finalize human use MiHFC design. The Phase I MiHFC design will be optimized to meet human use specifications established from user requirements. Aim 2: Infusion studies and analysis. Human ex vivo and baboon in vivo studies will be conducted to assess MiHFC safety and agent distribution and to develop of a prostate specific treatment planning system. Aim 3: Design verification and 510(k) submission. Design verification test data and FDA 510(k) clearance will facilitate clinical adoption and commercialization.

project_terms:
Adoption;Aging;Animals;Area;Benign Prostatic Hypertrophy;Cancer Etiology;Canis familiaris;Catheters;Cessation of life;Clinical;Computer software;Data;Development;Devices;Disease;Drug Delivery Systems;Dyes;Ethanol;Evaluation;Fiber;Health;Healthcare;Human;Image;Incidence;Infusion procedures;Injection of therapeutic agent;Kidney;Knowledge;Lead;Light;Liver;Magnetic Resonance;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Methylene blue;Modeling;Modification;Morbidity - disease rate;Needles;Operative Surgical Procedures;Oral;Organ;Outcome;Papio;Performance;Pharmaceutical Preparations;Phase;Population;Prostate;Prostatic Diseases;Research;Research Methodology;Research Personnel;Research Project Grants;Resources;Safety;Science;Solid;Structure;System;Testing;Therapeutic;Time;Treatment Cost;Urethra;Urologist;aging population;base;clinical application;clinical practice;commercialization;cost effective;design;drug distribution;effective therapy;human study;improved;in vivo;innovation;insight;meetings;men;minimally invasive;standard of care;tool;treatment planning

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  There is a significant demand for healthcare resources to treat and manage prostate diseases. The objective of this Phase II proposal is to develop an innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use.


application_id: 9084441
project_number: 4R01AG042475-04
project_title: CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD
administering_ic: NIA
award_notice_date: 2016-05-31
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AG
serial_number: 042475
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2013-06-01
project_end_date: 2018-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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): Alzheimer's disease (AD) manifests severe pathological changes in the CNS including increased levels of amyloid hyperphosphorylated tau and synaptic loss. Synaptic dysfunction is a hallmark of the disease that associates with the cognitive ability and level of dementia during the progression of AD. It is unclear why synaptic numbers are reduced in the early stages of AD and how it is linked to other features of the pathology. We believe that oxidative damage and microtubule/actin changes are early events in the progression of AD and underlie synaptic dysfunction. Increasing evidence suggests that the medial temporal lobe (MTL) is the earliest regions of the brain affected and may provide important clues to the progression of the disease. Our hypothesis is that multiple different cellular changes occur in the MTL initiating the loss of synaptic plasticity resulting in a declinein cognition and the onset of clinical AD. The proposed experiments will evaluate changes in this brain region in regards to synaptic proteins oxidative stress and structural proteins. Studies ar carried out on short post mortem samples from longitudinally followed individuals with detailed cognitive testing. Individuals with amnestic mild cognitive impairment (aMCI) will be compared to individuals that clinically show no cognitive impairment (NCI). The NCI group is further classified as individuals with very low pathology (LP- NCI) or high (AD levels) of histopathology (HP-NCI). Current literature suggests that HP-NCI represents individuals with preclinical AD. Aim one assess the direct relationship between different key synaptic proteins and oxidative stress in the MTL. Aim two probes whether or not NADPH-oxidase (NOX) activity and its subunits change during the disease progression and how it associates with changes in synaptic proteins and soluble A beta. The NOX enzyme is normally expressed throughout the central nervous system and is a key non-mitochondrial source of free radicals. The third aim explores whether or not key cytoskeletal proteins such as the actin binding protein cofilin and tau increase in the MTL and alters different levels of key synaptic proteins. Successful completion of the proposed studies will reveal new insights into the mechanisms underlying the very early stages in the progression of AD and contribute to the development of rational therapies.

project_terms:
Actin-Binding Protein;Actins;Adult;Affect;Alzheimer's Disease;Amyloid;Antioxidants;Area;Binding;Biochemical;Brain region;Clinical;Cognition;Cognitive;Cytoskeletal Proteins;Data;Dementia;Development;Disease;Disease Progression;Early Diagnosis;Enzymes;Etiology;Event;Free Radicals;Functional disorder;Health;Hippocampal Formation;Hippocampus (Brain);Histopathology;Impaired cognition;Individual;Lead;Link;Literature;Maintenance;Medial;Microtubules;Mission;Mitochondria;Molecular;NADPH Oxidase;Nerve Degeneration;Neuraxis;Neurofibrillary Tangles;Neuronal Dysfunction;Neurons;Oxidants;Oxidative Stress;Pathology;Play;Principal Investigator;Process;Production;Proteins;Reactive Oxygen Species;Research Support;Role;Sampling;Seminal;Source;Staging;Structural Genes;Subcellular Fractions;Symptoms;Synapses;Synaptic plasticity;System;Temporal Lobe;Testing;cofilin;cognitive ability;cognitive function;cognitive testing;cohort;dentate gyrus;design;differential expression;entorhinal cortex;frontal lobe;human tissue;hyperphosphorylated tau;insight;mental state;mild cognitive impairment;neurofibrillary tangle formation;novel marker;novel therapeutics;oxidative damage;pre-clinical;prevent;programs;research study;synaptic failure;tau Proteins;tau aggregation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Understanding cellular changes that occur in the early progression of AD will help to develop novel biomarkers for early detection. In addition it will help in designing specific novel therapies to slow or perhaps prevent the progression when detected early. The proposed studies are directly relevant to the mission of the NIA to support research aimed at understanding the cellular and clinical processes of dementia.


application_id: 9083578
project_number: 1U01AI123832-01
project_title: Role of TRPV1 in asthma exacerbation
administering_ic: NIAID
award_notice_date: 2016-01-15
opportunity_number: PA-13-302
application_type: 1
activity_code: U01
ic: AI
serial_number: 123832
program_official: MINNICOZZI, MICHAEL
project_start_date: 2016-01-15
project_end_date: 2018-12-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammatory reaction is known to lead to an increase in tissue temperature but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1) a ligand gated non-selective cation channel with a distinct sensitivity to heat is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction cough and other airway defense responses. Indeed our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.

project_terms:
Advanced Development;Afferent Neurons;Air;Allergens;Allergic inflammation;Animal Model;Asthma;Breathing;Bronchial Provocation Tests;Bronchial Spasm;Bronchoconstriction;C Fiber;Cations;Chronic;Coughing;Data;Development;Devices;Disease;Exhibits;Extrinsic asthma;Heating;Hyperventilation;Inflammation;Inflammation Mediators;Inflammatory;Institutional Review Boards;Ion Channel;Ipratropium;Irritants;Kentucky;Laboratories;Lead;Ligands;Lung;Measures;Mediating;Membrane;Mucous Membrane;Names;Neurons;Patients;Persons;Physiological;Pilot Projects;Play;Property;Protocols documentation;Rattus;Reaction;Reflex action;Reporting;Research;Research Personnel;Respiratory Signs and Symptoms;Respiratory System;Respiratory tract structure;Risk;Role;Sensory;Sensory Nerve Endings;Series;Symptoms;Technology;Teleconferences;Temperature;Testing;Tissues;Training;Universities;Vanilloid;Wisconsin;afferent nerve;airway hyperresponsiveness;allergic airway inflammation;asthmatic;asthmatic airway;asthmatic patient;cholinergic;clinically relevant;constriction;defense response;design;disabling symptom;experience;human subject;insight;interest;irritation;novel;novel therapeutic intervention;prevent;public health relevance;receptor;response;sensor;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Airway hypersensitivity characterized by symptoms of airway irritation cough and bronchospasm is a hallmark feature of airway inflammatory diseases. This study is designed to test a novel hypothesis that a specific ion channel named TRPV1 present in the airway sensory nerves plays an important role in the airway hypersensitivity found in patients with allergic asthma. Results of this translational study to be conducted in both asthmatic patients and pulmonary sensory neurons isolated from an animal model of asthma will help to advance the development of new therapeutic strategies for alleviating these debilitating symptoms.


application_id: 9081977
project_number: 1R01HL131925-01
project_title: Role of IKK in obesity and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2016-03-04
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 131925
program_official: KIRBY, RUTH
project_start_date: 2016-04-01
project_end_date: 2020-02-29
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKK/NF-B signaling. However the role of IKK in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKK deficiency (driven by a SM22Cre-IKK- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity metabolic disorders and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKK positively regulates adipogenesis indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKK is essential for adipogenesis and atherogenesis and that high-fat diet-induced IKK activation promotes adipocyte differentiation and adipose inflammation leading to increased obesity insulin resistance and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKK in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKK to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKK by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKK in adipogenesis and atherogenesis and will reveal a critical link between overnutrition inflammation and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKK inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.

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

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


application_id: 9080850
project_number: 1U01DE025833-01
project_title: Oral Health Promotion (OHPROM) Strategy for Persons with Intellectual & Developmental Disabilities
administering_ic: NIDCR
award_notice_date: 2016-03-18
opportunity_number: PAR-15-059
application_type: 1
activity_code: U01
ic: DE
serial_number: 025833
program_official: RICE, ELISE
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZDE1 CF (05)]
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: JOHNSON, KNOWLTON WILLIAM
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): People with intellectual and/or developmental disabilities (IDD) living in group homes are more likely to have poor oral hygiene poor dietary practices increased decay periodontal disease and total tooth loss than the general population-a significant health disparity. To improve the oral health care of this population we are conducting a stratified cluster Phase 2 randomized controlled trial to test for the efficacy of
an oral health promotion (OHPROM) strategy on persons with IDD living in group homes. This intervention is based on behavioral and public health theory derived from the literature and includes features to enhance sustainability.  The sample of consented participants is projected to be about 23 home managers 258 caregivers and 258 persons with IDD who reside in 86 group homes. Assuming the attrition rate observed in a pilot study it is projected that the final participants will be 20 managers 240 caregivers and 240 persons with IDD residing in 80 group homes. The homes are managed by three nonprofit partnering organizations and three sites of ResCare the nation's largest provider of residential services to persons with IDD in or near the Metro Louisville area in Kentucky and Southern Indiana. Managers are responsible for the conduct of caregivers in a small cluster of group homes are generally former caregivers and are paid staff. Caregivers are responsible for ensuring daily personal hygiene and dietary guidance for persons with IDD and are paid staff of the partner organizations. The OHPROM strategy is comprised of (a) planned action that entails caregivers signing a behavioral contract and engaging in oral health action planning for persons with IDD (b) caregiver capacity- building that includes didactic and observational learning as well as oral health devices (c) environmental adaptations with reminder posters and change of oral hygiene location (physical environment) and administrative oral health support (social environment) and (d) reinforcement through caregiver coaching.  The primary study objective is to assess change in oral health status of persons with IDD living in group homes. A second objective is to assess change in proximal and intermediate outcomes (i.e. mechanisms of change) and the extent to which these outcomes moderate the intervention effects on the oral health of persons with IDD. As a third objective the study will assess implementation quality as delivered to home managers and caregivers and the association of intervention components with the mechanisms of change.  The study results are intended to affect the fields of dentistry and behavioral research by demonstrating whether a theory-based prevention strategy can improve the oral health of persons with IDD living in group homes and may also improve the oral health of other at-risk dependent populations. Ultimately the study may produce changes in service organizations oral health care policies and practices of the study organizations. Diffusion of the tested oral health strategy if proven efficacious is also important; thus creating infrastructure for diffuson is also a study priority.

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


application_id: 9079260
project_number: 4R01CA125454-09
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2016-04-11
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 125454
program_official: AULT, GRACE S
project_start_date: 2007-09-13
project_end_date: 2018-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Basal-like breast cancer (BLBC) exhibits an aggressive clinical history with development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and cancer stem cell (CSC)-like features suggesting that activation of EMT program generates high-grade invasive cells with CSC-like traits in BLBC. Our long-term goal is to discover the intrinsic factors within tumor cells and the extrinsic signals from tumor microenvironments that regulate EMT and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last several years we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT; our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However how the extrinsic tumor milieu of BLBC is initiated and built up despite its paramount importance remains unaddressed. Recently we found that expression of the X-box binding protein (XBP1) was significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2 a major chemokine for tumor associated macrophages (TAMs) and lymphocytes. XBP1 is a key molecule in the most conserved "unfolded-protein response" (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in "unresolved ER stress" which signals endogenous cellular injury triggering leukocyte infiltration and a significant boost of inflammatory responses in target tissues. We hypothesize that the loss of XBP1 by Snail-mediated repression ignites an "inside out" signal for recruiting TAMs and lymphocytes which establish an inflammatory/wound stroma to further boost EMT and cultivate CSC-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis using a newly developed specific Snail inhibitor. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms responsible for Snail-mediated XBP1 repression in BLBC; (2) to delineate why loss of XBP1 enhances inflammation in BLBC; and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant because it will not only open a new paradigm that significantly affects our views on the co- evolvement of tumor cells and their microenvironments in breast cancer progression and metastasis but will also lay groundwork for developing new therapeutic strategies against this disease.

project_terms:
Address;Affect;BRCA1 gene;Binding Proteins;Boxing;Brain;Breast;Breast Cancer Cell;CCL2 gene;Caenorhabditis elegans;Cancer cell line;Cancer stem cell;Cells;Cellular Stress;Characteristics;Chromatin;Clinical;Complex;Data;Development;Disease;Distant Metastasis;Down-Regulation;E-Cadherin;Endoplasmic Reticulum;Environment;Enzymes;Epithelial;Exhibits;Fostering;Gene Silencing;Glycogen Synthase Kinase 3;Goals;Growth;Homeostasis;Human;IL8 gene;Immune;Infiltration;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-6;Intervention;Intestines;Intrinsic factor;Knowledge;Leukocytes;Location;Lung;Lymphocyte;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical Oncologist;Mesenchymal;Molecular;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathologist;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Proteins;Public Health;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Repression;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Snails;Stromal Neoplasm;Testing;Therapeutic Intervention;Tissues;Up-Regulation;cancer subtypes;cancer therapy;cell injury;chemokine;chromatin modification;coping;cytokine;endoplasmic reticulum stress;epithelial to mesenchymal transition;gene repression;genome wide association study;in vivo;inhibitor/antagonist;innovation;insight;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;novel;novel therapeutic intervention;outcome forecast;paracrine;prevent;programs;promoter;public health relevance;research study;response;success;targeted treatment;trait;tumor;tumor microenvironment;tumor progression;ubiquitin isopeptidase;ubiquitin-protein ligase;wound;young woman

public_health_relevance:
Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the co-evolvement between tumor cells and their microenvironments in tumor progression and metastasis. When successfully completed these studies will provide insights for the development of novel interventions to prevent and treat metastatic basal-like breast cancer.


application_id: 9075589
project_number: 1S10OD020067-01A1
project_title: Light Sheet Microscope
administering_ic: OD
award_notice_date: 2016-06-21
opportunity_number: PAR-15-088
application_type: 1
activity_code: S10
ic: OD
serial_number: 020067
suffix: A1
program_official: LEVY, ABRAHAM
project_start_date: 2016-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 CB-T (30)]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
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
project_abstract:
DESCRIPTION (provided by applicant):  This proposal requests funding for the purchase of a Zeiss Z.1 Lightsheet Microscope at the University of Kentucky which will be housed in a new Imaging Center operated by the College of Arts and Sciences Biology Department. This instrument would be the first of its kind in the state of Kentucky. The lightsheet microscope incorporates state-of-the-art technology that will allow users to conduct long-term time-lapse imaging of live specimens as well as to image whole fixed cleared tissues at subcellular resolution. Lightsheet microscopy has several advantages over conventional fluorescence microscopy techniques including greater sample penetration depth faster image acquisition times superior signal-to-noise ratio and significantly reduced exposure which minimizes photobleaching and toxicity. This equipment will serve a growing group of NIH-funded investigators in the Biology department studying developmental and regenerative processes in a variety of model organisms (mouse zebrafish salamander lamprey and fly) whose research will be greatly enhanced by the ability to conduct live cell and tissue imaging. It will also serve
scientists located in the neighboring Colleges of Medicine Agriculture and Pharmacy. Research areas that will be enhanced through the acquisition of this lightsheet microscope include studies of germ cell and organ system development tissue regeneration circadian rhythms the role of scaffolding proteins in hematopoiesis and the regulation of signaling pathways during development.

project_terms:
Agriculture;Animal Model;Area;Arts;Biology;Circadian Rhythms;Development;Equipment;Fluorescence Microscopy;Funding;Germ Cells;Hematopoiesis;Housing;Image;Kentucky;Lampreys;Life;Light;Medicine;Microscope;Microscopy;Mus;Noise;Penetration;Pharmacy facility;Photobleaching;Process;Regulation;Request for Proposals;Research;Research Personnel;Resolution;Role;Salamander;Sampling;Scaffolding Protein;Science;Scientist;Signal Pathway;Signal Transduction;Specimen;Systems Development;Techniques;Technology;Time;Tissue imaging;Tissues;Toxic effect;United States National Institutes of Health;Universities;Zebrafish;body system;college;fly;instrument;live cell imaging;regenerative;tissue regeneration

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Research into the cellular and molecular mechanisms of development and how these processes go awry in disease is greatly enhanced by the ability to study the expression of proteins and behavior of cells in living tissue. In this proposal funding s requested to enable the purchase of a lightsheet microscope a state-of-the-art fluorescence microscope that will permit long-term imaging of living specimens with unprecedented resolution. This instrument will significantly improve basic research programs aimed at understanding organ system development and regeneration cell-cell signaling circadian rhythms and neurobiology.


application_id: 9074053
project_number: 2T32ES007266-26A1
project_title: Training Grant in Molecular Mechanisms of Toxicity
project_terms: Grant;Molecular;Toxic effect;Training
administering_ic: NIEHS
award_notice_date: 2016-06-28
opportunity_number: PA-14-015
application_type: 2
activity_code: T32
ic: ES
serial_number: 007266
suffix: A1
program_official: SHREFFLER, CAROL A
project_start_date: 1990-07-01
project_end_date: 2021-06-30
study_section: Environmental Health Sciences Review Committee[EHS (TK)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: FAN, TERESA WHEI-MEI
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
project_abstract:
DESCRIPTION (provided by applicant)   
   
The objectives of the Molecular Mechanisms of Toxicity Training Program are to provide pre-doctoral trainees with a fundamental education in the mechanisms by which environmental exposures induce human disease integrated with the basic cellular processes upon which environmental agents impact and cause disease. The training program is based on an understanding of biochemistry physiology and molecular/cell biology toxicology courses in mechanisms by which environmental agents induce toxicity together with the cellular and molecular processes by which the body defends itself against environmental insult. This didactic training is intimately coupled with in-depth laboratory research training. The goal is to prepare the next generation of scientists to address the ever-present environmental challenges to human health by the prevention of disease either by nutritional or life-style intervention where possible or by otherwise exploiting human defense systems. The Training Program is based in the Department of Toxicology and Cancer Biology (DTCB) a basic science department in the College of Medicine that grants the Ph.D. in toxicology and provides an administrative and teaching nucleus of 18 Core Faculty. Joint Faculty from the Colleges of Medicine Pharmacy and Agriculture enrich the diversity of training opportunities; 26 of these Core and Joint Faculty with strong research programs make up the Training Grant Faculty. This application requests support for 4 pre-doctoral trainees and is focused on three disease areas that have an environmental basis: Cancer Cardiovascular Disease and Neurotoxicity/Neurodegenerative Disease. Oxidative stress DNA damage/repair and metabolomics are mechanistic themes that underlie many of the research programs and provide highly collaborative and multidisciplinary approaches to problems thereby providing a rich research training environment. The pre-doctoral training program requires a Biomedical Base (18 credits including Ethics in Scientific Research) a Toxicology Base (12-14 credits) and an Elective identified by the student's Advisory Committee (3 credits). Pre-doctoral trainees will be supported for a maximum of three years e.g. years 2-4 of doctoral training. Current enrollment in the Toxicology Ph.D. program is 25 including three Underrepresented Minority students. Recent minority graduates have been primarily recruited from the University of Puerto Rico and have been supported by T35 and R25 NIEHS mechanisms that support summer research experiences in Toxicology; this longstanding tradition of a diverse student body continues to attract new minority students to the training program. The University continues to provide strong support for the DTCB in the form of student fellowships supplementation to this Training Grant and new faculty lines space and equipment so that the program has grown vigorously over the last five years and is anticipated to continue to do so.


application_id: 9073542
project_number: 2T32ES011564-11A1
project_title: UofL Environmental Health Sciences Training Program
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2016-06-29
opportunity_number: PA-14-015
application_type: 2
activity_code: T32
ic: ES
serial_number: 011564
suffix: A1
program_official: SHREFFLER, CAROL A
project_start_date: 2004-07-01
project_end_date: 2021-06-30
study_section: Environmental Health Sciences Review Committee[EHS (TK)]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
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
project_abstract:
DESCRIPTION (provided by applicant)   
   
The investigators have made strategic changes in their environmental health sciences training program in response to the announced restructuring and redirection of NIEHS training programs. Participating Centers Institutes and Schools and the members of the training faculty provide critical resources for cutting edge basic science clinical research computational sciences and public health. Environmental health science partnerships have resulted in a very successful NIEHS training program in environmental health sciences.  The renewal application incorporates and integrates several Schools Centers and Institutes. The investigators propose a substantially improved pre-doctoral and postdoctoral training program that serves as an umbrella for interdisciplinary and integrated approaches to environmental health sciences. The training program will support six pre-doctoral and three postdoctoral trainees. Initial student recruitment and funding for pre-doctoral trainees is provided by the University of Louisville Integrated Programs in the Biomedical Sciences recruitment gateway.  As in the first cycle pre-doctoral trainees will not be recruited directly into the environmental health sciences training program. All faculty mentors are asked to nominate trainees who have completed an approved dissertation proposal with a defined focus in environmental health sciences research. Faculty mentors will be asked to nominate either existing postdoctoral fellows (for example those already matriculated into the Clinical Chemistry and Toxicology Translational Sciences Program) or from trainees to be recruited. Teams of mentors (basic and clinical scientists or basic and population-based scientists) will be particularly encouraged to emphasize the importance of multidisciplinary training and translation of basic science findings to the patient and/or community. The training program facilitates multidisciplinary approaches for effective intervention and interfaces exceptionally well with the NIH Roadmap as well as with the strategic plans of NIEHS and the University of Louisville.


application_id: 9072240
project_number: 2T35DK072923-11
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2016-03-09
opportunity_number: PA-14-016
application_type: 2
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2021-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animals;Authorship;Brain;Clinical;Conflict of Interest;Data;Diabetes Mellitus;Diabetic Nephropathy;Educational Curriculum;Endocrine;Endocrinology;Environment;Funding;Goals;Institutional Review Boards;Journals;Laboratories;Liver diseases;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Metabolism;NCI Scholars Program;National Institute of Diabetes and Digestive and Kidney Diseases;Outcome;Peer Review;Persons;Physicians;Pituitary Gland;Plagiarism;Publications;Publishing;Recruitment Activity;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Scientist;Structure;Students;Testing;Training;Training Programs;Training Support;Translational Research;Universities;Vertebrates;Work;base;career;design;ethnic disadvantage;ethnic minority population;experience;faculty research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver;peer;peer coaching;peptide hormone;posters;programs;responsible research conduct;skills;student training;summer research

public_health_relevance:
PUBLIC HEALTH RELEVANCE   
Understanding the aberrant hormonal and genetic regulation of cellular homeostasis is the key to unraveling chronic disease and to the development of new treatment strategies. The major goal of this project is to provide medical students who have completed at least one year of medical school with a hands-on summer research experience in NIDDK-focused research on endocrine-related health concerns to stimulate their interest in a research career.


application_id: 9072228
project_number: 1R24OD021479-01
project_title: Developing Regeneration Resources for a Model Amphibian
administering_ic: OD
award_notice_date: 2016-05-11
opportunity_number: PAR-13-252
application_type: 1
activity_code: R24
ic: OD
serial_number: 021479
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2016-06-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1 CB-J (55)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: THORSON, JON SCOTT
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accelerometer;Amaze;Ambystoma;Ambystoma mexicanum;Amphibia;Amputation;Animal Model;Biological;Biological Assay;Biological Process;Biology;CRISPR/Cas technology;Candidate Disease Gene;Cell Lineage;Cell Proliferation;Cells;Chemical Models;Chemicals;Chimeric Proteins;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Competence;Couples;Data;Development;Embryo;Epidermis;Event;FDA approved;Future;Gene Expression;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Models;Genetic Screening;Genetic Transcription;Guide RNA;Histology;Hormone use;Information Resources;Insertional Mutagenesis;Investigation;Knock-out;Libraries;Life;Maps;Mediating;Methods;Modeling;Molecular;Molecular Profiling;Monitor;Muscle satellite cell;Mutagenesis;Natural Products;Natural regeneration;Neuroglia;Organism;Pathway interactions;Pharmacology;Phenotype;Population;Process;Production;Reagent;Recruitment Activity;Regenerative Medicine;Regenerative response;Reporter;Reporting;Research;Research Infrastructure;Resources;Salamander;Signal Pathway;Signal Transduction;Signaling Protein;Site;Somatic Cell;Staging;Stem Cell Research;Stem cells;Tail;Testing;Thyroid Hormones;Time;Tissues;Transgenic Organisms;Tretinoin;Vertebrate Biology;blastema;chemical genetics;comparative efficacy;design;dosage;feeding;in vivo;inhibitor/antagonist;mutant;nerve stem cell;network models;notch protein;novel;progenitor;promoter;public health relevance;regenerative;screening;stem cell biology;tool;web site;wound


application_id: 9072003
project_number: 2T35ES014559-11
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2016-05-13
opportunity_number: PA-14-016
application_type: 2
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2021-04-30
study_section: Environmental Health Sciences Review Committee[EHS (TK)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: CAVE, MATTHEW C;MCCLAIN, CRAIG J.;SRIVASTAVA, SANJAY
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)   
   
This application is a competing renewal application for a T35 summer medical student training program in environmental health sciences research that has been funded by NIEHS for 10 years. The 2 specific aims are: 1) To provide hands-on training in basic and clinical environmental health-based research to medical students in a structured mentored environment; and 2) To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical environmental health-based research. A new feature (Distinction in Research Track) proposed will enhance training for the students to function as environmental health sciences specialists in an Academic Health Center setting. The program has supported the training of 6 second year-medical students each summer in environmental health sciences research topics including environmental cardiology environmental metabolic disease and environmental pulmonary disease with a particular focus on diabetes non-alcoholic fatty liver disease obesity and hormonal regulation of metabolism. Trainees can choose from research projects submitted by 23 mentors in the Schools of Medicine Dentistry and Public Health (ranking them 1-5 for interest) and are selected from the top half of the first year medical class at UofL for appointment to the T35 Training grant.  A successful effort has been made to recruit students from ethnic minorities and disadvantaged backgrounds. During the 11-week summer training students work with mentors on their research project in clinical or laboratory settings and complete training in the Responsible Conduct of Research (including topics on fabrication and falsification of data plagiarism managing scientific data publication practices and responsible authorship mentorship stewardship and conflict of interest). Trainees working with human subjects complete human subject and IRB training prior to beginning their research. Likewise trainees who will use vertebrate animals in their research are required to complete a training course for animal research. All trainees will attend a weekly "Environmental Health Sciences Conference" designed to introduce clinical and translational research in environmental health sciences to T35 trainees. The conference culminates with each Trainee presenting his/her research project to peers and mentors. Trainees also present the results of their research as posters with peers at a School of Medicine week-long celebration of research that includes nationally recognized physician scientists as keynote speakers. Training in the NIEHS T35 program will encourage students to participate in the new Distinction in Research (DIR) Track in the Medical School for a continued longitudinal research experience in years 2-4 of medical training which allows them to develop research-oriented skills and to complete a translational research project in the third/fourth years. Publication of peer-reviewed articles as some have achieved will serve as outcomes of DIR training as well as the strength of residency training and first/future permanent positions.

project_terms:
Animal Experimentation;Appointment;Authorship;Cardiology;Clinical;Clinical Research;Conflict of Interest;Data;Diabetes Mellitus;Environment;Environmental Health;Funding;Future;Grant;Health;Institutional Review Boards;Laboratories;Liver diseases;Lung diseases;Medical;Medical Students;Mentors;Mentorship;Metabolic Diseases;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Physicians;Plagiarism;Positioning Attribute;Public Health Dentistry;Publications;Recruitment Activity;Research;Research Project Grants;Research Training;Residencies;Scientist;Specialist;Structure;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;base;design;ethnic disadvantage;ethnic minority population;experience;health science research;hormone regulation;human subject;interest;medical schools;non-alcoholic fatty liver;peer;peer coaching;posters;programs;responsible research conduct;skills;student training;symposium

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request annual support for 6 medical student trainees for a 10-week training experience for the next 5 years. The overarching scientific theme of research that links the faculty to this T35 Training Grant is the common interest of the faculty in research
training of medical students in the investigators' laboratories in elucidating the health outcomes of exposure of normal and obese individuals to various environmental or common chemicals in the environment. In addition the investigators will use the T35 Training Grant to entice our medical students into their new Distinction in Research Track designed to allow students to pursue research interests throughout the 2-4 years of Medical School curriculum with an eye toward building a pipeline of diverse translational clinician-researchers in the future.


application_id: 9071384
project_number: 5R01CA188354-03
project_title: Non-peptide proteasome inhibitors as a novel anticancer agent
administering_ic: NCI
award_notice_date: 2016-05-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188354
program_official: VERMA, SHARAD KUMAR
project_start_date: 2014-07-07
project_end_date: 2019-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to develop next-generation proteasome inhibitors that will serve as effective therapies 1) for multiple myeloma (MM) patients refractory to the existing proteasome-targeting drugs bortezomib and carfilzomib as well as 2) for patients with solid cancers. In the last decade the FDA has approved the proteasome-targeting drugs bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) for the treatment of MM patients. These agents have greatly improved the prognosis of MM and firmly validated the proteasome as an important anticancer target. However many patients eventually develop resistance after prolonged proteasome inhibitor therapy and few effective treatment options exist for such patients. In addition the potential of proteasome-targeting drugs remain untapped for the treatment of solid cancers despite their promising anticancer activities in preclinical models of solid cancers. Thus it is critically important to develop novel proteasome inhibitors which can overcome the limitations of existing proteasome inhibitors and deliver the therapeutic benefits of proteasome inhibitor therapy to cancer patients of all types including solid cancers. We hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and solid cancer patients. This is based on the drawbacks arising from the structural features shared among bortezomib carfilzomib and nearly all proteasome inhibitors in drug development pipelines. Specifically the structural features of peptide backbones and reactive pharmacophores contribute to a high susceptibility to chemical/metabolic inactivation and off-target interactions causing unwanted toxicities and an inability to achieve sufficient drug penetration within solid cancer sites. Using step-wise screening approaches combining virtual screen and in vitro enzyme kinetics we identified several promising hits with diverse non-peptide scaffolds and proteasome inhibitory potencies. G4-1 a 135-substitutive pyrazole derivative is our current lead candidate displaying its anticancer activity in multiple cancer cel lines including cell lines resistant to bortezomib or carfilzomib. In addition to having excellentmetabolic stability G4-1 displayed promising anticancer efficacy and safety profiles in vivo. Withthe goal of further improving the potency and other pharmacokinetic properties of G4-1 to be suitable for oral dosing we propose the following aims: 1) to extend our lead optimization effortsin developing more potent proteasome inhibitors with improved drug-like properties 2) to investigate the cytotoxic mechanism of action of optimized non-peptide proteasome inhibitors and 3) to evaluate the in vivo anticancer efficacy safety and pharmacokinetic profiles of selected lead non-peptide proteasome inhibitors. Successful completion of the proposed work will yield novel non-peptide proteasome inhibitors that can advance to next stages of drug development efforts and ultimately lead to effective therapies for patients with MM and solid cancers.

project_terms:
Active Sites;Bioavailable;Bortezomib;Cancer Patient;Cancer cell line;Cell Line;Chemicals;Clinic;Clinical;Clinical Trials;Data;Dose;Drug Kinetics;Drug Stability;Drug Targeting;Drug resistance;Effectiveness;Enzyme Kinetics;Evaluation;FDA approved;Goals;Health;Hematologic Neoplasms;Human;In Vitro;Lead;Left;Libraries;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Mind;Molecular;Multiple Myeloma;Mus;Oral;Patients;Penetration;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Predisposition;Property;Proteasome Inhibitor;Pyrazoles;Refractory;Relapse;Research;Resistance;Resistance development;Safety;Solid;Specificity;Staging;Structure-Activity Relationship;Therapeutic;Toxic effect;Translating;Velcade;Vertebral column;Work;Xenograft procedure;anticancer activity;base;cancer cell;cancer site;cell killing;chymotrypsin;cytotoxic;design;drug candidate;drug development;effective therapy;improved;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;intraperitoneal;molecular dynamics;multicatalytic endopeptidase complex;next generation;novel;novel anticancer drug;novel therapeutics;outcome forecast;pharmacophore;pre-clinical;scaffold;screening;small molecule;success;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  With the remarkable success of the two proteasome inhibitor drugs bortezomib and carfilzomib in treating multiple myeloma patients extensive efforts have been under way to extend their therapeutic benefits to a larger number of patients with refractory multiple myeloma and those with solid cancers. However the effectiveness of the currently available proteasome inhibitors is limited by poor in vivo stability and unwanted toxicit arising from their structural features. In the proposed study we will develop proteasome inhibitors with novel structural scaffolds thus achieving improved stability efficacy and safety profiles against human multiple myeloma and solid cancers.


application_id: 9069894
project_number: 5R01GM109195-02
project_title: Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy
administering_ic: NIGMS
award_notice_date: 2016-06-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 109195
program_official: EDMONDS, CHARLES G
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The technological development of nanomaterials has been underway for decades. Only in the past decade has serious attention been paid to their potential unwanted health and environmental effects. Many nanomaterials do not readily dissolve or disintegrate in biological and environmental milieu. As a result they can persist where they are sequestered (in mammals mostly in mononuclear phagocyte system organs such as the liver spleen and bone marrow) for months possibly years often associated with inflammatory/oxidative stress responses including granuloma. These unwanted effects have been seen with nanoceria (nanoscale cerium dioxide). On the other hand nanoceria has been shown to be an effective anti-inflammatory/antioxidant in numerous cellular cell and whole animal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects result from its auto-catalytic redox behavior (oxidation from Ce (III) to Ce (IV) and reduction back to Ce(III)). The first specific aim of this project will determine if nanoceria can produce inflammatory/pro- oxidant effects in the absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects when inflammation/oxidative stress is elevated and determine the lowest observed adverse dose and lowest observed beneficial dose. Four nanoceria will be studied: a 5 and a 30 nm nanoceria extensively studied for their distribution persistence and effects in the rat (preliminary findings) and a third that others have demonstrated produces beneficial inflammatory/pro-oxidant effects. These three will be synthesized and extensively characterized in-house. The fourth will be NM-212 a commercial nanoceria that is being extensively studied by the inhalation route by others. Due to the very low oral and pulmonary absorption of nanomaterials nanoceria will be delivered by intravenous injection to establish sufficient levels in multiple organs to study its biodistribution persistene biotransformation and effects. Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammalian cells over months to a more stable form. This appears to occur via dissolution and formation of very small nanoceria particles. These very small nanoceria particles have a greater enrichment of Ce (III) on their surface; therefore they are expected to have enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced benefit over time associated with nanoceria's persistence and bioprocessing. The second specific aim will test the hypothesis that the distribution form and effects of nanoceria change over time due to its bioprocessing in the liver to smaller more antioxidant forms. The third specific aim will identify factors that contribute to nanoceria dissolution and precipitation and mediate its bioprocessing and precipitation in the liver. The proposed studies will identify nanoceria doses that maximize its efficacy relative to its unwanted effects elucidate nanoceria's long term fate in a model mammal the rat and provide the insight into its biotransformation that may enable safer by design nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.

project_terms:
3-Dimensional;Address;Adverse effects;Affect;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Area;Attention;Back;Behavior;Biodistribution;Biological;Biological Availability;Bone Marrow;Breathing;Buffers;Camping;Cells;Characteristics;Chemicals;Coculture Techniques;Development;Diesel Fuels;Dose;Employee Strikes;Environmental Health;Family;Future;Goals;Granuloma;Health;Housing;Inflammation;Inflammatory;Lipopolysaccharides;Liver;Lung;Mammalian Cell;Mammals;Measures;Mechanics;Mediating;Medical;Metabolic Biotransformation;Modeling;Mononuclear;Oral;Organ;Oxidation-Reduction;Oxidative Stress;Phagocytes;Physiological;Pilot Projects;Polishes;Precipitation;Property;Rattus;Reactive Oxygen Species;Recycling;Reporting;Research;Research Personnel;Route;Safety;Spleen;Stress;Surface;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;absorption;base;biological adaptation to stress;biological systems;bioprocess;body system;catalyst;ceric oxide;design;insight;interest;intravenous injection;metal oxide;nanomaterials;nanoscale;nanotherapy;novel;oxidation;particle;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cerium dioxide nanomaterials (nanoceria) have many current commercial uses including as a diesel fuel additive to catalyze combustion and in chemical-mechanical polishing to manufacture integrated circuits with future applications expected in fuel cells and batteries. Nanocerias have been shown to produce adverse effects as well as beneficial antioxidant/anti-inflammatory effects the latter suggesting potential medical applications. The proposed research will determine the influence of dose and biotransformation on long-term nanoceria effects with the goal of minimizing its adverse and maximizing its beneficial effects supporting its design for safe use for its many potential applications.


application_id: 9069362
project_number: 4R01AA019953-05
project_title: Receptor-mediated effects of ethanol in lung tissue injury and repair
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: PA-08-164
application_type: 4
activity_code: R01
ic: AA
serial_number: 019953
program_official: LIN, LI
project_start_date: 2012-09-01
project_end_date: 2018-05-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Respiratory Distress Syndrome the most severe form of acute lung injury has been found to occur more frequently in alcoholics. In fact chronic alcohol use is not only associated with increased incidence of acute lung injury but also increased mortality. Despite its importance the exact mechanisms by which alcohol abuse renders the host susceptible to acute lung injury remain poorly defined. We have identified a cell surface sensor for alcohol in lung cells and believe that it mediates many of the detrimental effects of alcohol in lung. In view of its perceived importance this project seeks to further characterize this 'alcohol receptor' and investigate its role in the development of acute lung injury in the setting of chronic alcohol exposure. The work proposed was prompted by novel observations showing that: 1) receptors members of the nicotinic acetylcholine receptor (nAChR) family mediate the effects of ethanol in lung fibroblasts and 2) that ethanol-induced oxidant stress (through oxidation of the extracellular cysteine/cystine redox potential) might directly activate nAChRs. These observations have important implications in vivo since we have shown that subjects with chronic alcohol abuse who are otherwise 'healthy' show evidence of oxidant stress as well as activation of lung tissue remodeling. Based on the above we hypothesize that chronic ethanol exposure renders the host susceptible to acute lung injury by acting on nAChRs present on lung cells. Furthermore we hypothesize that oxidant stress can amplify these events by activating nAChRs directly through actions on specific cysteine residues strategically located near the ligand binding site of the receptor; new preliminary data support this hypothesis. Ultimately downstream signals triggered by nAChRs result in a cascade of events that render the host susceptible to acute lung injury. This hypothesis will be tested in specific aims designed to: 1) Characterize the role of nAChRs in mediating the effects of ethanol in lung cells 2) Examine the mechanisms by which a specific form of oxidant stress influences ethanol-induced nAChR activation and 3) Determine the role of nAChRs in mediating ethanol-induced susceptibility to acute lung injury in vivo.

project_terms:
Acetaldehyde;Acute Lung Injury;Adult Respiratory Distress Syndrome;Affect;Alcohol abuse;Alcohol consumption;Alcohols;American;Animals;Antioxidants;Binding;Binding Sites;Biological Assay;Biology;Bronchoalveolar Lavage Fluid;Bungarotoxins;Cell surface;Cells;Chemicals;Chronic;Country;Cysteine;Cystine;Data;Development;Diagnosis;Diagnostic;Epithelial Cells;Ethanol;Event;Family;Fibroblasts;Fibronectins;Glycoproteins;Human;Incidence;Individual;Injury;Lead;Ligand Binding;Link;Lung;Matrix Metalloproteinases;Mediating;Methods;Neurotoxins;Nicotinic Receptors;Oxidants;Oxidation-Reduction;Phenotype;Point Mutation;Predisposition;Receptor Activation;Reporting;Research;Respiratory physiology;Risk;Rodent;Role;Signal Transduction;Small Interfering RNA;Structure of parenchyma of lung;Testing;Time;Tissues;Work;alcohol effect;alcohol exposure;alcohol use disorder;base;chronic alcohol ingestion;design;extracellular;in vivo;inhibitor/antagonist;injury and repair;interest;lung injury;lung repair;meetings;member;mortality;novel;oxidant stress;oxidation;problem drinker;receptor;respiratory distress syndrome;response;sensor

public_health_relevance:
Chronic ethanol use has been associated with increased susceptibility to acute lung injury a condition that affects over 200000 Americans and that is associated with ~40% mortality. This project will explore how ethanol exposure renders the host susceptible to this condition by examining the cellular mechanisms that mediate the effects of ethanol in lung cells and how this impacts lung injury and repair.


application_id: 9069361
project_number: 4R01AA020051-05
project_title: RAX PKR and ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AA
serial_number: 020051
program_official: AKBAR, MOHAMMED
project_start_date: 2012-09-01
project_end_date: 2018-05-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Fetal Alcohol Spectrum Disorders (FASD) are a range of permanent birth defects caused by maternal alcohol consumption during pregnancy. The prevalence of FASD in populations of younger school children is recently estimated as high as 2-5% in the United State and is more common than Down syndrome and autism. FASD-related costs are more than $6 billion annually. Identification of the mechanism of ethanol toxicity in the brain and determination of the effective therapeutic target(s) are cited as importat goals in the NIAAA Strategic Plan for 2009-2014.  Central nervous system (CNS) damage is a major feature observed in FASD patients. The cerebellum is one of the most sensitive areas in the CNS to ethanol toxicity. Neuronal loss is one of the most deleterious effects of ethanol and is responsible for many of the behavioral deficits observed in FASD. In the animal model exposure of infant rodents to ethanol during a portion of the brain growth spurt period - postnatalday (PD) 4 to 9 equivalent to the human third trimester - causes a significant loss of cerebellum Purkinje and granule neurons. However the underlying mechanism for ethanol-induced neuronal loss in the developing cerebellum is still largely unclear. The goal of this proposed study is to identify the mechanism underlying ethanol neurotoxicity and the novel target(s) for the prevention and treatment of FASD.  The double-stranded RNA (dsRNA)-activated protein kinase (PKR) organizes the cellular self-defense system in response to diverse physiochemical stresses or viral infection by regulating a variety of downstream target proteins and signal pathways. Activation of PKR by its intracellular activator RAX under physiochemical stress conditions leads to protein synthesis inhibition as well as apoptosis and has been implicated in the pathogenesis of a number of neurodegenerative diseases.  The central hypothesis of the proposed study is that RAX-mediated PKR activation regulates ethanol- induced neuronal loss in the developing cerebellum.  Specific Aim 1: To investigate whether PKR activation through RAX/PKR interaction regulates ethanol- induced neuronal apoptosis in the developing cerebellum of the mouse.  Specific Aim 2: To determine whether inhibition of PKR by targeting RAX or PKR expression or by PKR inhibitors alleviates ethanol-induced neuronal loss in the developing cerebellum of the mouse.  Specific Aim 3: To determine whether RAX+/- mice N-PKR-/- mice or PKR-inhibitor-injected mice are more resistant to ethanol-induced cerebellar behavioral dysfunction.

project_terms:
Affect;Animal Behavior;Animal Model;Animals;Apoptosis;Apoptotic;Area;Autistic Disorder;Behavioral;Binding;Brain;Cells;Cerebellum;Child;Congenital Abnormality;Cytoplasmic Granules;Development;Disease;Dominant-Negative Mutation;Double-Stranded RNA;Down Syndrome;Ethanol;Ethanol toxicity;Fetal Alcohol Spectrum Disorder;Functional disorder;Goals;Growth;Health;Human;In Vitro;Infant;Inhibition of Apoptosis;Investigation;Learning Disabilities;Mediating;Mental Retardation;Molecular;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Nervous System Trauma;Neuraxis;Neurodegenerative Disorders;Neurons;Outcome;Oxidative Stress;Pathogenesis;Patients;Play;Population;Prevalence;Prevention;Protein Synthesis Inhibition;Proteins;Psyche structure;Public Health;Reporting;Resistance;Rodent;Role;Schools;Series;Severities;Signal Pathway;Social Problems;Strategic Planning;Stress;System;Testing;Third Pregnancy Trimester;Transgenic Mice;United States;Virus Diseases;Weight;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;alcohol sensitivity;behavior test;behavioral impairment;behavioral study;cell type;cost;disability;eIF-2 Kinase;effective therapy;inhibitor/antagonist;innovation;mouse model;neuron apoptosis;neuron loss;neurotoxicity;novel;novel strategies;postnatal;response;therapeutic target

public_health_relevance:
This proposed study targets Fetal Alcohol Spectrum Disorders (FASD) a range of permanent birth defects caused by alcohol consumption during pregnancy. FASD is a national public health concern as those affected suffer a lifelong disability with no current cure. The outcome may identify therapeutic target(s) for the prevention or treatment of FASD.


application_id: 9069009
project_number: 4R01HD075783-04
project_title: Evaluating the long-term effects of Green Dot on teen dating violence prevention
administering_ic: NICHD
award_notice_date: 2017-01-26
opportunity_number: PA-09-169
application_type: 4
activity_code: R01
ic: HD
serial_number: 075783
program_official: WHITE, DELLA
project_start_date: 2013-09-06
project_end_date: 2018-11-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: FOLLINGSTAD, DIANE RUTH
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our purpose is to evaluate the longer-term impact of Green Dot across the Bluegrass an active bystanding-based randomized intervention trial in 26 high schools across Kentucky designed to reduce dating and sexual violence in a cohort of seniors as they transition into young adulthood. Our central question is: Does Green Dot continues to have an effect in changing the culture of violence acceptance and reducing violence perpetration among students exposed to Green Dot relative to those not exposed as this cohort enters young adulthood? In this prospective cohort of approximately 7500 students we will measure the individual level exposure to the Green Dot program and into young adulthood allowing us to estimate the risk of dating and sexual violence victimization and perpetration. Very few studies have prospectively estimated the risk of dating and sexual violence among a cohort randomized to a primary prevention intervention and followed into young adulthood. This R01 is also unique because cohort members will be followed independent of whether they do or do not attend college. Individually following this cohort of seniors represents a significant value-added and time-sensitive opportunity because the full implementation of Green Dot began in late 2011. Only now (2013-15) would we anticipate seeing an effect of Green Dot among rising seniors on changing bystanding and potentially reducing violence. Aim 1. Prospectively determine whether and how the Green Dot intervention reduces rates of teen dating and sexual violence into young adulthood by (a) changing social norms of violence acceptance (b) increasing active bystanding and (c) diffusing the intervention through peer networks. Approximately 7500 high school seniors who attended Kentucky high schools randomized to the Green Dot intervention (n~3750) or control schools (n~3750) will be followed 42 months into young adulthood. Aim 2. To determine the potentially modifying effects of participants' post-high school life experience on the association between exposure to the Green Dot intervention and bystanding actions teen dating and sexual violence incidence. Post-high school experience will be categorized as attending any form of college or university versus no additional education. Specific life stressors such as relationship status pregnancy military deployment family and peer violence and substance abuse will also be explored. This cohort study is appropriately powered (90%) to address both aims. Comparisons will be made at 6-month intervals and across the 42-month follow-up and the interaction of intervention by time will be evaluated. Generalized Estimating Equations will be used to test the impact of Green Dot over time while taking clustering of high schools and correlation among repeated measurements among individual students into account and adjusting for confounders. This prospective cohort builds upon a large population-based and promising primary prevention intervention designed to reduce dating and sexual violence among high school students and provides an important test of the longer-term efficacy of this program into young adulthood.

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

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


application_id: 9068816
project_number: 5R01AR067188-02
project_title: Interplay of androgens microbiota and immunoregulation in lupus
administering_ic: NIAMS
award_notice_date: 2016-08-10
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067188
program_official: MANCINI, MARIE
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Agonist;Androgen Receptor;Androgens;Autoimmune Diseases;Castration;Cell physiology;Complex;Cytoprotection;Data;Defect;Dendritic Cells;Development;Diabetes Mellitus;Disease;Environment;Estrogens;Exhibits;Feces;Female;Gonadal Steroid Hormones;Health;Human;Immune response;Immune system;In Vitro;Inbred NOD Mice;Incidence;Inflammatory;Insulin-Dependent Diabetes Mellitus;Intestines;Knowledge;Lead;Link;Lupus;Mediating;Men's Role;Microbiological Techniques;Modeling;Mus;Pathogenesis;Phytol;Play;Prevention strategy;Production;Property;Puberty;RXR;Receptor Signaling;Regulatory T-Lymphocyte;Role;Severity of illness;Systemic Lupus Erythematosus;Techniques;Therapeutic;Treatment Protocols;Tretinoin;Volatile Fatty Acids;Woman;base;commensal microbes;disorder prevention;fecal transplantation;gender difference;gut microbiota;immunoregulation;imprint;in vivo;innovation;male;men;metabolome;metabolomics;microbiota;mortality;mouse model;next generation sequencing;novel;novel therapeutics;sex


application_id: 9068720
project_number: 4R01AG029623-11
project_title: Role of TWEAK in skeletal muscle metabolism
administering_ic: NIA
award_notice_date: 2016-05-30
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2018-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
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 applicant): During last funding period we identified and established that TWEAK cytokine is a major regulator of skeletal muscle mass during aging and disuse conditions. We have now obtained strong evidence suggesting that the TWEAK causes insulin resistance in skeletal muscle. However the mechanisms by which TWEAK induces muscle atrophy or insulin resistance remain less well understood. PGC-1 cofactor plays a major role in regulation of skeletal muscle mass fiber-type composition and mitochondrial biogenesis. Our preliminary studies have shown that TWEAK suppresses the expression of PGC-1 and mitochondrial content and inhibits insulin signaling in skeletal muscle. We have also found that disuse conditions or type II diabetes involve the inducible expression of TWEAK receptor Fn14 (but not TWEAK itself) in skeletal muscle. Our initial analysis has revealed that both human and mouse Fn14 promoter contains CpG rich regions and that demethylation of Fn14 promoter could be a crucial event for the induction of Fn14 expression in skeletal muscle. In the next phase of this project we will investigate the mechanisms by which TWEAK causes sarcopenia disuse-related muscle atrophy and insulin resistance and how the expression of Fn14 gets up regulated in skeletal muscle in different conditions. We will address the following three specific aims: AIM I. Investigate the role of PGC-1 in TWEAK-mediated skeletal muscle atrophy in vivo. Hypothesis 1: TWEAK causes muscle atrophy and fiber-type switching through down-regulation of PGC-1 expression. AIM II. Investigate the key mechanisms by which TWEAK-Fn14 system induces insulin-resistance in adult and/or aged skeletal muscle. Hypothesis 2: TWEAK induces insulin resistance by inhibiting insulin receptor substrate (IRS1) phosphorylation and diminishing oxidative phosphorylation in skeletal muscle. AIM III: Investigate the molecular events leading to increased expression of TWEAK receptor Fn14 in skeletal muscle. Hypothesis 3: Demethylation of CpG islands in Fn14 promoter followed by binding of SP1 transcription factor triggers the expression of Fn14 in skeletal muscle in catabolic states. Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Atrophic;Binding;Binding Sites;Biogenesis;Chronic Disease;Computer Simulation;Consensus;CpG Islands;Denervation;Development;Diabetes Mellitus;Disease;Down-Regulation;Etiology;Event;Fiber;Funding;GLUT4 gene;Genetic;Glucose;HDAC4 gene;HDAC5 gene;Health;Heart failure;Human;IRS1 gene;Immobilization;In Vitro;Injury;Insulin;Insulin Receptor;Insulin Resistance;Lead;MAP3K7 gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Medicine;Methyltransferase;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;NF-kappa B;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;PPAR gamma;Pathway interactions;Phase;Phosphorylation;Physiological;Play;Population;Proteins;Regulation;Reporting;Role;Signal Transduction;Skeletal Muscle;Specificity;Syndrome;System;TRAF6 gene;Testing;Therapeutic Intervention;Transcription Initiation Site;Transgenic Organisms;Ubiquitin;Up-Regulation;aged;cofactor;cytokine;demethylation;diminished oxidative phosphorylation;epigenetic regulation;glucose uptake;improved;in vivo;inducible gene expression;insight;insulin sensitivity;insulin signaling;multicatalytic endopeptidase complex;muscle aging;muscle form;neuromuscular activity;new therapeutic target;novel;older patient;overexpression;prevent;promoter;receptor;research study;sarcopenia;skeletal;skeletal muscle metabolism;skeletal muscle wasting;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drug target to preserve muscle mass and function in aging human population.


application_id: 9068064
project_number: 5R01DA036553-03
project_title: Selective Monoamine Release as a Treatment for Cocaine Use Disorders
administering_ic: NIDA
award_notice_date: 2016-11-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036553
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
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:
DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e. 30-40) were the most effective and specific in terms of reducing cocaine taking. For example methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration PHEN is converted to phenmetrazine which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover PHEN reduces COC-maintained responding but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence which will enhance the probability of success when advanced to a clinical trial.

project_terms:
Abstinence;Attenuated;Behavior Therapy;Behavioral;Binding;Cardiovascular system;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Cocaine Users;Communities;Data;Development;Dextroamphetamine;Disease;Dopamine;Dose;Enrollment;Goals;Human;Laboratories;Laboratory Procedures;Laboratory Study;Maintenance;Methamphetamine;Methods;Modeling;Monkeys;National Institute of Drug Abuse;Norepinephrine;Obesity;Oral Administration;Outcome Measure;Parents;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phenmetrazine;Placebos;Presynaptic Terminals;Probability;Procedures;Psychostimulant dependence;Public Health;Research;Safety;Schedule;Self Administration;Serotonin;Specificity;Testing;amphetamine use;clinical efficacy;clinical practice;clinical predictors;cocaine use;drug reinforcement;experimental study;indexing;innovation;knowledge of results;laboratory experiment;monoamine;novel;pre-clinical;preclinical study;prevent;primary outcome;programs;public health relevance;reinforcer;reuptake;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preclinical data indicate that maintenance on selective monoamine releasers reduces cocaine taking. The goal of this project is to demonstrate that maintenance on a selective monoamine releaser with limited abuse potential phendimetrazine reduces cocaine taking in a sophisticated predictive human laboratory self- administration model.


application_id: 9067846
project_number: 5K23NR014883-03
project_title: Interventions in Nutrition Education and Skills
administering_ic: NINR
award_notice_date: 2016-03-02
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: NR
serial_number: 014883
program_official: DIANA, AUGUSTO
project_start_date: 2014-04-18
project_end_date: 2017-03-31
study_section: Nursing Science Review Committee[NRRC(58)]
contact_pi_person_id: 11333924
contact_pi: HARDIN-FANNING, FRANCES
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Individuals living in rural Appalachian food deserts have among the highest cardiovascular disease (CVD) rates in the nation. Nine risk factors account for 90% of all CVD risk and eight of those factors excluding smoking are influenced by nutritional habits. Diet is dependent upon individual and environmental factors particularly in rural food deserts where socioeconomic factors contribute to poor eating habits. Few researchers have developed and tested strategies aimed at improving dietary patterns in rural food deserts and there has been no significant improvement in the dietary behaviors of most rural Appalachians over the past several decades. Given the disproportionate CVD rates and economic disadvantage in this region it is vital to develop and test cost-effective interventions that target the individual and environmental barriers to healthy eating that are specific to this region. Through a training plan that includes mentoring by a team of nursing and nutritional scientists and formal course work seminars and a research study this K23 Award will engender the skills to develop and test novel interventions aimed at increasing consumption of CVD risk- reducing foods in rural Appalachia. The applicant completed her doctorate in nursing in 2011 and has since conducted preliminary studies that inform the need to develop and test individualized nutritional interventions that address the unique barriers to healthy eating in rura Appalachia. The broad hypothesis of this program of research is that nutritional behavior change interventions individualized to each participant's specific motivation and ability are more likely to yield long-term behavior change than standardized interventions delivered en masse. A pilot study will be conducted in six Appalachian food desert counties with participants in three counties serving as controls and participants in the other three counties receiving an individualized intervention. The specific aims of the study are to: 1) test the outcome of an individualized intervention aimed at increasing consumption of CVD-risk reducing foods and 2) determine whether health literacy financial status and risk of food insecurity moderate the effectof the intervention. Outcome variables will be measured using a food frequency questionnaire food security survey and by monitoring monthly grocery purchases. The combination of a structured training plan and the research project will support the applicant's long-term goal of becoming an independent investigator in primary CVD prevention focused on improving nutrition. Specifically the applicant will obtain training in the principles of a) conducting rigoous trials of individualized dietary interventions in the context of austere environments b) assessingnutritional status and c) improving scientific productivity (grant-writing and publishing). The research study will provide the preliminary data research skills and expertise needed to apply for R01 grant funding to conduct controlled trials of individualized interventions aimed at improving dietary patterns of individuals living in rural food deserts and other austere environments with similar barriers to healthy eating.

project_terms:
Accounting;Address;Alcohol consumption;Apolipoprotein A-I;Apolipoproteins B;Appalachian Region;Area;Behavior;Behavior Therapy;Cardiovascular Diseases;Chronic Disease;Consumption;Control Groups;Country;County;Data;Diet;Diet Habits;Dietary Intervention;Dietary Practices;Discipline of Nursing;Economically Deprived Population;Economics;Effectiveness;Environment;Environmental Risk Factor;Exhibits;Food;Food Preservation;Frequencies;Funding;Goals;Grant;Habits;Health;Health Food;Healthy Eating;Heart Diseases;Hypertension;Individual;Intervention;Knowledge;Knowledge acquisition;Life;Measures;Mentored Patient-Oriented Research Career Development Award;Mentors;Monitor;Motivation;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Outcome;Participant;Physical activity;Pilot Projects;Play;Population;Poverty;Productivity;Psychosocial Factor;Public Health;Publishing;Questionnaires;Research;Research Personnel;Research Project Grants;Risk;Risk Factors;Rural;Scientist;Smoking;Socioeconomic Factors;Structure;Surveys;Team Nursing;Testing;Training;Training Programs;United States;Waist-Hip Ratio;Work;Writing;base;behavior change;burden of illness;cardiovascular disorder prevention;cardiovascular disorder risk;control trial;cost;cost effective;effective intervention;empowered;food consumption;food security;group intervention;health literacy;high risk;improved;innovation;intervention effect;literacy;metropolitan;motivational enhancement therapy;nonmetropolitan area;novel;nutrition;nutrition education;personalized strategies;programs;research study;skills;theories;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The knowledge gained from this project will help fulfill the need for developing and testing individualized interventions aimed at improving eating habits and thereby lowering risk and cost burden of heart disease in rural Appalachian food deserts. Currently there has been little research on the effectiveness of dietary behavior change strategies aimed at reducing cardiovascular disease risk for this region which has the country's highest heart disease rates and is one of the most economically disadvantaged areas. This research has the potential to significantly impact short and long-term heart disease rates in this and similar regions.


application_id: 9067065
project_number: 261201300013I-0-26100005-1
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2016-04-30
contact_pi_person_id: 14073759
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF - TASK ORDER TITLE: CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) ; PERIOD OF PERFORMANCE 05/01/2015-04/30/2016

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

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


application_id: 9066684
project_number: 5R01DK098176-03
project_title: Thrombospondin 1 in obesity associated inflammation and insulin resistance
administering_ic: NIDDK
award_notice_date: 2016-05-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 098176
program_official: ABRAHAM, KRISTIN M
project_start_date: 2014-08-20
project_end_date: 2018-05-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: 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): Increased accumulation of adipose tissue macrophages (ATMs) promotes obesity-associated chronic inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese condition the mechanisms underlying ATMs recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice preliminary studies revealed a novel role for TSP1 in stimulating macrophage recruitment and activation in adipose tissue that contributes to inflammation and insulin resistance resulting from high fat diet-induced obesity (DIO). Moreover TSP1 promoting macrophage migration and activation is through the N-terminal domain and the type 1 repeats to interact with receptors LRP1 and CD36 respectively. Blocking the interactions of TSP1/LRP1 and TSP1/CD36 inhibited TSP1 stimulation of macrophage function. Based on these data we hypothesize that blockade of the stimulatory effect of TSP1 on macrophage function prevents/ameliorates obesity-associated inflammation and insulin resistance. To test this hypothesis in Aim 1 tissue specific TSP1 knockout mice will be used to definitively answer the question of whether adipocyte-derived TSP1 serves as a primary chemokine to stimulate macrophage accumulation in adipose tissue and promotes the development of obesity-associated inflammation and insulin resistance. In Aim 2 utilizing the identified stimulatory domains on TSP1 as targets based on their available x-ray crystal structures new decoy peptides will be designed by structure-based computational design strategy. The inhibitory effect of decoy peptides on TSP1stimulation of macrophage function will be tested. In Aim 3 whether blocking of TSP1/CD36 interaction can prevent/ameliorate obesity-associated inflammation and insulin resistance in vivo will be tested. Together these proposed studies may lead to novel therapeutics for obesity-induced insulin resistance and metabolic complications and therefore have significant clinical relevance.

project_terms:
Address;Adipocytes;Adipose tissue;Binding;CD36 gene;Cardiovascular Diseases;Cells;Chemotactic Factors;Chronic;Data;Development;Diet;Disease;Fibrosis;Genotype;Health;High Fat Diet;Human;Hypertension;In Vitro;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Kidney;Kidney Diseases;Knockout Mice;Lead;Macrophage Activation;Mediating;Mediator of activation protein;Metabolic;Modeling;Molecular;Mus;N-terminal;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Peptides;Phenotype;Play;Proteins;Reporting;Resistance development;Rodent;Role;Signal Transduction;Structure;TLR4 gene;Testing;Thrombospondin 1;Tissues;Visceral;Wild Type Mouse;Work;base;chemokine;clinically relevant;clinically significant;design;glucose tolerance;human subject;improved;in vivo;insulin sensitivity;macrophage;migration;novel;novel therapeutics;obesity treatment;prevent;receptor;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is prevalent worldwide and is associated with insulin resistance and the development of type 2 diabetes. The proposed studies will provide novel information on the mechanisms of obesity-induced adipose tissue macrophage infiltration and activation and importantly will develop novel therapeutic strategies in the treatment of obesity-induced insulin resistance a problem of immense clinical significance.


application_id: 9066573
project_number: 5R21AI113348-02
project_title: Engineering pancreatic islets with TG protein to overcome rejection
administering_ic: NIAID
award_notice_date: 2016-04-26
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 113348
program_official: BOURCIER, KATARZYNA
project_start_date: 2015-05-12
project_end_date: 2018-04-30
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) continues to be a major source of morbidity and mortality in over 0.9% US population with an economic burden in billions of dollars. The two current methods used to treat T1D are insulin therapy and allogeneic islet/pancreas transplantation (Tx) both of which have major limitations. Insulin administration does not completely prevent the complications associated with diabetes. Allogeneic islet/pancreas Tx suffers from rejection as well as renal and islet toxicities associated with chronic use of immunosuppressive drugs. Therefore the primary objective of this grant proposal is to establish a novel immunomodulatory protocol to confer tolerance to allogeneic islet grafts inthe absence of continuous immunosuppression. This will be achieved by engineering allogeneic islets ex vivo to transiently display on their surface a novel form of TGF1 SA-TGF protein and use the engineered islets to induce tolerance and treat T1D using rodent models.  T1D and allogeneic islet cell destruction is primarily mediated by T cells directed at unique beta cell and Tx antigens. Controlling the function of T pathogenic cells is therefore critical to tolerance induction to auto/alloantigens and treatment of T1D using allogeneic islets. We herein propose to use SA-TGF as an immunomodulatory molecule to achieve this goal. TGF1 has pleiotropic immune functions and is critical for tolerance to self-antigen. TGF also plays an important role in acquired tolerance to auto and alloantigens using various immunomodulatory approaches. Most importantly ectopic expression of TGF in pancreatic islets using transgenic systems or viral vectors proved effective in inducing tolerance to autoantigens in NOD mouse model of human T1D. However continuous expression of this molecule is associated with massive fibrosis and long-term beta cell failure. Importantly transient expression of TGF in beta cells using inducible transgenic systems overcame its deleterious effects without compromising its tolerogenic function. Inasmuch as this transgenic approach is not applicable to clinical islet Tx we envisioned that the transient display of TGF at protein level on the surface of islets in a clinically applicable manner may achieve tolerance without its reported complications arising from continuous expression. In limited preliminary studies we demonstrated that the transient display of SA-TGF on pancreatic islets was effective in overcoming rejection in a chemically induced islet Tx model. Building on these strong preliminary data we herein propose to use SA-TGF-engineered allogeneic islets as a means of immunomodulation to prevent graft rejection and treat diabetes in chemically and spontaneously diabetic mouse models. A series of studies will be conducted to delineate the implicated mechanisms of the tolerance. Rapid and transient display of SA-TGF protein on pancreatic islets offers a whole new means of intervention in the areas of autoimmunity and Tx. This approach possesses the simplicity safety and efficacy required to make it a clinically relevant alternative that may accomplish the same goals as gene therapy in the treatment of a broad spectrum of immune-based diseases including T1D.

project_terms:
Affect;Affinity;Alloantigen;Allogenic;Antigens;Applications Grants;Area;Autoantigens;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Beta Cell;Biological;Biotin;C57BL/6 Mouse;Cells;Characteristics;Chimeric Proteins;Chronic;Clinical;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Economic Burden;Ectopic Expression;Engineering;Failure;Family suidae;Fibrosis;Generations;Goals;Graft Rejection;Graft Survival;Health;Homeostasis;Human;IL2RA gene;Immune;Immune response;Immune system;Immunosuppressive Agents;Inbred BALB C Mice;Inbred NOD Mice;Insulin;Insulin-Dependent Diabetes Mellitus;Intervention;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Kidney;Ligands;Maintenance;Mediating;Membrane;Memory;Methods;Modeling;Molecular;Molecular Chaperones;Morbidity - disease rate;Mus;Natural immunosuppression;Natural regeneration;Pancreas;Pancreas Transplantation;Pharmaceutical Preparations;Play;Population;Proteins;Protocols documentation;Recovery;Regulation;Regulatory T-Lymphocyte;Reporting;Rodent Model;Role;Safety;Series;Signal Transduction;Sirolimus;Source;Splenocyte;Streptavidin;Suggestion;Surface;System;T-Lymphocyte;Therapeutic;To autoantigen;Toxic effect;Transforming Growth Factor beta;Transgenic Organisms;Transplantation;Viral Vector;base;clinically relevant;crosslink;design;diabetic;effective therapy;efficacy testing;gene therapy;human disease;immune function;immunoregulation;improved functioning;islet;lymph nodes;macrophage;mortality;mouse model;novel;novel strategies;pleiotropism;prevent;receptor;standard care

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the population worldwide. Insulin as a standard treatment although effective in treating T1D has major long-term complications therefore the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. In this application we propose a novel engineering approach to display an immunomodulatory protein on the surface of allogeneic pancreatic islets (a source of insulin producing beta cells) and use the engineered islets to cure T1D in a mouse model (NOD) of the human disease without continuous use of immunosuppressive drugs; If effective this approach may have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9066278
project_number: 3R01DA032910-03S1
project_title: Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment
administering_ic: NIDA
award_notice_date: 2015-05-12
opportunity_number: RFA-DA-12-001
application_type: 3
activity_code: R01
ic: DA
serial_number: 032910
suffix: S1
program_official: SHIH, MING L
project_start_date: 2012-03-01
project_end_date: 2017-02-28
study_section: ZDA1-JXR-D(06)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Development of a truly effective anti-cocaine medication has been very challenging particularly for treatment of cocaine overdose. There is still no FDA-approved anti-cocaine medication. Enhancing cocaine metabolism by administration of butyrylcholinesterase (BChE) has been recognized as a promising treatment strategy for cocaine abuse. However the catalytic activity of this plasma enzyme is low against the naturally occurring (-) - cocaine. Our recent integrated computational-experimental effort has led to discovery of high-activity mutants of human BChE known as cocaine hydrolases (CocHs) with >1000-fold improved catalytic efficiency against cocaine compared to wild-type BChE. In vivo evidences indicate that our discovered CocHs are promising candidates for development of an anti-cocaine medication especially for the overdose treatment. In this proposed project we focus on the selection and optimization of the most promising CocH as a novel therapeutic candidate for cocaine overdose treatment through a combined use of various in silico in vitro and in vivo approaches. The specific aims are: (1) To prepare and characterize the discovered CocHs in vitro for their catalytic activity and stability; (2) To characterize the CocHs in vivo for their potency biological/circulatory half-lives and immunogenicity by using the CocH materials prepared in Aim 1; (3) To design prepare and characterize new CocH entities that have not only a high in vivo potency but also a higher thermal stability and a longer circulatory half-life without immunogenicity. Accomplishment of this proposed investigation will result in the identification and development of the most promising CocH entity that has a high in vivo potency in the protective and rescuing effects a high stability and a sufficiently long biological half-life without immunogenicity. The CocH entity optimized in this investigation is expected to be highly effective and safe as an exogenous enzyme for cocaine overdose treatment in humans.

project_terms:
Acute;Amino Acids;Antibodies;Binding (Molecular Function);Binding Sites;Biological;Butyrylcholinesterase;Clinical Trials;Cocaine;Cocaine Abuse;Computer Simulation;Development;Dose;Drug Kinetics;Enzymes;FDA approved;Goals;Goat;Half-Life;Human;Hydrolase;In Vitro;Investigation;Investigational Drugs;Medical;Metabolism;Milk;Mutation;Neuraxis;Neurons;Overdose;Pharmaceutical Preparations;Pharmacodynamics;Plasma;Production;Proteins;Technology;Toxic effect;Transgenic Organisms;Vaccines;Work;addiction;base;cocaine overdose;design;enzyme therapy;immunogenicity;improved;in vivo;large scale production;mutant;novel;novel therapeutics;public health medicine (field);research study;scale up;small molecule;social;stable cell line;therapy development;treatment strategy

public_health_relevance:
Accelerating cocaine metabolism has been recognized as a promising treatment strategy for anti-cocaine medication. Accomplishment of the proposed investigation will result in the identification of reliable candidates of a novel enzyme therapy for cocaine overdose.


application_id: 9066059
project_number: 4R37AI052218-15
project_title: In vitro glycorandomization of natural products
administering_ic: NIAID
award_notice_date: 2016-05-19
opportunity_number: PA-11-260
application_type: 4
activity_code: R37
ic: AI
serial_number: 052218
program_official: DAVIS, MINDY I
project_start_date: 2002-06-03
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The attachment of sugars to naturally-occurring and/or synthetic small molecules can dramatically influence the corresponding mechanism pharmacodynamics pharmacokinetics and even patent life of the parental structure. Yet due to the technical challenges associated with conventional glycosylation strategies the application of glycosylation in the context of drug discovery and/or development remains underexplored. An overarching aim of this program has been to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of target scaffolds to ultimately enable such drug discovery/development exploration. Toward this goal the first phase of this study (years 1-5) led to the key proof of concept for  chemoenzymatic glycorandomization (a one pot three enzyme strategy capable of activating and attaching free monosaccharides to complex natural product scaffolds) and also provided fundamental information regarding two critical but poorly understood enzyme classes (anomeric sugar kinases and sugar-1-phosphate nucleotidylyltransferases). The second phase of this project (years 6-10) dramatically expanded the attempted application of this first generation system toward a range of diverse scaffolds leading to success in many cases but also exposing key limitations of the platform. Importantly the work conducted during the second phase also led to fundamental new knowledge regarding glycosyltransferase (GT)-catalyzed reactions that serves as the basis from which to launch the third phase of this study. Specifically the proposed third phase of this study (years 11-15) takesadvantage of our recent abilities to evolve highly permissive GTs and also drive GT-catalyzed reactions in reverse to enable next generation single enzyme or dual enzyme transglycosylation strategies for differential glycosylation of an array of structurally-diverse scaffolds (including natural product-based or synthetic glycosylated or non-glycosylated parental scaffolds). We propose to take full advantage of the current state of the art to: i) narrow the gaps of knowledge in understanding functional GT structure-activity-relationships; ii) specifically develop a range o catalysts for the production of novel sugar nucleotides (anticipated to be of broad use to the glycobiology community); iii) develop a range of catalysts for the differential glycosylation of a key set of structurally diverse anti-infective and anticancer scaffolds; and iv)exploit the corresponding differentially glycosylated scaffolds as a novel source for the discovery of new antiinfective  and anticancer leads.

project_terms:
Amino Acids;Anti-Bacterial Agents;Anti-Infective Agents;Antiviral Agents;Automobile Driving;Biological;Biological Assay;Cardenolides;Catalysis;Cell Proliferation;Chemistry;Ciprofloxacin;Collaborations;Communities;Complement;Complex;Daptomycin;Development;Directed Molecular Evolution;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Evolution;Generations;Glucose;Glycobiology;Glycosides;Goals;In Vitro;Investments;Knowledge;Legal patent;Libraries;Life;Macrolides;Methods;Minocycline;Modeling;Monosaccharides;Mutagenesis;National Institute of Allergy and Infectious Disease;Natural Products;Novobiocin;Nucleotides;Pharmacodynamics;Phase;Phosphotransferases;Positioning Attribute;Predisposition;Production;Pyrimidine;Reaction;Reagent;Sirolimus;Source;Specificity;Structural Models;Structure;Structure-Activity Relationship;System;Thymidine;Toxic effect;Uridine;Ursidae Family;Variant;Vertebral column;Work;analog;anticancer activity;base;bufadienolide;catalyst;design;design and construction;drug development;drug discovery;functional group;glycosylation;glycosyltransferase;innovation;inorganic phosphate;liquid chromatography mass spectrometry;member;next generation;novel;pathogen;pre-clinical;progenitor;programs;research study;scaffold;screening;small molecule;success;sugar;sugar nucleotide;tool;user-friendly

public_health_relevance:
We propose to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of complex target scaffolds to enable glycoconjugation as a tool for drug discovery and development. The models selected as part of the current study are anticipated to hold particularly high potential for the discovery of new antibacterial antiviral and anticancer leads.


application_id: 9065726
project_number: 4R01ES021502-05
project_title: FRESH: Dual Home Screening for Lung Cancer Prevention
administering_ic: NIEHS
award_notice_date: 2016-05-23
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: ES
serial_number: 021502
program_official: BOYLES, ABEE
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The purposes of this randomized controlled trial are to test the effectiveness of Freedom from Radon Exposure and Smoking in the Home (FRESH) a dual home screening and tailored environmental feedback intervention designed to reduce environmental risks for lung cancer and to identify factors associated with monetary incentives for radon mitigation. The combination of firsthand smoke secondhand smoke (SHS) and radon exposure increases the risk of lung cancer nearly tenfold. The long-term goals are to foster environmental justice by reducing home exposure to radon and SHS and to promote equity in radon mitigation by policy change to provide tax credits. A randomized controlled trial enrolling 550 primary care patients will test four hypotheses controlling for contextual factors of age gender home smoking and socioeconomic status (SES): 1) Those who receive FRESH will be more likely to take action to test and mitigate for radon and institute and enforce a smoke-free home policy compared to the control group; 2) Those receiving FRESH will have lower radon and home SHS levels at 15 months post-intervention compared to the control group; 3) Those who receive FRESH will have greater increases in perceived risk of lung cancer and synergistic risk perception (SHS x radon) health-related self-concept readiness to change and self-efficacy to prevent lung cancer and a greater decrease in lung cancer worry compared to controls at 15 months post-intervention; and 4) Those with at least one smoker in the home will be less likely to take action to reduce exposure to radon and SHS. The Treatment group (n = 275) will receive free test kits in the primary care clinic to measure their homes for radon and SHS at baseline receive their test results and the tailored environmental feedback intervention and take part in baseline and three follow up online surveys and home testing 15 months post-intervention. Those with high radon will receive a voucher for 30% of the cost up to $600 for radon mitigation. The Control group (n = 275) will receive information on how to request test kits for radon and SHS and a brochure on radon and SHS and take part in all study surveys. Participants in both groups will be asked to test their homes for radon and SHS 15 months post-intervention. Project      The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home.

project_terms:
Address;Adopted;Adoption;Age;Area;Behavior;Clinic;Clinical;Control Groups;Counseling;Effectiveness;Enrollment;Environmental Risk Factor;Environmental Tobacco Smoke;Event;Exposure to;Feedback;Fostering;Freedom;Gender;Goals;Government;Health;Home environment;Housing;Incentives;Institutes;Intervention;Malignant neoplasm of lung;Measures;Modeling;Non-smoker;Pamphlets;Participant;Patients;Policies;Preventive service;Primary Health Care;Process;Psychosocial Factor;Public Health;Radon;Randomized Controlled Trials;Readiness;Research;Risk;Risk Factors;Safety;Screening for Lung Cancer;Secondary Prevention;Self Concept;Self Efficacy;Smoke;Smoke-free home;Smoker;Smoking;Socioeconomic Status;Staging;Surveys;Taxes;Test Result;Testing;Tobacco Use Cessation;Tobacco smoke;base;behavior change;cancer diagnosis;contextual factors;cost;environmental justice;environmental tobacco smoke exposure;follow-up;heuristics;high risk;innovation;intervention effect;lung cancer prevention;neglect;post intervention;prevent;prospective;remediation;risk perception;screening;therapy design;treatment group;voucher

public_health_relevance:
The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home


application_id: 9065720
project_number: 5R03DK101705-03
project_title: Reducing Diabetes Risk for Rural Appalachian Grandparent Headed Households
administering_ic: NIDDK
award_notice_date: 2016-04-28
opportunity_number: PAR-13-074
application_type: 5
activity_code: R03
ic: DK
serial_number: 101705
program_official: WADDY, SALINA P
project_start_date: 2014-07-01
project_end_date: 2017-11-30
study_section: ZDK1-GRB-9(J1)S
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Residents of rural Appalachian Kentucky suffer rates of type II diabetes mellitus (DM) that are among the highest and most rapidly increasing in the country. Members of grandparent headed households (GHH) one of the fastest growing family constellations in rural Appalachian Kentucky and the US may be particularly vulnerable to health threats elevating their risk for DM. While the literature provides a starting point for the examination of this health disparity little is known about the socioecological factors that influence the risk for DM among GHH. Given the increasing prevalence of GHH their vulnerability to health threats and the current lack of information about their DM risk factors w propose to holistically examine the socio-ecological context of the health of GHH in rural Appalachian Kentucky in order to implement a culturally and contextually appropriate family intervention to reduce diabetes risk. We will conduct a two phase mixed methods study that culminates in a feasibility trial of such an intervention in rural Appalachian Kentucky. Phase I ofthe proposed study will utilize a simultaneous mixed methods design to assess socioecologic and biological risk of diabetes for GHH family members via surveys biological measures in-depth interviews with family members key informants interviews and a community assessment. Seventy families that are headed by a grandparent have one or more family members at risk for diabetes and include at least one grandchild ages 10 to 14 will be included in this phase of the study with 20 of those families participating in the in-depth qualitative interviews. Phase II of he study will include selection and refinement of an appropriate intervention to reduce diabetes risk for the families. Based on phase I findings and existing literature we will select an evidence based intervention and refine it to be culturally and contextually appropriate for the rural Appalachian families that are the focus of this project in collaboration with our strong network o community partners. Finally we will test he feasibility and acceptability of the refined intervention with 10 GHH. The proposed study will serve as the foundation for interventions for families in other rural areas with notable diabetes disparities.

project_terms:
Address;Adult;Advocacy;Affect;Age;American;Appalachian Region;Area;Asthma;Belief;Biological;Caregivers;Caring;Censuses;Centers for Disease Control and Prevention (U.S.);Child;Chronic Disease;Collaborations;Communities;Coronary heart disease;Country;Data;Development;Diabetes Mellitus;Emotional;Employment;Evidence based intervention;Family;Family health status;Family member;Food;Foundations;Goals;Head;Health;Health behavior;Health behavior outcomes;Household;Household Heads;Household and Family;Hypertension;Intervention;Interview;Kentucky;Life;Literature;Measures;Medical;Mental Depression;Methods;Minority;Non-Insulin-Dependent Diabetes Mellitus;Phase;Physical activity;Physical environment;Physically Handicapped;Population;Poverty;Predisposing Factor;Prevalence;Preventive;Public Health;Research;Risk;Risk Factors;Risk Reduction;Rural;Social Environment;Social Health Services;Socioeconomic Status;Stress;Substance abuse problem;Surveys;System;Testing;Vulnerable Populations;Work;base;design;diabetes control;diabetes risk;experience;grandchild;grandparent;health care availability;health disparity;informant;innovation;member;nutrition;peer;phase 2 study;prevent;rural area;sedentary lifestyle;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Rapidly increasing rates of type 2 diabetes mellitus are a pressing public health concern. Residents of rural Appalachian Kentucky suffer disproportionately from this chronic disease. Members of grandparent headed households may be especially vulnerable to this threat for a number of reasons. The proposed project will allow us to holistically examine the socio-ecological context of this condition in this vulnerable group.We will also develop and pilot a culturally and contextually appropriate family intervention to reduce diabetes risk in grandparent headed households.


application_id: 9065696
project_number: 4R01CA166327-04
project_title: Regulation of Tumor Metabolism by Retinoblastoma Protein
administering_ic: NCI
award_notice_date: 2016-05-18
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 166327
program_official: SPALHOLZ, BARBARA A
project_start_date: 2013-06-01
project_end_date: 2018-05-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 8077717
contact_pi: CLEM, BRIAN F
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tumorigenesis requires not only loss of proliferative control but also a metabolic shift towards increased glucose and glutamine consumption required for increased energy production and to drive the de novo biosynthesis of nucleotides amino acids and lipids essential for cell division. These processes are primarily driven through oncogenes or loss of tumor suppressors which act to circumvent normal regulatory pathways. The retinoblastoma (Rb) protein the first described tumor suppressor is extensively involved in cell cycle regulation and perturbations within the Rb pathway are found in most tumor types. Beyond cell cycle control Rb has been implicated in multiple additional biochemical pathways known to be involved in tumor progression such as metastasis and angiogenesis. However little is known about the role of Rb in regulating the unique changes in metabolism that have been observed in human cancers. Using stable 13C-glucose isotopomer NMR analyses we found that triple knock-out (TKO) of all three Rb family members in mouse embryonic fibroblasts (MEFs) resulted in increased glucose uptake and flux to lactate and simultaneously decreased glucose-derived carbon incorporation into TCA cycle intermediates relative to wild-type (WT) MEFs. This metabolic shift was mediated by changes in the expression of multiple glycolytic enzymes including increased Glut-1 HK2 PK-M2 levels and decreased HK1 ALT1 and PCB. To supplement this loss of glucose carbons for anaplerosis within the TCA cycle we speculated that the Rb TKO MEFs may increase glutamine uptake for both bioenergetic and anabolic precursors. We observed that loss of Rb caused increased 13C- glutamine uptake and flux into glutamate and TCA cycle intermediates via enhanced expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). Further glutamine carbon is capable of facilitating oxygen consumption and glutamine withdrawal resulted in significant decrease in ATP levels in the TKO cells. Importantly this shift towards glutamine utilization was essential fo the survival of Rb TKO MEFs and not for the WT MEFs and addition of exogenous -ketoglutarate was able to rescue both ATP levels and cell viability in the Rb-depleted cells. Mechanistically E2F-1 -2 & -3 functionally alter both glucose and glutamine uptake and E2F-1 & -3 were observed to directly associate with the promoters of Glut-1 and ASCT2. Combined these studies suggest that the Rb/E2F cascade directly regulates two key metabolic pathways that are necessary for neoplastic growth. We hypothesize that inactivation of the Rb protein in human cancers leads to a global metabolic shift towards enhanced glycolysis and glutamine utilization which in turn is required for neoplastic immortalization and transformation. We will test this hypothesis by conducting the following Specific Aims: 1. To determine the precise metabolic transporters enzymes and pathways that are modulated by the loss of Rb and the relative requirements of these metabolic targets for the survival and growth of Rb-proficient and Rb-deficient MEFs human normal epithelial cells and human cancer cells. 2. To determine the effects of Rb1 deletion on glucose/glutamine metabolism and growth of lung adenocarcinomas in vivo. 3. To correlate the loss of Rb function with changes in the 13C-glucose utilization by human lung tumors in vivo.

project_terms:
ATP Synthesis Pathway;Affect;Alanine Transaminase;Amino Acids;Antineoplastic Agents;Biochemical Pathway;Bioenergetics;Biological Markers;Cancer Etiology;Carbon;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Survival;Cell division;Cells;Characteristics;Citric Acid Cycle;Complex;Consumption;Data;Development;E2F transcription factors;E2F1 gene;Embryo;Enzymes;Epithelial Cells;Family member;Fibroblasts;Functional disorder;Gene Expression;Genes;Genomics;Glucose;Glutamates;Glutaminase;Glutamine;Glycolysis;Growth;HK2 gene;Health;Histones;Human;Knock-out;Knockout Mice;Lipids;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Molecular Target;Mus;Neoplasm Metastasis;Neoplasms;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Nucleotide Biosynthesis;Oncogenes;Oxygen Consumption;Pathway interactions;Polychlorinated Biphenyls;Positron-Emission Tomography;Process;Production;Promoter Regions;Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Retinoblastoma;Retinoblastoma Protein;Role;TOCSY;Testing;Transcription Repressor/Corepressor;Tumor Suppressor Proteins;Wild Type Mouse;Withdrawal;alpha ketoglutarate;angiogenesis;base;bcr-abl Fusion Proteins;c-myc Genes;cancer cell;cell transformation;chromatin remodeling;enzyme pathway;glucose uptake;in vivo;macromolecule;metabolic phenotype;mitochondrial metabolism;neoplastic;neoplastic cell;potential biomarker;promoter;small molecule;tumor;tumor initiation;tumor metabolism;tumor progression;tumorigenesis;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We anticipate that these studies will further expand our understanding of the role of the retinoblastoma protein (Rb) in tumor initiation and progression by detailing the precise regulatory mechanisms of Rb on tumor cell metabolism. These findings also may enable the identification of new molecular targets for development of anti-cancer agents as well as potential biomarkers for tumors that may be more responsive to anti-metabolic therapies.


application_id: 9065680
project_number: 4R01CA175003-04
project_title: Activating Bax as a therapeutic strategy for lung cancer
administering_ic: NCI
award_notice_date: 2016-06-01
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 175003
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2013-08-01
project_end_date: 2018-05-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However many of these strategies target the interaction among various Bcl-2 proteins particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein Bax s involved in the development of tumors and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigmsdirect activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.

project_terms:
Address;Alleles;Anus;Apoptosis;Apoptosis Regulation Gene;Apoptotic;BCL-2 Protein;BCL2 gene;Bax protein;Binding;Biochemical;Biological;Cancer Patient;Carboplatin;Cell Death;Cells;Cellular biology;Cessation of life;Computer Simulation;Development;Electrophysiology (science);Generations;Growth;Health;Human;In Situ;In Vitro;Inhibition of Apoptosis;Killings;Lead;Ligands;Link;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Mus;Neoplasm Transplantation;Organelles;Patch-Clamp Techniques;Pathway interactions;Pharmaceutical Preparations;Process;Property;Protein Family;Resistance;Role;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Time;Toxic effect;Transplantation;Tumor Cell Line;Xenograft Model;base;cancer cell;cancer therapy;cytotoxic;cytotoxicity;design;improved;in vivo;inhibitor/antagonist;neoplastic;neoplastic cell;novel;novel therapeutics;pharmacophore;preclinical study;pro-apoptotic protein;research study;screening;small hairpin RNA;small molecule;small molecule libraries;tumor;tumor growth;tumor xenograft;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is designed to address the question of whether inducing apoptosis by direct activation of the pro- apoptotic protein Bax will be an effective chemotherapeutic treatment for cancer. By carrying out the experiments proposed in this study we hope to develop agents for the selective activation of Bax as a novel anti-neoplastic strategy.


application_id: 9064405
project_number: 1R21AI122894-01
administering_ic: NIAID
award_notice_date: 2016-01-20
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 122894
program_official: PESCE, JOHN T
project_start_date: 2016-02-01
project_end_date: 2018-01-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-02-01
project_title:
The cell cycle of T. gondii bradyzoites within tissue cysts:in vivo development of an HIV-AIDS opportunistic parasite

project_abstract:
DESCRIPTION (provided by applicant): Toxoplasmic encephalitis (TE) is one of the HIV-AIDS defining opportunistic infections that is associated with the reactivation of the chronic form of te infection mediated by bradyzoites within tissue cysts in the CNS. Despite the central role in the
pathogenesis of HIV-AIDS associated toxoplasmosis little is known about the biology of tissue cysts and the bradyzoite stage of the parasite they contain. Among the key limitations in studying the progression of the chronic phase and the mechanisms by which latency is established maintained and lost during reactivation has been that rigorous insights into the physiology and development of bradyzoites in vivo has not been possible. Toward removing this major limitation we have initiated a comprehensive research program to understand bradyzoite biology by the development of approaches that directly address bradyzoite replication within tissue cysts in the in vivo context. These initial studies reveal that bradyzoites possess a previously unappreciated capacity for replication and metabolism that can be exploited in the development drugs to target what has been a traditionally refractory state. With the present study we aim to establish not only a new paradigm for bradyzoite biology but also develop the experimental methodologies to dissect bradyzoite replication we have been able to conclusively detect occurs challenging the existing dogma that bradyzoites are largely dormant entities. Our initial studies provide a new window into the dynamics of bradyzoite growth within tissue cysts which exhibit a level of complexity and sophistication that has not been previously appreciated. In this exploratory and developmental study we focus on the generation of new experimental approaches to directly interrogate and dissect the progression of the cell cycle within bradyzoites. Such insights would fill a vast gap in our knowledge that has stymied the development of treatments that are targeted toward the elimination of tissue cysts and bradyzoites. Targeting of tissue cysts and bradyzoites would eliminate the primary trigger of toxoplasmic encephalitis in the HIV-AIDS.

project_terms:
Accounting;Acquired Immunodeficiency Syndrome;Acute;Address;Animals;Biochemical;Biology;Blood;Bromodeoxyuridine;Cell Culture Techniques;Cell Cycle;Cell Cycle Progression;Cerebral Toxoplasmosis;Chronic;Chronic Phase;Cyst;Cytokinesis;DNA biosynthesis;Data;Development;Disease;Drosophila genus;Effectiveness;Encephalitis;Event;Exhibits;Exploratory/Developmental Grant;Foundations;Gene Expression;Generations;Growth;HIV;Housing;Human;Immune;Incidence;Infection;Knowledge;Label;Life;Life Cycle Stages;Maintenance;Meat;Mediating;Metabolism;Methodology;Methods;Molecular;Monitor;Natural immunosuppression;Nucleotides;Oocysts;Opportunistic Infections;Parasites;Parasitic infection;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phosphotransferases;Physiology;Population;Positioning Attribute;Prevalence;Refractory;Regulation;Reporter;Research;Role;Serological;Signal Transduction;Source;Specificity;Staging;Standardization;System;Testing;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Work;base;drug development;high reward;high risk;imaging software;in vivo;insight;latent infection;programs;public health relevance;statistics;therapy development;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In spite of their central role in the pathogenesis of cerebral toxoplasmosis in HIV-AIDS the biology of bradyzoites and the tissue cysts within which they reside remain poorly understood. With this proposal apply newly developed approaches to directly investigate bradyzoite growth while defining their cell cycle within tissue cysts in vivo.
This work fills a critical gap in our knowledge by applying mechanistic approaches to address fundamental questions of direct importance to the understanding of toxoplasma pathogenesis.


application_id: 9063521
project_number: 4R01DE023206-04
project_title: Structure-based design and synthesis of peptidominetics targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2016-05-10
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: DE
serial_number: 023206
program_official: LUNSFORD, DWAYNE
project_start_date: 2013-07-23
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1-MOSS-F(02)M]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: LUZZIO, FREDERICK ANTHONY
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a widespread and costly disease that is primarily manifest in the oral cavity but is also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens a recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that disrupts host-microbe homeostasis by inducing populational changes in the biofilm that contribute to inflammation. Thus preventing P. gingivalis colonization of the oral cavity may not only limit periodontitis and have a positive impact on severe systemic diseases improving the health status of a significant portion of the adult population. The ideal niche for P. gingivalis is the subgingival pocket but prior to colonizing this niche P. gingivali associates with streptococci in the supragingival biofilm. This interaction is an ideal target for therapeutic intervention since it represents one of the first events that promotes colonization of the oral cavity by P. gingivalis. The basic science discoveries that form the foundation for this proposal arise from our previous work showing that the association of P. gingivalis with streptococci is driven by a protein-protein interaction. Our mechanistic characterization of this interaction led to the development of a peptide (designated BAR) that potently inhibits P. gingivalis colonization of the oral cavity. However peptides are not ideal therapeutic agents due to their high cost of production and susceptibility to degradation. This application addresses these shortcomings using a structure-based approach to design and synthesize non-peptide mimetics of BAR. The first Aim will apply our knowledge of the structure and mechanism of action of BAR to design and chemically synthesize inexpensive peptidomimetic inhibitors of P. gingivalis colonization using an innovative synthetic approach called click chemistry. The second Aim of this study will assess the biologic activity of the compounds to identify lead compounds that potently inhibit P. gingivalis adherence to streptococci and the formation of P. gingivalis biofilms. The most active lead compounds will subsequently be tested in Aim 3 for inhibition of P. gingivalis virulence using an animal model of periodontitis. Thus our prior mechanistic studies uniquely position us to design and develop new potential treatments for periodontitis and its systemic sequelae by specifically targeting P. gingivalis colonization of theoral cavity. The inherent stability and low toxicity of click chemistry products may also facilitat the rapid formulation of compounds in a mouth rinse varnish or toothpaste that will be suitable for clinical testing.

project_terms:
3-Dimensional;Accounting;Address;Adherence;Adult;Alveolar Bone Loss;Animal Model;Antigens;Atherosclerosis;Back;Basic Science;Biochemical;Biological Assay;Boxing;C-terminal;Chemistry;Coupled;Development;Disease;Enzyme-Linked Immunosorbent Assay;Event;Expenditure;Formulation;Foundations;Health;Health Status;Heart Diseases;Homeostasis;I-antigen;Infection;Inflammation;Knowledge;Lead;Measures;Mediating;Microbe;Microbial Biofilms;Minor;Modeling;Modification;Molecular Models;Mouth Diseases;Mus;Nuclear Receptors;Oral cavity;Organism;Outcome;Peptide Hydrolases;Peptides;Periodontitis;Population;Porphyromonas gingivalis;Positioning Attribute;Predisposition;Prevention;Production;Protein Binding Domain;Proteins;Publishing;Rheumatoid Arthritis;Streptococcus;Streptococcus gordonii;Structural Genes;Structural Models;Structure;Systemic disease;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Tissues;Toothpaste;Toxic effect;United States;Variant;Varnish;Virulence;Work;base;cost;cycloaddition;design;feeding;flexibility;improved;inhibitor/antagonist;innovation;microbial;microbial host;mimetics;molecular modeling;mouse model;multidisciplinary;oral biofilm;oral streptococci;pathogen;peptidomimetics;polypeptide;prevent;protein protein interaction;research clinical testing;scaffold;small molecule;subgingival biofilm;synthetic peptide;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Periodontitis is a common oral disease that is present in up to 40% of the adult population in the United States. Annual expenditures for treatment and prevention of periodontitis exceed $15 billion. Although periodontitis is primarily manifest in the oral cavity it is also associated with systemic illnesses such as heart disease and rheumatoid arthritis. An important recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that induces populational changes in the oral biofilm that contribute to inflammation. Thus limiting P. gingivalis colonization of the oral cavity may have positive impact periodontal health and on other systemic illnesses associates with periodontitis. This multidisciplinary study will use molecular modeling and protein structural information to design and synthesize compounds that specifically target the periodontal pathogen P. gingivalis and block its colonization of the oral cavity. These compounds represent new potential therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


application_id: 9063180
project_number: 4R01NS084823-04
project_title: Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
administering_ic: NINDS
award_notice_date: 2016-04-18
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: NS
serial_number: 084823
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-VH-B(03)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
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): The plaques in the brain during Alzheimer's diseases (AD) are primarily composed of amyloid- (A) peptide. Although a strong association between A fibrinogen (Fg) and elevated level of homocysteine (Hcy) i.e. hyperhomocysteinemia (HHcy) during AD is well- documented the mechanism of amyloid plaque formation is unclear. The long-term goal of this project is to understand the mechanisms of cerebrovascular permeability leading to amyloid plaque formation. We have shown that elevated levels of Hcy and Fg i.e. hyperfibrinogenemia (HFg) increase cerebrovascular permeability and Fg can cross vascular endothelial cell (EC) layer secondary to activation of matrix metalloproteinase-9 (MMP-9). In addition increased levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) which enhances collagen content in subendothelial matrix (SEM) are associated with AD. In pilot studies we found that while HHcy enhances vascular permeability through mainly the paracellular pathway HFg activates mainly the transcellular transport. We also found that blood level of Fg is increased during HHcy. Therefore Fg can have an additive effect in HHcy-induced cerebrovascular permeability. We found that HHcy increases collagen level in SEM and Fg and A depositions in brain vasculature. While HHcy increases MMP-9 activity and enhances the paracellular transport as well as homocyteinylates Fg (making fibrin clots more rigid) Fg enhances the transcellular transport through caveolin-1 (Cav-1) signaling (via phosphorylation of Cav-1). However the role of Hcy and Fg in Hcy-Fg-A-collagen complex formation is unclear. The hypothesis of this proposal is that HHcy increases vascular permeability by primarily affecting the endothelial cell (EC) junction proteins and activating MMP-9 and indirectly by increasing blood content of Fg which enhances transcellular transport leading to an enhanced Hcy- Fg-A-collagen complex formation. We will test this hypothesis with three specific aims: 1) To determine whether the HHcy instigates cerebrovascular permeability via paracellular transport leading to enhanced cerebrovascular crossing of fibrinogen 2) To determine whether the fibrinogen deposition enhances cerebrovascular permeability mainly through caveolar transcytosis via Cav-1 signaling secondary to MMP-9 activation 3) To determine whether the HHcy increases fibrinogen-A-collagen complex accumulation in mouse brains secondary to increasing tissue inhibitor of metalloproteinase-1. To define specific causative effects of Hcy Fg MMP-9 Cav-1 and TIMP-1 in Fg-Ab-collagen complex formation the studies will be done on pial vessels of wild type (WT) Cystathionine -Synthase heterozygote (CBS+/-) mice (a model of HHcy) MMP-9 gene knockout (MMP9-/-) CBS and MMP-9 double knockout (CBS+/-/MMP9-/-) Cav-1 gene knockout (Cav1-/-) Fg -chain-deficient (Fg-/-) CBS+/-/Fg-/- HFg transgenic (HFg) HFg/MMP9-/- CBS+/-/Cav1-/-/MMP9-/- CBS+/- /HFg CBS+/-/HFg/MMP9-/- TIMP-1 gene knockout (TIMP1-/-) CBS+/-/TIMP1-/- double knockout Fg-/-/MMP1-/- and CBS+/-/Fg-/-/TIMP1-/- mice using a newly developed dual-tracer probing method that allows separation of paracellular from transcellular transport. Formation of Fg-A-collagen complex in brain cortex will be assessed with immunohistochemical analysis. The results of the proposed research should uncover the molecular mechanisms regulating Hcy-Fg-A-collagen complex formation and lead to effective strategies for the treatment of cerebrovascular complications during diseases such as AD.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid;Binding;Blood;Brain;CAV1 gene;Caveolae;Cerebrovascular system;Coagulation Process;Collagen;Complex;Cryoultramicrotomy;Cystathionine;Dementia;Deposition;Development;Disease;Endothelial Cells;Extravasation;Fibrin;Fibrinogen;Gelatinase B;Goals;Health;Heterozygote;Homocysteine;Homocystine;Hyperhomocysteinemia;Immunohistochemistry;Intercellular Junctions;Interstitial Collagenase;Knock-out;Knowledge;Lead;MMP9 gene;Matrix Metalloproteinases;Measures;Methods;Mission;Modeling;Molecular;Mus;Neurodegenerative Disorders;Pathway interactions;Peptides;Permeability;Phosphorylation;Pilot Projects;Presenile Alzheimer Dementia;Proteins;Public Health;Research;Role;Sampling;Secondary to;Senile Plaques;Signal Transduction;TIMP1 gene;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tracer;Transgenic Organisms;United States National Institutes of Health;Vascular Endothelial Cell;Vascular Permeabilities;caveolin 1;cerebrovascular;design;knockout gene;novel;occludin;transcytosis;treatment strategy;vascular endothelial cadherin-2;venule

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common form of dementia and it is not a normal part of aging. Up to 5 percent of people with the disease have early onset AD. The plaques in the brain during AD are primarily composed of amyloid- (A) peptide. Although a strong association between A fibrinogen (Fg) and homocysteine (Hcy) is well-documented the mechanism is unclear. Our findings show that at elevated levels Hcy increases cerebrovascular permeability to proteins leading to Fg deposition in brain cortical vessels. We also found that this Fg is associated with increased levels of A and collagen in brain vasculature. These effects of Hcy and Fg were diminished in the absence of matrix metalloproteinase-9 (MMP-9) activity. The long-term goal of this project is to understand mechanisms leading to brain Fg-A-collagen complex formation. The knowledge of mechanisms that control the amyloid plaque formation will lead to the design of therapeutic strategies for the control of this devastating neurodegenerative disease. The proposed research is relevant to public health and to the mission of NIH because it will clarify a novel pathogenic causal relationship into the role of Hcy Fg and MMPs in development of AD.


application_id: 9062524
project_number: 4R01NS079637-05
project_title: Vascular breakdown in Alzheimers Disease with cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2016-04-06
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: NS
serial_number: 079637
program_official: CORRIVEAU, RODERICK A
project_start_date: 2012-07-01
project_end_date: 2018-04-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema.  Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice.  The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema and finally to establish the effect CBVD has on the response to A-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.

project_terms:
APP-PS1;Adverse effects;Affect;Aging;Alzheimer's Disease;Amyloid;Amyloid deposition;Animals;Basement membrane;Blood Vessels;Blood flow;Brain;Brain Pathology;Cerebrovascular Circulation;Cerebrovascular Disorders;Clinical Trials;Cognition;Comorbidity;Contrast Media;Deposition;Diet;Extravasation;Gadopentetate Dimeglumine;Generations;Genetic;Goals;Hippocampus (Brain);Hyperhomocysteinemia;Image;Immunotherapy;Inflammation;Inflammatory;Inhibition of Matrix Metalloproteinases Pathway;Injection of therapeutic agent;Interleukin-1;Left;MMP2 gene;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediating;Membrane Proteins;Modeling;Modification;Mus;Pathogenesis;Pathology;Patients;Perfusion;Predisposition;Production;Proteins;Research Proposals;Role;Scanning;Signal Transduction;Site;Spin Labels;System;TIMP1 gene;TIMP2 gene;Thalamic structure;Tight Junctions;Time;Tissue Harvesting;Transgenic Mice;Weight;amyloid pathology;anakinra;arteriole;brain health;contrast enhanced;density;inhibitor/antagonist;mouse model;neuroinflammation;receptor;response;secretase;targeted treatment;therapeutic target;vasogenic edema

public_health_relevance:
Cerebrovascular disease commonly occurs with aging as does Alzheimer's disease. In fact it is estimated that 40% of Alzheimer's patients also have cerebrovascular disease. Our research proposal will examine the impact cerebrovascular disease has on the progression of amyloid pathology a brain pathology in Alzheimer's disease. Our overall goal is to enhance our understanding of the relationship between cerebrovascular disease and Alzheimer's disease and how one can affect the other.


application_id: 9062417
project_number: 5R33DA035641-04
project_title: Buprenorphine Treatment and Health Reform: Availability Utilization and Quality
administering_ic: NIDA
award_notice_date: 2016-04-11
opportunity_number: RFA-DA-13-001
application_type: 5
activity_code: R33
ic: DA
serial_number: 035641
program_official: DUFFY, SARAH Q
project_start_date: 2013-05-01
project_end_date: 2018-04-30
study_section: NSS
contact_pi_person_id: 8146786
contact_pi: KNUDSEN, HANNAH
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:
Although its implementation is likely to vary across states due to the recent Supreme Court decision passage of the Affordable Care Act (ACA) is expected to dramatically impact the delivery of substance use disorder (SUD) treatment through changes to treatment financing and greater integration of mainstream health care and SUD treatment. The evolving system of buprenorphine treatment for opioid use disorders (OUDs) is a prime example of integration. While this system has grown substantially in the past decade research is limited regarding how physicians are implementing this lifesaving treatment and whether they are delivering HIVrelated services. It is unknown how the ACA will impact the delivery of buprenorphine treatment. The proposed study seeks 1 year of R21 support to establish study feasibility and 4 years of R33 support to conduct a longitudinal study of buprenorphine implementation that integrates multi-level data on state-level variations in ACA implementation with longitudinal surveys of buprenorphine-prescribing physicians. The primary aim of the R21 phase is to determine the feasibility of conducting a longitudinal study that integrates physician-level and state-level data collection through research procedures linked to 4 milestones encompassing the construction of the physician sample survey development through qualitative and cognitive interviews and generation of a protocol for longitudinal collection of state-level data on ACA implementation. The three specific aims of the proposed R33 study are: (1) To estimate cross-sectional and longitudinal models of buprenorphine utilization as well as the implementation of high-quality clinical practice behaviors (CPBs) and HIV-related services in buprenorphine treatment in the context of states implementation of the ACA; (2) To examine the relative importance of patient payment source (e.g. Medicaid private insurance or out-of-pocket) and other patient characteristics on physician decision-making during buprenorphine treatment; and (3) To model the state-level associations between the implementation of the ACA and two state-level outcomes: utilization of buprenorphine within Medicaid and the number of physicians holding the X-license for prescribing buprenorphine. These aims will be accomplished through ongoing collection of policy and administrative data at the state-level with 4 annual surveys of a nationally representative sample of 1200 physicians who hold the X-license to prescribe buprenorphine. This longitudinal survey design will support fielding four unique conjoint analyses each addressing a key domain of physician decision-making while also collecting data on CPBs over time. Data analysis will include cross-sectional multivariate models of decision-making and multi-level longitudinal analyses of CPB adoption and implementation to test theory-driven hypotheses. By measuring the quality availability and utilization of buprenorphine treatment in the US this research may identify treatment gaps for which interventions may be developed to improve treatment quality for OUDs while contributing to scientific knowledge regarding the impact of the ACA on US treatment services.

project_terms:
Address;Adoption;Affordable Care Act;Behavior;Buprenorphine;Characteristics;Clinical;Cognitive;Collection;Data;Data Analyses;Data Collection;Decision Making;Development;District of Columbia;Drug Utilization;Feasibility Studies;Future;Generations;Growth;Guidelines;HIV;HIV risk;Health;Health Care Reform;Healthcare;Individual;Insurance;Intervention;Interview;Knowledge;Licensing;Link;Longitudinal Studies;Longitudinal Surveys;Mainstreaming;Measurement;Measures;Medicaid;Methodology;Modeling;Monitor;Opiate Addiction;Opioid;Outcome;Patient Selection;Patients;Persons;Pharmaceutical Preparations;Phase;Physicians;Policies;Procedures;Protocols documentation;Quality of Care;Research;Sampling;Services;Source;Statutes and Laws;Substance Use Disorder;Supreme Court Decisions;Surveys;System;Technology;Testing;Time;Variant;base;clinical care;clinical decision-making;clinical practice;court;design;improved;innovation;longitudinal design;medical specialties;opioid use disorder;payment;theories

public_health_relevance:
This research will provide significant information about the implementation of buprenorphine for the treatment of opioid dependence by physicians in the context of the Affordable Care Act including clinical decisionmaking and treatment quality. Measuring the quality of buprenorphine treatment may identify important targets for future interventions to improve the quality of care received by opioid-dependent patients while providing vital information regarding how health care reform is impacting this sector of the US treatment system.


application_id: 9062280
project_number: 5F31AG048697-02
project_title: Testing a Values-Based Approach to Healthcare Decision-Making in Older Adults
administering_ic: NIA
award_notice_date: 2016-06-24
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: AG
serial_number: 048697
program_official: NIELSEN, LISBETH
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-F16-L(20)L]
contact_pi_person_id: 11980340
contact_pi: GEIGER, PAUL J
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 purpose of this proposal is to provide research training in the intersecting fields of emotion regulation aging and decision-making in healthcare. Despite natural declines in physical and cognitive function older adults maintain good emotion regulation abilities leading to emotional wellbeing and resilience. This phenomenon can partially be explained by socio-emotional selectivity theory (SST) which posits that when time is perceived as a limited resource emotional wellbeing becomes a top priority. Although this positivity effect maintains emotional wellbeing it may disrupt information
processing related to healthcare decision-making. Older adults request less information from their doctors are less likely to ask for a second opinion make their decisions more quickly and devote more attention to positive medical information compared with younger adults. Although these strategies fulfill goals of emotional wellbeing they do not allow for fully informed decisio-making. Research has shown these SST effects are malleable and temporarily reversible when older adults are primed to reduce their emotional focus or increase the amount of information they gather. However older adults do not normally gather extensive information because it does not support present-moment emotional wellbeing; instead it reduces positive affect and may reduce self-regulatory capacities required for emotion regulation. The research component of this proposal will investigate a personal values-based strategy for reducing the positivity effect n information processing related to healthcare decision-making. Writing about personal values increases positive affect counteracts self-regulatory fatigue and reduces defensiveness while reading threatening health information. Values-based interventions have been extensively studied but rarely applied to older adults. This study will integrate two broad areas of research (aging emotion and decision- making and the role of values in decision-making) that has great promise in improving decision-making across the lifespan. Didactic and experiential training in aging and values-based research will include (1) regular meetings with University of Kentucky Sanders Brown Center for Aging faculty members (2) coursework covering aging decision-making and advanced statistics (3) intensive statistics training program (4) visiting scholar training with leaders in the field of aging and decision-making. In order to foster professional development proposed activities include (1) attending and presenting research at multiple national conferences and (2) pursuing additional research questions with access to an R01-funded longitudinal dataset of community-dwelling older adults. Finally a substantial emphasis will be placed on ethical training including (1) a course on ethical research with older adults (2 a course based on NIH guidelines for Responsible Conduct of Research and (3) regular meetings with advisors to discuss ethical issues. This proposal provides extensive training to build a research career devoted to the development of novel emotion regulation interventions that enhance the lives of older adults.

project_terms:
Address;Affect;Age;Aging;Area;Attention;Cognitive;Communities;Data Set;Decision Making;Development;Elderly;Emotional;Emotions;Ethical Issues;Ethics;Faculty;Failure;Fatigue;Fostering;Funding;Goals;Guidelines;Health;Healthcare;Informal Social Control;Intervention;Kentucky;Laboratories;Laboratory Study;Lead;Length;Life;Literature;Longevity;Maintenance;Measures;Medical;Medicare;Memory;Motivation;Participant;Patient Self-Report;Personal Satisfaction;Physical Function;Population;Process;Psyche structure;Reading;Research;Research Training;Resources;Role;Second Opinions;Techniques;Testing;Time;Training;Training Programs;United States National Institutes of Health;Universities;Well in self;Writing;age effect;age related;base;career;cognitive function;computerized;cost;design;effective intervention;emotion regulation;improved;information gathering;information processing;meetings;member;novel;positive emotional state;psychosocial;public health relevance;resilience;responsible research conduct;satisfaction;skills;statistics;symposium;theories;visiting scholar;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Older adults use a variety of cognitive techniques to focus their attention primarily on positive information. Despite effectively maintaining emotional wellbeing these techniques lead to incomplete information processing which can be problematic when making important decisions related to healthcare and medical treatment. The purpose of the proposed project is to: (1) study the effects of a values-based induction on the process of healthcare decision-making in older adults and (2) provide didactic and experiential training in psychosocial functioning and decision-making in older adults ethical issues in research with this population and the methodological and statistical skills necessary to investigate emotion regulation strategies to improve healthcare-related information processing in older adults.


application_id: 9061638
project_number: 5R03CA179661-02
project_title: Statistical Methods for Environmental Data Subject to Detection Limits
administering_ic: NCI
award_notice_date: 2016-04-26
opportunity_number: PAR-12-039
application_type: 5
activity_code: R03
ic: CA
serial_number: 179661
program_official: LIU, BENMEI
project_start_date: 2015-05-01
project_end_date: 2017-04-30
study_section: ZCA1-TCRB-Y(O3)
contact_pi_person_id: 10443718
contact_pi: CHEN, LI
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): As researchers investigate the relationship between cancer and exposure to environmental chemicals such as trace elements pesticides and dioxins they often find concentrations that are lower than limits deemed reliable enough to report as numerical values. The detection limit (DL) may be a fixed number in some studies but it can also vary widely from sample to sample in other studies. For the latter the DL may be correlated with the exposure level as observed in a colon cancer study in Kentucky. The data subject to DLs present challenges for data analysis and interpretation. In this proposal we focus on two important statistical problems encountered in the analysis of data from environmental epidemiologic studies: (a) estimation of the chemical distribution in a specific group; and (b) comparison of distributions among groups. For these two problems ad hoc parametric and nonparametric methods have been proposed. Ad hoc methods are ill-advised unless there are relatively few measurements below DLs; and parametric methods can lead to markedly biased results when the parametric model is misspecified. Nonparametric methods have received increasing attention in recent years because of their robustness. However current nonparametric methods simply borrow the commonly used methods for right-censored survival data and do not take into account the following two unique characteristics of environmental exposure data with DLs: (a) it is not meaningful to define the hazard function for an exposure measurement; and (b) DL values are observable for all subjects including those whose actual exposure levels are detected. In addition current nonparametric methods do not allow for sampling weights which are typically present in survey data such as the National Health and Nutrition Examination Survey (NHANES). Due to these issues current nonparametric methods may lead to the following four problems for the analysis of environmental exposure data with DLs: (a) lack of meaningful interpretation; (b) inefficient results; (c) inability to deal with thesituation that the exposure level and DL are correlated; and (d) inability to handle survey data with sampling weights. To address the aforementioned problems we will develop unified and efficient nonparametric estimation and testing methods that can (a) deal with possible correlation between the exposure level and DL; (b) incorporate sampling weights. We will utilize state-of-the-art methods for censored survival data and tailor them to environmental exposure data with DLs. The proposed methods will be applied to data from a recently conducted colon cancer case-control study in Kentucky an ongoing lung cancer case-control study in Kentucky and the NHANES. 1

project_terms:
Accounting;Address;Adopted;Arsenic;Attention;Cancer Control;Carpet;Case Study;Case-Control Studies;Characteristics;Chemicals;Chromium;Colon Carcinoma;Data;Data Analyses;Detection;Development;Dioxins;Dust;Environmental Carcinogens;Environmental Epidemiology;Environmental Exposure;Epidemiologic Studies;Evaluation;Exposure to;Future;Health;Interest Group;Kentucky;Lead;Literature;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Methodology;Methods;Modeling;NHANES;Nickel;Non-Hodgkin's Lymphoma;Numerical value;Occupational Epidemiology;Outcome;Pesticide Residues;Pesticides;Reporting;Research Personnel;Risk;Sampling;Statistical Methods;Structure of nail of toe;Surveys;Survival Analysis;Testing;Trace Elements;Validation;Weight;base;cancer prevention;comparison group;environment related cancer;environmental chemical;hazard;improved;innovation;insight;interdisciplinary collaboration;malignant breast neoplasm;novel;organochlorine exposure;public health relevance;simulation;statistics;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application proposes to develop a novel statistical method to improve the analysis of environmental data subject to detection limits. The success of this project will result in an innovative statistical approach to more accurately assess the potential risk posed by environmental carcinogens such as arsenic chromium and nickel on the development and progression of colon and lung cancers. The proposed method if shown to be more optimal than existing methods will benefit any environmental exposure study (regardless of health outcome) where the measurements are subject to detection limits.


application_id: 9061596
project_number: 5R01AI118814-02
project_title: Lead Optimization of ML336 a Potent VEEV Inhibitor
administering_ic: NIAID
award_notice_date: 2016-04-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 118814
program_official: DAVIS, MINDY I
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: GOLDEN, JENNIFER E.;JONSSON, COLLEEN B
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Alphavirus;Americas;Amidines;Antiviral Agents;Asses;Biodistribution;Biotechnology;Chemicals;Chemistry;Consultations;Disease;Dose;Drug Kinetics;Encephalitis;Future;Health;Human;In Vitro;Knowledge;Lead;Metabolic;Molecular Bank;Mus;Nonstructural Protein;Outcome;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Preclinical Drug Development;Property;RNA Viruses;RNA chemical synthesis;RNA replication;Regimen;Replication-Associated Process;Research;Research Design;Research Methodology;Resistance;Series;Solubility;Structure;Structure-Activity Relationship;Testing;Therapeutic;Toxic effect;Trinidad;United States National Institutes of Health;Vaccines;Venezuelan;Venezuelan Equine Encephalitis Virus;Virus Inhibitors;Western Equine Encephalitis Virus;analog;cytotoxicity;efficacy testing;health economics;high throughput screening;improved;in vitro Assay;in vitro activity;in vivo;insight;interest;mouse model;novel;pathogen;pre-clinical;preclinical study;replicase;research clinical testing;small molecule;small molecule therapeutics;viral RNA;viral resistance


application_id: 9061536
project_number: 4R01AG026307-10
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2016-05-06
opportunity_number: PA-09-216
application_type: 4
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(02)M]
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:
DESCRIPTION (provided by applicant): Older adults are at high risk for a number of health problems including cardiovascular disease infectious disease and cancer. Underlying at least part of this risk is immunological aging but not all older adults experience immunological aging to the same degree nor do they experience the same health risk and health problems. The purpose of this project is to measure individual differences and changes in self-regulation over time in older adults and to link self-regulation to subjective health health risks and clinicallyrelevant markers of immunological aging including inflammation and markers of lymphocyte terminal differentiation and replicative senescence. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation neuropsychology autonomic and inflammatory biology immunology and longitudinal design and analysis. The first period of the study focused on risk factors especially stress and repetitive thought and their effects on psychological well-being subjective health and immune response to vaccination. The renewal continues assessment of these risk factors to provide continuity in this longitudinal dataset and adds innovation in the assessment of factors that may promote healthy aging and mitigate against effects of risks. Specifically the aims of the study are first to test the effects of a elf-regulatory constellation (comprising self-regulation executive cognitive function and heart rate variability [HRV]) on subjective psychological social and physical health and markers of immunological aging. Second we will test the relationships between this constellation and risk factors such as age and stress. Third we will test the ability of the constellation to moderate rik effects. A further aim is to support a "call for collaboration" in which we propose to work with other investigators whose hypotheses can be tested with study data from 2001 through the current renewal. At 6- month intervals older adults (N = 150) will complete measures of the self-regulatory constellation: behavioral emotional social and cognitive self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. They will complete measures of risk including stress pain physical activity BMI and waist circumference. Finally they will complete measures of psychosocial health including depression perceived cognitive and physical health and marital satisfaction. Blood draws will be synchronized with these visits and assays performed on these samples will capture two aspects of immunological aging: increases in serum proinflammatory cytokines and their soluble receptors and increases in markers of terminal differentiation and senescence in T cells and NK cells. This renewal will be innovative in its comprehensive assessment of self-regulation as well as risk; the longitudinal design that allows for the study of change and lagged mediational and bidirectional effects; and the focus on the role of self-regulation in healthy aging.

project_terms:
Accounting;Age;Aging;Back;Behavioral;Biological Assay;Biological Markers;Biology;Blood;Cardiovascular Diseases;Cell Aging;Cognitive;Collaborations;Communicable Diseases;Data;Data Set;Elderly;Emotional;Funding;Health;Immune;Immune response;Immune system;Immunologic Markers;Immunology;Individual;Individual Differences;Inflammatory;Influenza vaccination;Informal Social Control;Interleukin-6;Link;Longitudinal Studies;Lymphocyte;Malignant Neoplasms;Measures;Mental Depression;Mental Health;Natural Killer Cells;Neuropsychology;Outcome;Pain;Personal Satisfaction;Physical activity;Psychological Factors;Research;Research Personnel;Resistance;Rest;Risk;Risk Factors;Role;Sampling;Serum;Short-Term Memory;Stress;T-Lymphocyte;Testing;Time;Vaccination;Visit;Work;age related;clinically relevant;cognitive function;cohort;cytokine;experience;feeding;healthy aging;heart rate variability;high risk;indexing;inflammatory marker;innovation;longitudinal analysis;longitudinal design;member;physical conditioning;physical inactivity;prospective;psychologic;psychosocial;receptor;satisfaction;senescence;shift work;social;waist circumference

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With age come changes in the immune system that can increase the risk of poor health. However not all older adults experience these changes to the same degree. This project will continue to track a cohort of older adults examining psychological factors that may be protective for psychological and physical health and delay immunological aging as well as those factors that may confer risk and the interactions between protective and risk factors.


application_id: 9060751
project_number: 4R01CA172379-04
project_title: Novel resveratrol analogs and colorectal cancer treatment
administering_ic: NCI
award_notice_date: 2016-05-10
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 172379
program_official: EMENAKER, NANCY J
project_start_date: 2013-08-06
project_end_date: 2018-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment; however prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently we reported that resveratrol which is found in the skin of red grapes significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by anR21 grant (RCA139359) we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound FlDAS-4r inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated biologically active form of FIDAS-4r we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM) thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents; 2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth; and 3) To characterize novel FIDAS agents using in vivo mouse models.

project_terms:
APC gene;Accounting;Adenomatous Polyposis Coli;Adverse effects;Affect;Anabolism;Animal Model;Antineoplastic Agents;Binding;Biological;Biological Assay;Biological Process;CTNNB1 gene;Cancer Cell Growth;Cancer Etiology;Cell Proliferation;Cell model;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Colorectal Cancer;Development;Disclosure;Drug Targeting;Epigenetic Process;Event;Family;Funding;Future;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Grapes;Growth;Half-Life;Human;Hypermethylation;In Vitro;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolism;Methionine;Modeling;Molecular;Molecular Target;Mus;Mutation;Natural Products;Neoplasms;Nude Mice;Organoids;Pathway interactions;Patients;Polyamines;Publications;Reporting;Resveratrol;Role;S-Adenosylmethionine;Signal Pathway;Signal Transduction;Skin;Testing;Therapeutic;Therapeutic Agents;Toxic effect;United States;Xenograft procedure;analog;base;cancer cell;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;drug candidate;efficacy testing;histone methylation;in vivo;inhibitor/antagonist;invention;methionine adenosyltransferase;mortality;mouse model;nanomolar;novel;promoter;public health relevance;research study;targeted treatment;trans-resveratrol;tumor metabolism;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer death in the United States. Resveratrol and its novel analogs are promising agents for colorectal cancer prevention and treatment. This project will explore novel mechanisms of action of resveratrol analogs using cell and animal models of colorectal cancer in order to develop better chemopreventive and therapeutic agents in the future.


application_id: 9060653
project_number: 3UH3TR000875-03S1
project_title: Fruit exosome-like particles for therapeutic delivery of extracellular miRNAs
administering_ic: NCATS
award_notice_date: 2015-09-09
opportunity_number: PA-14-077
application_type: 3
activity_code: UH3
ic: TR
serial_number: 000875
suffix: S1
program_official: TAGLE, DANILO A
project_start_date: 2013-08-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1(50)-R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: GUO, PEIXUAN
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop exosome-like nanoparticles as a delivery vehicle for targetable delivery of extracellular RNA (exRNA) primarily focusing on miRNAs which modulate gene expression and induce immune responses upon delivery in mouse tumor models. Development of exRNA-based therapeutics must overcome challenges including issues of delivery potential off-target effects safety toxicity the cost of large scale production elimination of potential biohazards to the environmen and tissue specificity. Unlike the situation with artificially synthesized nanoparticles or liposomes naturally derived nanoparticle-size exosomes are released from many different types of cells. miRNAs and RNAs can be encapsulated in naturally derived exosomes and the RNAs are stable and a number of miRNAs can be naturally encapsulated simultaneously in these exosomes. Recently data published by ours and other groups have demonstrated that mammalian exosomes can deliver poorly soluble agents chemotherapeutic drugs and siRNA in vivo. A limitation of this mode is the need for large-scale production of exosomes and potential biosafety. Our preliminary data show that exosome-like nanoparticles can be isolated in large quantities from the tissue of edible plants including grapes. We have demonstrated that exosome-like nanoparticles from grapes are composed of small RNAs proteins and lipids. An edible plant-derived nano-vector (EPNV) assembled from grape exosome-like derived lipids is capable of encapsulating siRNAs. Co-delivery of folic acid with the chemotherapy drug paclitaxel by EPNVs results in an increased efficiency in tumor tissue targeting. Reducing the size of EPNVs by passing them through an appropriate pore size filter significantly enhances EPNV translocation to the brain and oral administration of the EPNVs results in their migration to the liver. Based on these preliminary data and the current literature we propose to: (1) Determine whether an EPNV can deliver therapeutic miR17 via oral administration to target metastatic colon tumor in the liver subsequently inducing NK cell activation to kill metastatic tumor cells; (2) Determine whether miR155 encapsulated in EPNV promotes differentiation of myeloid derived suppressor cells (MDSCs) into mature dendritic cells in mouse breast/brain tumor models; (3) Determine whether a therapeutic dose of miRNA17 or miRNA155 delivered by EPNV induces no side-effects in mouse tumor models; and (4) Determine whether EPNV can be produced in large scale amounts economically for use in clinical settings. Demonstration of using a EPNV-based delivery system loaded with a desired therapeutic extracellular RNA (exRNA) including microRNA to target to inflammatory cells and tumor cells in vivo would not only be a significant step forward in the treatment of cancer but also provide a powerful tool foridentifying the role and effects of each small RNA encapsulated in resident or circulating microvesicles on the recipient cells. We will accomplish this in our study by knock-out and knock-in strategies.

project_terms:
Adverse effects;Animals;Antibodies;Biohazardous Substance;Biological Assay;Brain;Brain Neoplasms;Breast;Cells;Clinic;Clinical;Colon Carcinoma;Colonic Neoplasms;Curcumin;DNA;Data;Dendritic Cells;Development;Disease;Dose;Down-Regulation;Edible Plants;Encapsulated;Environment;Evaluation;Folic Acid;Fruit;Gene Expression;Goals;Grapefruit (food);Grapes;Health;Human;Immune response;Immunotherapy;In Vitro;Inflammatory;Intranasal Administration;Killings;Knock-in Mouse;Knock-out;Laboratories;Light;Lipids;Liposomes;Literature;Liver;MHC Class I Genes;Malignant Neoplasms;Mammalian Cell;Metastatic Neoplasm to the Liver;MicroRNAs;Modeling;Mus;Myelogenous;Myeloid Cells;NK Cell Activation;Neoplasm Metastasis;Non-Viral Vector;Nucleic Acids;Oral Administration;Paclitaxel;Pharmaceutical Preparations;Phenotype;Play;Prevention;Production;Proteins;Protocols documentation;Publishing;RNA;Research Personnel;Role;Safety;Science;Signal Transduction;Small Interfering RNA;Small RNA;Specificity;Suppressor-Effector T-Lymphocytes;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Tomatoes;Toxic effect;Tumor Tissue;Viral Vector;aqueous;base;cancer cell;cancer therapy;cell type;chemotherapeutic agent;chemotherapy;cost;expression vector;extracellular;in vivo;intravenous administration;large scale production;migration;mouse model;nanoparticle;nanosized;nanovector;neoplastic cell;overexpression;particle;prevent;receptor;targeted delivery;therapeutic miRNA;tool;trafficking;tumor;vector-induced

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The concept that extracellular RNA (exRNA) may alter target cell phenotypes by way of intercellular signaling is becoming universally accepted in science. Whether exRNA can be used as a therapeutic agent is not known. The overall goal of this study is to develop grape lipid derived nano vectors for the delivery of exRNAs as therapeutic agents to target tumor cells as well as inflammatory cells in animal tumor models. Additionally we will assess the therapeutic potential of exRNA used in a clinical setting.


application_id: 9060377
project_number: 5R01ES025515-02
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2016-01-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 025515
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: ZHANG, ZHUO
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
2 year old;Adult;Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;Breeding;Cell Death;Cells;Chemopreventive Agent;Chronic;Data;Development;Diet;Elements;Environmental Carcinogens;Epidemiologic Studies;Epithelial;Event;Exhibits;Exposure to;Female;Gene Expression;Gene Targeting;Generations;Genes;Life;Literature;Lung;Luteolin;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metal exposure;Molecular;Mus;Nutritional;Occupational;Oncogenic;Oxidative Stress;Pathway interactions;Pregnancy;Premalignant;Prevention;Prevention strategy;Property;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Pathway;Signal Transduction;Source;Staging;Stress;Superoxide Dismutase;Time;Tumor Tissue;Tumorigenicity;Up-Regulation;angiogenesis;antioxidant enzyme;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;combat;drinking water;exposed human population;in vivo;insight;male;malignant state;novel;offspring;pregnant;prevent;promoter;public health relevance;tumor;tumorigenesis


application_id: 9059615
project_number: 5R21AI118818-02
project_title: Recognition of Pneumocystis trophs by murine dendritic cells
administering_ic: NIAID
award_notice_date: 2016-04-22
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 118818
program_official: LOVE, DONA
project_start_date: 2015-05-01
project_end_date: 2017-10-31
study_section: Special Emphasis Panel[ZRG1-AARR-K(04)M]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pneumocystis (PC) is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals and is one of the original AIDS-defining pathogens. Even though the incidence of PCP has dropped with the advent of highly active anti-retroviral therapy mortality rates due to PCP has not changed and HIV-infected individuals are still susceptible to PCP when they are not compliant with their HIV therapy or when the virus becomes resistant to therapy. Though much is known about Pneumocystis and the immune response to it there are still large gaps in our understanding of how the organism is recognized and cleared by the immune system. PC has two identifiable life forms the cyst or ascus that is surrounded by a fungal cell wall composed of -glucans and chitin and the trophozoite or spore form that is devoid of a cell wall but unlike most medically relevant fungi has a cell membrane that contains cholesterol rather than the ergosterol. It is wellestablished that both macrophages and dendritic cells recognize the cyst form of PC through the -glucan receptor dectin-1. However the cyst form of the organism represents a small proportion of the total lung burden particularly late in infection when the trophic forms are as much as 90% of the organisms in the lungs. It is not known how dendritic cells and macrophages recognize the trophic forms of PC. The goal of this project is to identify the receptors that dendritic cells and macrophages use to recognize the trophic forms of PC particularly early during infection before specific antibody is formed and whether the trophic forms stimulate the cells to produce immune mediators. Our hypothesis is that the trophic forms of PC bind to one or more c-type lectin receptors (CLRs) via mannosylated proteins resulting in a dampened inflammatory response by suppressing signaling through dectin-1. Two specific aims are proposed to address the hypothesis. Aim 1 will determine whether the trophic forms of PC bind CLR and transmit a signal. Aim 2 will determine the mechanism of suppression of inflammation induced by the trophic forms of PC. Together these aims will provide important new information about whether dendritic cells and macrophages are stimulated by PC or alternatively whether the trophic forms dampen immunity and escape innate immune surveillance.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Alveolar;Alveolar Macrophages;Antibodies;Binding;Biological Response Modifiers;C Type Lectin Receptors;Cell Wall;Cell membrane;Cell physiology;Cells;Chitin;Cholesterol;Chromoblastomycosis;Cyst;Data;Dendritic Cells;Drops;Ergosterol;Genes;Glucans;Goals;HIV;HIV therapy;Health;Highly Active Antiretroviral Therapy;Host Defense;Human;Immune;Immune response;Immune system;Immunity;Immunocompromised Host;Immunologic Surveillance;Incidence;Individual;Infection;Inflammation;Inflammatory Response;Interleukin-1 beta;Interleukin-6;Lectin Receptors;Life;Ligation;Link;Lung;Mannose;Morbidity - disease rate;Mus;Myeloid Cells;Organism;Pneumocystis;Pneumocystis carinii Pneumonia;Pneumonia;Proteins;Reproduction spores;Signal Transduction;Signaling Molecule;Surface;TNF gene;Technology;Thick;Vaccines;Virus;Yeasts;adaptive immunity;beta-Glucans;beta-glucan receptor;cytokine;dectin 1;design;extracellular;fungus;immunosuppressed;macrophage;mannose receptor;mortality;mouse dectin-2;nano-string;pathogen;receptor;response;therapy resistant

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Pneumocystis is a fungal pathogen that causes pneumonia in immunodeficient individuals particularly those infected with HIV. The goal of this study is to understand how one of the life forms of Pneumocystis interacts with dendritic cells a part of the immune system. Understanding these interactions are important for devising new treatments as well as for generating vaccine strategies.


application_id: 9059183
project_number: 5R01NS093920-02
project_title: Microglia responses to CNS injury: targeting p38 MAPK signaling
administering_ic: NINDS
award_notice_date: 2016-04-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 093920
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AD pathology;Acute;Address;Adult;Adverse effects;Alzheimer's Disease;Astrocytes;Brain;Brain Injuries;Cells;Central Nervous System Diseases;Chronic;Clinical;Cognitive deficits;Craniocerebral Trauma;Data;Dementia;Development;Diffuse;Disease;Disease Progression;Dose;Drug Kinetics;Endothelial Cells;Exhibits;Foundations;Functional disorder;Funding;Future;Gene Expression Profile;Health;Immune response;Impaired cognition;Impairment;Inflammatory;Inflammatory Response;Injury;Intervention;Knockout Mice;Lead;MAPK14 gene;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Myeloid Cells;Nervous System Physiology;Nervous System Trauma;Neuroglia;Neurologic;Neurons;Outcome;Paracrine Communication;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Population;Production;Property;Protein Isoforms;Proteins;Reagent;Recruitment Activity;Reporting;Research;Risk;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Surveys;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;analog;biological adaptation to stress;cell type;central nervous system injury;cytokine;defined contribution;effective therapy;improved outcome;inhibitor/antagonist;macrophage;monocyte;mouse model;nervous system disorder;neuroinflammation;novel;prevent;response;small molecule;small molecule inhibitor;stressor;targeted treatment;therapeutic development;therapeutic target;translational study


application_id: 9058983
project_number: 5R03AI117361-02
project_title: Targeting NAD biosynthesis in Mycobacterium tuberculosis
administering_ic: NIAID
award_notice_date: 2016-04-19
opportunity_number: PA-13-304
application_type: 5
activity_code: R03
ic: AI
serial_number: 117361
program_official: LACOURCIERE, KAREN A
project_start_date: 2015-05-01
project_end_date: 2017-10-31
study_section: Special Emphasis Panel[ZRG1-IDM-T(82)S]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) the causative agent of tuberculosis (TB) represents a major threat to TB control. There is an urgent need for development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of antimicrobial compounds active against Mtb. Nicotinamide mononucleotide adenylyltransferase (NadD) an essential enzyme of NAD biosynthesis represents a highly promising target for drug development against bacterial pathogens. In recent years there have been a number of NadD inhibitors developed and validated against Escherichia coli Bacillus subtilis and B. anthracis. Published data indicate tha NadD is required for the growth and survival of mycobacteria. Thus this recent progress provides a starting point for pursuing this enzyme as a target for the development of novel anti-tubercular drugs. The experiments in this proposal are designed to find inhibitors of Mtb NadD using a combination of structural biology approach and our recently developed virtual screening (VS) methodology. We propose to use our crystal structure of Mtb NadD and previously identified scaffolds active against E. coli and B. anthracis NadD to apply an iterative ligand- an structure-based VS approach to discover the NadD inhibitors. The VS method will exploit databases with approved drugs that have already been shown to be safe in humans. Upon successful completion of this project we will obtain a number of potent and safe lead compounds that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant targets.

project_terms:
Address;Adverse effects;Anabolism;Animal Model;Anti-Bacterial Agents;Antibiotics;Antitubercular Agents;Bacillus anthracis;Bacillus subtilis;Biochemical Pathway;Biological Assay;Cell Death;Cell physiology;Communicable Diseases;Complex;Data;Databases;Development;Drug Targeting;Drug resistance in tuberculosis;Effectiveness;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Escherichia coli;Fingerprint;Genus Mycobacterium;Goals;Growth;Health;Homologous Gene;Human;In Vitro;Intervention;Lead;Ligands;Metabolic Pathway;Methodology;Methods;Molecular Weight;Multi-Drug Resistance;Mycobacterium smegmatis;Mycobacterium tuberculosis;Nicotinamide adenine dinucleotide;Nicotinamide-Nucleotide Adenylyltransferase;Nicotinate-nucleotide adenylyltransferase;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Property;Public Health;Publishing;Recycling;Reporting;Research;Roentgen Rays;Role;Staging;Structure;Testing;Time;Tuberculosis;antimicrobial;base;chemotherapy;combat;design;drug development;drug discovery;extensive drug resistance;improved;in vivo;inhibitor/antagonist;innovation;insight;mycobacterial;new therapeutic target;next generation;nicotinate mononucleotide;nicotinic acid adenine dinucleotide;novel;pathogen;programs;research study;resistant strain;scaffold;screening;small molecule;small molecule libraries;structural biology;success;treatment duration;treatment strategy;tuberculosis treatment;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The rapid rise in the occurrence of drug-resistant TB cases represents a major global public health problem. Our long-term goal is to develop novel classes of anti-mycobacterial compounds to combat the multidrug- resistant and extensively drug-resistant M. tuberculosis infections. We propose to discover inhibitors of an essential metabolic pathway in mycobacteria a yet unexplored drug target.


application_id: 9058305
project_number: 3R01NS065842-08S1
administering_ic: NINDS
award_notice_date: 2015-05-13
opportunity_number: PA-14-077
application_type: 3
activity_code: R01
ic: NS
serial_number: 065842
suffix: S1
program_official: KOENIG, JAMES I
project_start_date: 2015-05-01
project_end_date: 2016-03-31
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-05-01
project_title:
Alpha5Beta1 Integrin inhibition as a Profound Blood-Brain Barrier Stabilizing Neuroprotective Stroke Therapy

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

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

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


application_id: 9058097
project_number: 4R01GM099744-06
project_title: Sirt1 regulation of NFkB activation and inflammatory responses in sepsis
administering_ic: NIGMS
award_notice_date: 2016-05-04
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: GM
serial_number: 099744
program_official: DUNSMORE, SARAH
project_start_date: 2013-06-01
project_end_date: 2019-04-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: 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:
DESCRIPTION (provided by applicant): Septic shock is a systemic inflammatory response syndrome that causes multiple organ damage and death. Currently there is no efficient treatment for the disease. Identifying novel therapeutic targets that can help control sepsis-induced inflammation is crucial to treat this devastating disease. Activation of complex inflammatory networks is responsible for the excessive systemic inflammatory response in sepsis. NF-kB has been demonstrated as a central player that regulates these inflammatory networks in sepsis. However molecular regulation of NF-kB activity in sepsis remains largely unknown. Recent studies indicate that acetylation is a new mechanism in NF-kB activation. It has been reported that Sirt1 a deacetylase widely expressed in all tissues interacts with NF-kB and inhibits NF-kB activity by deacetylation in several in vitro and in vivo systems. Yet the function and regulation of Sirt1 in sepsis-induced inflammatory responses have not been studied. Using mouse models of sepsis we demonstrate that Sirt1 controls inflammatory responses during sepsis by regulating NF-kB acetylation and activation. Our preliminary data showed that induction of sepsis triggered NF-kB acetylation and activation in wild type mice which were further increased in Sirt1 knockout mice. Interestingly Sirt1 activation by resveratrol or Sirt1 gene delivery inhibited sepsis-induced NF-kB acetylation. Furthermore we showed that caspase activation resulted in Sirt1 degradation which may function as a new pathway to aggravate systemic inflammation in sepsis. In the proposed studies we will test the hypothesis that Sirt1 controls NF-k B activation and inflammatory responses during sepsis. Our specific aims are: (1) to define the role of Sirt1 in sepsis-induced NF-kB activation and systemic inflammation. We will use inducible Sirt1 knockout mice to assess the role of Sirt1 in sepsis-induced systemic inflammation; we will examine the role of caspase in Sirt1 regulation of NF-kB activation and inflammatory signaling during sepsis; (2) to specifically dissect Sirt1 control of NF-kB activation in endothelial cell inflammatory responses during sepsis. We will define Sirt1 control of sepsis-induced NF-kB activation and inflammatory signaling in endothelial cells. We will use endothelial-specific Sirt1 knockout mice to assess the role of endothelial Sirt1 in NF-kB modulation and inflammatory signaling in sepsis; (3) to explore the therapeutic potential of modulating NF-kB activation by Sirt1 activators and Sirt1 gene delivery in sepsis-induced inflammation. We will explore the therapeutic potential of Sirt1 activators on sepsis-induced NF-kB activation and inflammatory signaling; we will evaluate whether Sirt1 gene delivery can effectively protect against sepsis-induced inflammation by inhibiting NF-kB-regulated inflammatory signaling. Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation and validate the potential of Sirt1 as a therapeutic target to treat sepsis-associated inflammatory tissue damage.

project_terms:
Acetylation;Bacterial Infections;Caspase;Cause of Death;Cessation of life;Complex;Critical Illness;Data;Deacetylase;Deacetylation;Disease;Endothelial Cells;Gene Delivery;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Knockout Mice;Molecular;Multiple Organ Failure;NF-kappa B;Organ;Pathway interactions;Patients;Regulation;Reporting;Resveratrol;Role;Sepsis;Sepsis Syndrome;Septic Shock;Signal Transduction;System;Testing;Therapeutic;Tissues;Wild Type Mouse;in vivo;inflammatory modulation;mouse model;new therapeutic target;novel;therapeutic target

public_health_relevance:
Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation and validate the potential of Sirt1 as a therapeutic target to treat sepsis- associated inflammatory tissue damage.


application_id: 9058073
project_number: 5R01DK093462-06
project_title: Role of Ceramide-induced Kidney Cell Death in Acute Kidney Injury
administering_ic: NIDDK
award_notice_date: 2016-06-02
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 093462
program_official: SADUSKY, ANNA BURKART
project_start_date: 2012-09-17
project_end_date: 2018-04-30
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a devastating disease with a high mortality rate. Apoptosis and necrosis play major roles in AKI but there is a fundamental knowledge gap of the factors regulating their induction in AKI. Continued existence of this gap represents a significant problem as AKI has a high mortality rate and there are very few therapeutic interventions to alter the clinical course of this disease. The long-term goal is t uncover mechanisms involved in AKI for the development of novel therapeutics to protect the kidney. Ceramides regulate apoptosis and necrosis and are elevated in the kidney in several models of AKI. The factors that regulate production of ceramides during kidney apoptosis and necrosis and whether ceramides lead to apoptotic versus necrotic kidney cell death are completely unknown. Likewise there are many different ceramide species and the roles for particular ceramide species in AKI have not been determined. This proposal will answer these questions to achieve the objective of developing ceramides as novel therapeutic approaches for the treatment of AKI. Preliminary data demonstrate that: (i) long-chain ceramides (C16 - C20- ceramides) are generated via de novo synthesis during kidney cell apoptosis and blocking their generation inhibits apoptosis; (ii) the pro-apoptotic BCL-2 protein BAK is a key regulator of ceramide synthases (CerS) and long-chain ceramide generation during kidney cell apoptosis; (iii) acid sphingomyelinase (aSMase) generated very long-chain ceramides (C24-C26-ceramides) occurs in kidney cell necrosis; (iv) kidney cortical CerS and acid SMase are activated and specific ceramides elevated several-fold in in vivo rodent models of AKI (cisplain nephrotoxicity and rhabdomyolysis-induced AKI); and (v) mice given inhibitors of enzymes responsible for ceramide synthesis are protected from cisplatin-induced AKI. This expanding and developing body of work has led us to propose the following hypothesis: nephrotoxic stimuli elevate specific species of kidney ceramides through CerS and SMase-mediated pathways inducing kidney cell death and ultimately kidney failure. This hypothesis will be tested with threespecific aims: (1) determine the mechanism by which BAK regulates CerS activity and generation of specific long-chain ceramides during kidney cell apoptosis; (2) determine the contribution of SMase-generated ceramide to kidney cell necrosis; and (3) determine the in vivo contribution of CerS and aSMase to cisplatin-induced AKI in mice. The approach is innovative because it will identify the mechanism by which BAK regulates ceramide synthases as well as the specific role of individual ceramide species in vivo in AKI. The proposed research is significant as it advances our current knowledge of mechanisms of kidney cell death AKI. Ultimately such knowledge has the potential to greatly improve the treatment of AKI.

project_terms:
Acids;Acute Renal Failure with Renal Papillary Necrosis;Apoptosis;Apoptotic;BAX gene;BCL-2 Protein;Bioenergetics;Biological Assay;Cell Death;Cells;Ceramides;Cisplatin;Clinical Course of Disease;Data;Development;Disease;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Figs - dietary;Generations;Glycerol;Goals;In Vitro;Individual;Injury;Intervention;Kidney;Kidney Failure;Knockout Mice;Knowledge;Lead;Measures;Mediating;Modeling;Mus;N-palmitoylsphingosine;Necrosis;Nephrotoxic;Pathway interactions;Play;Production;Protein Isoforms;Proximal Kidney Tubules;Public Health;Research;Rhabdomyolysis;Rodent Model;Role;Sphingolipids;Stimulus;Supportive care;Testing;Therapeutic Intervention;Time;acid sphingomyelinase;base;dihydroceramide desaturase;improved;in vivo;inhibitor/antagonist;innovation;kidney cell;mortality;nephrotoxicity;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;research study;therapeutic development

public_health_relevance:
This proposal will advance current knowledge of mechanisms of acute kidney injury by identifying factors that regulate generation of specific ceramide speciesduring kidney apoptosis and necrosis. The proposed research is relevant to public health because acute kidney injury has a high mortality rate with very few therapeutic interventions. Thus information gained from the enclosed studies has the potential to improve the treatment of acute kidney injury.


application_id: 9058060
project_number: 5R01ES021771-03
project_title: Apoptosis resistance and Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2016-04-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 021771
program_official: REINLIB, LESLIE J
project_start_date: 2014-08-01
project_end_date: 2019-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
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): Chromate (Cr (VI)) compounds are toxic and carcinogenic on humans. Our preliminary studies show that exposure of human lung bronchial epithelial (BEAS-2B) cells to Cr (VI) generated reactive oxygen species (ROS). Through ROS reactions Cr(VI) caused cell transformation leading to tumorigenesis. However once cells were transformed the capability of those cells to generate ROS was decreased. Expressions of antioxidant regulative nuclear factor Nrf2 its positive regulator p62 and several major antioxidant enzymes were increased. Apoptosis eliminates DNA-damaged or mutated cells. When cells acquire apoptosis resistance they continue to proliferate leading to carcinogenesis. Cr(VI)-transformed cells developed apoptosis resistance as indicated by reductions of cleaved poly(ADP-ribose) polymerase (C-PARP) and cleaved caspase 9 (C-caspase 9) and by elevation of anti- apoptotic protein Bcl-2. Binding of Nrf2 to antioxidant response element (ARE) of Bcl-2 gene was increased indicating the possibility of Nrf2 in up-regulation of Bcl-2. In Cr (VI)-transformed cells inhibition of p62 by its shRNA reduced Nrf2 expression leading to induction of apoptosis. These results provide a linkage among p62 Nrf2 Bcl- 2 and apoptosis resistance. The central hypothesis of this application is that due to up-regulations of p62 and Nrf2 and decreased generation of ROS Cr (VI)-transformed cells develop apoptosis resistance and increase cell survival invasion and migration contributing to overall mechanism of Cr (VI)-induced carcinogenesis. Aim 1 will investigate the mechanism of decreased ROS generation of Cr(VI)-transformed cells. We will carry out comparative studies using non-transformed and Cr(VI)- transformed cells to study each key step of major Cr(VI)- induced ROS generation pathway and identify the specific step responsible for decreased ROS generation in Cr(VI)-transformed cells. We will also investigate the contribution of elevated antioxidant level by focusing on Nrf2 and Nrf2 targeting antioxidants. Aim 2 will investigate apoptosis resistance and its role in enhanced proliferation invasion and migration of Cr(VI)-transformed cells. We will alter ROS production by up-regulation of key proteins involved in ROS generation pathway and by down-regulation of key antioxidant enzymes to study the role of ROS in apoptosis resistance. We will investigate whether Nrf2-regulated Bcl-2 induction is a key event. We will alter apoptosis resistance by modifying Bcl-2 Bcl-xL Mcl-1 or Bax expression to investigate the role of apoptosis resistance in Cr(VI)-enhanced cell proliferation invasion and migration. Aim 3 will investigate the role of apoptosis resistance in Cr(VI)-induced tumorigenesis and metastasis using animal models. We will investigate the role of ROS by altering ROS generation including modification of antioxidant enzymes and Nfr2. The role of p62 will be investigated by inhibiting its expression. The role of apoptosis resistance will be investigated by alternation of apoptosis regulative proteins Bcl-2 Bcl-xL Mcl-1 or Bax. The same approaches will be used to investigate the role of ROS p62 and apoptosis resistance in metastasis of Cr(VI)-transformed cells using animal models.

project_terms:
Animal Model;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;CASP9 gene;Carcinogens;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chromates;Cleaved cell;Comparative Study;DNA Damage;Down-Regulation;Epithelial;Equilibrium;Event;Exhibits;Generations;Health;Heme;Human;Induction of Apoptosis;Industry;Lung;Malignant - descriptor;Mediating;Modification;Mutate;NQO1 gene;Neoplasm Metastasis;Normal Cell;Nuclear;Oxidases;Oxidoreductase;Oxygenases;Pathway interactions;Play;Poisons;Poly(ADP-ribose) Polymerases;Process;Production;Proliferating;Promoter Regions;Proteins;Quinine;Reaction;Reactive Oxygen Species;Regulation;Resistance;Response Elements;Role;Staging;Superoxide Dismutase;System;Testing;Up-Regulation;antioxidant enzyme;carcinogenesis;catalase;cell transformation;chromium hexavalent ion;exposed human population;genetic regulatory protein;migration;overexpression;small hairpin RNA;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cr(VI)-containing compounds are human carcinogens. The mechanism of their carcinogenesis remains to be investigated. This application will study the roles of p62 Nrf2 reactive oxygen species and apoptosis resistance in Cr(VI)-induced carcinogenesis.


application_id: 9058010
project_number: 4K08DA032296-06
project_title: African American Offenders: Drug Use Mental Health and HIV Risk
administering_ic: NIDA
award_notice_date: 2016-04-14
opportunity_number: PA-11-193
application_type: 4
activity_code: K08
ic: DA
serial_number: 032296
program_official: JONES, DIONNE
project_start_date: 2012-05-01
project_end_date: 2018-04-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
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:
DESCRIPTION (provided by applicant):  The primary goal of this K08 award is to further develop a productive independent research career in drug abuse research. The training and career development plan will enhance Dr. Stevens-Watkins's research experience in primary data collection with prisoners focused on drug use mental health and HIV thus resulting in the clarification of the specific aims of an R01 submission in years 4 and 5. The proposed training objectives are: (1) to receive training in the epidemiology of drug abuse mental health and HIV as they relate to health disparities among African Americans; (2) to further develop expertise in research with special populations biostatistics and advanced quantitative analyses including non-linear categorical models and structural equation modeling; (3) to use the data collected in the proposed research plan as pilot data for an R01 research proposal. The specified training goals are aligned with the research aims and compliment the clinical experience of the candidate. Dr. Stevens-Watkins will be sponsored by her established mentors Drs. Carl Leukefeld and Carrie Oser both with expertise in drug abuse and HIV research. Of high significance HIV has recently been termed a "crisis" in the African American community. The overall goal of the proposed research plan is to better understand the complex and dynamic relationship between drug use mental health and HIV risk among African American male prisoners nearing community re-entry. The specific aims are (1) to explore drug use symptoms of depression and anxiety and HIV risk behaviors among African American male inmates by conducting a thorough literature review and devising an analytical model using biostatics multivariate analytic techniques with available data; (2) to identify prevalence incidence and predictors of drug use disorders anxiety depressive disorders and HIV sexual risk behaviors among 205 incarcerated African American men; (3) to examine the knowledge patterns and perceived cultural and community barriers to utilizing individual and health resources and their relationship to substance abuse recovery and HIV risk behaviors among 205 African American men upon release from prison. Baseline data will be collected in prison and follow-up data collection will occur when participants have been released in the community after 3-months. The proposed research plan will offer HIV testing and counseling to an at-risk population that has historically been difficult to engage in research and HIV testing subsequently significantly impacting public health by possibly preventing the spread of HIV. The candidate's immediate career goals include published manuscripts and R01 funding by the end of K08 funding with an ultimate career goal of becoming an independent clinical drug abuse researcher. This proposal includes an outstanding mentoring team as well as a feasible training and research plan utilizing resources offered by both Spalding University and the University of Kentucky.

project_terms:
African American;Anxiety;Award;Biometry;Career Choice;Chronic;Clinical;Communities;Complex;Counseling;Data;Data Analyses;Data Collection;Depressive disorder;Development Plans;Drug Use Disorder;Drug abuse;Drug usage;Environment;Epidemiology;Equation;Funding;Goals;HIV;HIV Infections;HIV risk;Health;Health Resources;Housing;Human immunodeficiency virus test;Imprisonment;Incidence;Individual;Intervention;Interview;Kentucky;Knowledge;Life;Manuscripts;Mediating;Mental Depression;Mental Health;Mental Health Services;Mentors;Methods;Modeling;Outcome;Participant;Pattern;Phase;Populations at Risk;Pre-Post Tests;Prevalence;Prisoner;Prisons;Process;Protocols documentation;Psychologist;Public Health;Publishing;Recording of previous events;Recovery;Research;Research Personnel;Research Proposals;Research Training;Resources;Review Literature;Risk;Risk Behaviors;Social support;Specific qualifier value;Structural Models;Substance abuse problem;Techniques;Testing;Training;Universities;Unsafe Sex;Writing;anxiety symptoms;career;career development;community reentry;correctional system;depressive symptoms;drug testing;experience;follow-up;health disparity;health service use;high risk;high risk sexual behavior;impression;improved;intravenous drug use;male;men;men who have sex with men;named group;offender;prevent;psychologic;public health research;racism;sex risk

public_health_relevance:
The proposed project has significant public health implications for reducing the spread of HIV among the African American community by offering testing and by targeting men exiting prison re-entering the community. The proposed project will generate an improved understanding of the complex relationship between drug use mental health and HIV risk among an at-risk group.


application_id: 9057139
project_number: 5R01HL124170-02
project_title: Shear-Induced Hemostatic Dysfunction and Bleeding in CF-VAD Patients
administering_ic: NHLBI
award_notice_date: 2016-04-04
opportunity_number: PAR-13-137
application_type: 5
activity_code: R01
ic: HL
serial_number: 124170
program_official: LEE, ALBERT
project_start_date: 2015-04-20
project_end_date: 2017-02-01
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 7119111
contact_pi: WU, ZHONGJUN JON
other_pis: GRIFFITH, BARTLEY P
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: ORGANIZED RESEARCH UNITS
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months respectively. These survival rates are approaching those of heart transplant patients. However bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications we propose to conduct a series of clinical biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements. Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether a combination of clinical hematology biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluiddynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic next generation biocompatible VADs.

project_terms:
Adult;Adverse event;Affect;Annual Reports;Biocompatible;Biological;Biological Markers;Biomedical Engineering;Blood;Blood Coagulation Factor;Blood Platelets;Blood flow;Blood specimen;Cells;Characteristics;Clinical;Clinical Management;Data;Databases;Destinations;Device Designs;Device or Instrument Development;Devices;Diagnosis;Disease;Elements;Engineering;Environment;Event;Failure;Functional disorder;Goals;Health;Heart Transplantation;Heart failure;Hematology;Hemorrhage;Hemostatic Agents;Hemostatic function;Implant;Infection;Injury;Interagency Registry for Mechanically Assisted Circulatory Support;Knowledge;Laboratories;Link;Liquid substance;Logistic Regressions;Measures;Mechanics;Medical;Modeling;Molecular;Molecular Profiling;Myocardial;Organ failure;Outcome;Patients;Physiological;Plasma;Quality of life;Recovery;Research;Risk;Series;Staging;Stratification;Structure;Survival Rate;Technology;Testing;Thrombosis;Time;Transplant Recipients;Ventricular;Weight;base;clinically significant;design;experience;hemodynamics;implantation;improved;indexing;next generation;novel;profiles in patients;research study;shear stress;success;ventricular assist device

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. Bleeding is a significant problem for the VAD therapy. The goal of this project is to seek a better understanding of shear-induced hemostatic dysfunction and bleeding in CF-VAD patients. This knowledge can be used by clinicians to match patient specific pre-implant blood profiles with predicted fluid dynamics of CF- VADs to mitigate bleeding risks in patients and by engineers to develop less traumatic next generation biocompatible VADs. A significant portion of the 250000 patients with advanced HF in the US will benefit from the improved VAD technology and clinical management.


application_id: 9056623
project_number: 5R01ES024757-02
project_title: Coal Ash and Neurobehavioral Symptoms in Children Aged 6-14 Years Old.
administering_ic: NIEHS
award_notice_date: 2016-01-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 024757
program_official: GRAY, KIMBERLY A
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Behavioral Genetics and Epidemiology Study Section[BGES]
contact_pi_person_id: 8476117
contact_pi: ZIEROLD, KRISTINA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Coal ash is generated when power plants burn coal for energy. Coal ash is not classified as a hazardous waste so there are no federal regulations that govern its use storage or disposal. Most coal ash is stored in open landfills or in ponds. There are over 800 coal ash storage sites in the U.S. and many are located near residential communities. Coal ash includes many components but fly ash which is comprised of small spherical particles is the greatest component. Composition of fly ash varies but it frequently contains toxic metals (e.g. arsenic cadmium chromium copper lead manganese and mercury) polycyclic aromatic hydrocarbons (PAHs) and radioactive elements. Neurobehavioral disorders in children are associated with exposure to many of the metals that are contained in fly ash. Thus children exposed to fly ash are potentially at risk of developing neurobehavioral disorders. Children are exposed to fly ash via inhalation and ingestion from fugitive dust emissions that come off the landfills and the ponds.  This project will investigate the effect of fy ash on children who live in neighborhoods near two coal ash storage sites in Louisville Kentucky. Some children live in homes within 150 feet of coal ash landfills and ponds. Working with neighborhoods within 10 miles of the coal ash storage sites we will complete four specific aims: (1) Characterize indoor exposure from fly ash and heavy metals in homes of children residing near coal ash store sites compared to children living further away from coal ash storage sites (2) Determine if the heavy metal body burden differs from children residing near coal ash storage sites compared to children living further away from storage sites (3) Assess if increased fly ash exposure and greater heavy metal body burden is associated with poorer neurobehavioral performance and more neurobehavioral symptoms (4) Utilize mapping spatial analysis and modeling applications of geographic information systems (GIS) for household recruitment analysis of distance decay effects surface interpolation of Aims 1 and 2 results and fate and transport modeling of fly ash.  Three hundred and sixty children aged 6-14 will be recruited for this study. Neurobehavioral performance will be tested using the Behavioral Assessment Research System and neurobehavioral symptoms will be assessed by the Child Behavior Checklist (CBCL). Any child who has a CBCL t score =7 will be further assessed through a Structured Clinical Interview for the Diagnosis of DSM Disorders (SCID). Environmental sampling in the homes will be completed to determine the presence of fly ash and metals. Toenail samples will be collected from the children and analyzed for heavy metals. Questionnaires and an in-home assessment will help to characterize environmental exposure history and health history of the children. The results will provide evidence to define the environmental health impact of coal ash.

project_terms:
14 year old;Area;Aromatic Polycyclic Hydrocarbons;Arsenic;Attention deficit hyperactivity disorder;Autistic Disorder;Behavior Disorders;Behavior assessment;Blood Circulation;Body Burden;Breathing;Burn injury;Cadmium;Caliber;Child;Child Behavior Checklist;Chromium;Clinical;Coal;Communities;Copper;Developmental Delay Disorders;Diagnosis;Diagnostic and Statistical Manual of Mental Disorders;Disease;Dust;Emotional disorder;Environmental Exposure;Environmental Health;Exposure to;Focus Groups;Geographic Information Systems;Hazardous Substances;Hazardous Waste;Health;Heavy Metals;Home environment;Household;Human;Ingestion;Interview;Kentucky;Lead;Learning;Life;Low income;Lung;Manganese;Maps;Mercury;Metals;Methods;Modeling;Neighborhoods;Neurobehavioral Manifestations;Parents;Participant;Particle Size;Pathway interactions;Performance;Power Plants;Principal Investigator;Property;Public Health;Questionnaires;Radioactive;Radioactive Elements;Recording of previous events;Recruitment Activity;Regulation;Research;Research Personnel;Residual state;Risk;Sampling;Site;Structure;Structure of nail of toe;Surface;Surveys;Symptoms;Testing;Time;Toxic effect;United States;Work;aged;base;coal ash;community partnership;fly ash;follow-up;foot;hazard;improved;indoor exposure;junior high school;landfill;neurobehavioral;neurobehavioral disorder;neurotoxic;particle;pollutant;remediation;systems research;toxic metal

public_health_relevance:
PUBLIC HEALTH RELEVANCE: An estimated 1.54 million children in the U.S. are exposed to coal ash yet the research investigating the health impacts from exposure is scarce. Children exposed to coal ash which is comprised of small particles containing multiple heavy metals are potentially at risk for developing neurobehavioral symptoms. This study which will be the first todocument coal ash exposure heavy metal body burden and neurobehavioral performance and symptoms in children may provide evidence of the environmental and health impact of coal ash.


application_id: 9056562
project_number: 5R01HL122581-03
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2016-04-30
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 122581
program_official: ADHIKARI, BISHOW B
project_start_date: 2014-06-01
project_end_date: 2019-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-Q(02)]
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acrolein;Advanced Glycosylation End Products;Aerobic Exercise;Affect;Aldehyde Reductase;Amino Acids;Anserine;Antioxidants;Attenuated;Biochemical;Brain;Buffers;Cardiac;Cardiac Myocytes;Carnosine;Cause of Death;Clinical;Development;Dipeptides;Drug Metabolic Detoxication;Enzymes;Excision;Excretory function;Fructose;Functional disorder;Glutathione S-Transferase;Glyceraldehyde;Glycolysis;Health;Heart;Heart Injuries;In Situ;Inflammation;Inflammatory;Injury;Intervention;Ischemia;Lead;Link;Lipids;Mediating;Mediator of activation protein;Membrane Lipids;Metabolic;Metals;Modeling;Mus;Myocardial;Myocardial Ischemia;Myocardial Reperfusion;Outcome;Pathway interactions;Peptides;Perfusion;Physiological;Process;Property;Proteins;Pyruvaldehyde;Reactive Oxygen Species;Recovery;Reperfusion Injury;Reperfusion Therapy;Research;Role;Skeletal Muscle;Stress;System;Testing;Therapeutic;Tissues;Toxic effect;Work;adduct;aldehyde dehydrogenases;analog;base;chelation;crosslink;design;effective intervention;effective therapy;link protein;multicatalytic endopeptidase complex;myocardial damage;myocardial infarct sizing;novel;overexpression;oxidation;prevent;protein aggregation;sugar


application_id: 9056525
project_number: 4R01DK074720-09
project_title: Novel hematopoietic effects of C5 cleavage fragment
administering_ic: NIDDK
award_notice_date: 2016-04-25
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: DK
serial_number: 074720
program_official: ROY, CINDY
project_start_date: 2007-03-01
project_end_date: 2017-07-16
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Both pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) and myeloablative conditioning for transplantation activate the complement cascade (CC) in bone marrow (BM) and in the previous funding period we focused on the role of the third complement component (C3) in mobilization and homing of HSPCs. In this competing renewal we will focus on the fifth complement component (C5) which is located downstream from C3. C5 cleavage leads to generation of the potent anaphylatoxins C5a and desArgC5a and generation of non-lytic and lytic C5b-C9 known as the membrane attack complex (MAC). Our recently published data support a crucial role for C5a/C5b-C9 in trafficking of HSPCs. In particular C5-deficient mice are poor mobilizers in response to granulocyte colony stimulating factor (G-CSF) and exhibit delayed hematopoietic reconstitution after transplantation with wild type (WT) BM cells. Based on these findings the central hypothesis of this competing renewal is that the activation of distal steps of the complement cascade and release of C5a and C5b-C9 (MAC) are important regulators of mobilization and homing of HSPCs. To address this hypothesis we propose: Specific Aim 1. The molecular basis of the mobilization defect in C5-deficient mice. Based on our observation that C5-deficient mice are poor G-CSF mobilizers we will address whether C5 cleavage is i) required for circadian HSPC mobilization ii) mobilization of HSPC induced by other agents and iii) whether C5 activation and S1P plasma level correlates with mobilization efficacy in patients. We will also focus on the role of erythrocyte-released S1P in mobilization by performing mobilization studies in CD55/CD59-deficient mice that are highly sensitive to C5b-C9 (MAC) lysis. Finally we will focus on the role of C5b-C9-induced release of S1P in mobilization observed in patients with hemolytic syndromes. Specific Aim 2. The molecular basis of the homing defect in C5-deficient mice. We found that the CC is activated in lethally irradiated mice and that C5-deficient mice engraft poorly with WT BM cells. To shed more light on the role of the distal part of the CC (C5a/C5b-C9) in homing/engraftment we will study whether conditioning for transplantation by chemotherapy also activates the CC in BM and study the effect of C5a/C5b-C9 on expression of i) HSPC chemoattractants in BM ii) adhesion/tethering molecules for HSPCs on BM endothelium and ii) on secretion of factors facilitating homing. Specific Aim 3. The C5a/C5b-C9-induced BM stroma-derived cathelicidin (LL-37) as a potent homing sensitizing factor. We found that LL-37 like C3a is a very strong priming factor for SDF-1 that becomes upregulated in BM stroma after conditioning for transplantation in a C5a/C5b-C9-dependent manner. In an immunodeficient mouse model we will test whether short exposure of HSPCs to LL-37 before transplantation increases homing of human BM- and umbilical cord blood (UCB)-derived HSPCs. We will also address whether LL-37 also primes the responsiveness of HSPCs to other homing factors and focus on the molecular mechanism of these phenomena.

project_terms:
Address;Adhesions;Adult;Anaphylatoxins;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotactic Factors;Circadian Rhythms;Collaborations;Complement;Complement 3a;Complement 5a;Complement Activation;Complement Membrane Attack Complex;Complement component C5;Cytolysis;Data;Defect;Development;Dinoprostone;Distal;Endothelium;Engraftment;Erythrocytes;Exhibits;Fibroblasts;Funding;Generations;Granulocyte Colony-Stimulating Factor;Growth;Health;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Human;Integrin alpha4beta1;Integrins;Investigation;Lead;Life;Ligands;Light;Link;Lipids;Lytic;Molecular;Mus;Natural Immunity;Nucleotides;Osteoblasts;Patients;Physiological;Plasma;Polysaccharides;Process;Publishing;Role;Stem cells;Syndrome;Testing;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Vascular Cell Adhesion Molecule-1;Work;base;cathelicidin;ceramide 1-phosphate;chemotherapy;complement C3 precursor;complement C5b;immunodeficient mouse model;leukemia;novel;novel therapeutics;peripheral blood;reconstitution;response;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Section In this competing renewal we will focus on the role of a major component of innate immunity namely activation of the complement cascade in trafficking of hematopoietic stem/progenitor cells. This application will allow us to better understand this process as well as lead to the development of novel therapeutic strategies to treat patients with leukemias and inborn defects of hematopoiesis by transplantation of hematopoietic stem cells.


application_id: 9055552
project_number: 5F30ES025099-02
project_title: Xenobiotic Receptors Modulate PCB-induced Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: ES
serial_number: 025099
program_official: SCHUG, THADDEUS
project_start_date: 2015-04-15
project_end_date: 2020-04-14
study_section: Special Emphasis Panel[ZRG1-F06-S(20)L]
contact_pi_person_id: 12058438
contact_pi: CLAIR, HEATHER B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is intimately associated with obesity diabetes and the metabolic syndrome. Traditionally NAFLD has been associated with caloric excess on a susceptible genetic background however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of steatosis and steatohepatitis particularly in
the context of hypercaloric diet coexposure. Our proposed study uses exposure parameters informed by our recent analysis of serum samples from a previously-described cohort of individuals residing in Anniston AL who were exposed to high levels of PCB-containing waste. Although many of these individuals have serum levels of PCBs above that found in the general population of the US their exposures remain well below the levels implicated in acute liver injury. Nevertheless these individuals have significantly elevated biomarkers of liver injury as well as elevated inflammatory cytokines elevated prevalence of diabetes and increased BMI when compared to an unexposed population. A frustrating finding of previous toxicity studies has been the very different pathological response of mice and humans to such subacute chronic and environmentally relevant PCB exposures. Our preliminary data in a mouse model of subacute PCB exposure shows paradoxical elevations of liver injury biomarkers fatty change and inflammatory cytokines at lower exposure vs. higher exposure to a PCB mixture (20mg Aroclor 1260/kg body weight vs. 200mg/kg body weight Aroclor 1260). In two knockout mouse models that lack the constitutive androstane receptor (CAR) or the pregnane and xenobiotic receptor (PXR) our laboratory has found differential transcription of the gene targets of these receptors in response to Aroclor 1260 and high-fat diet exposure. These patterns of pathological and phenotypic responses are consistent with a transcription-factor based mechanism of PCB toxicity. The differences in disease endpoints may therefore be due to differences in ligand specificity and target gene cohort between the human and mouse forms of these receptors. We therefore propose to expand our investigation of receptor-based mechanisms of PCB toxicity with the use of a novel triple-transgenic mouse model expressing human forms of AhR PXR and CAR. We hypothesize that using both an acute-exposure primary hepatocyte culture and a whole animal chronic exposure model we will find that differences in the structure and function of these receptors will drive a differential transcriptioal response to PCBs and ultimately differences in PCB-associated disease endpoints.

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

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


application_id: 9055456
project_number: 1R21AG050146-01A1
project_title: Testing a therapeutic strategy for hippocampal sclerosis of aging a key AD mimic
administering_ic: NIA
award_notice_date: 2015-12-21
opportunity_number: PAR-13-049
application_type: 1
activity_code: R21
ic: AG
serial_number: 050146
suffix: A1
program_official: WISE, BRADLEY C
project_start_date: 2016-01-01
project_end_date: 2017-11-30
study_section: Drug Discovery for the Nervous System Study Section[DDNS]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. Poor understanding of these diseases has hampered AD clinical trials while leaving important illnesses largely unaddressed from a clinical research perspective. A common and high-morbidity "AD mimic" is hippocampal sclerosis of aging (HS-Aging). HS-Aging is characterized by cell loss and astrocytosis in the hippocampus with phosphorylated TDP-43 (P-TDP-43) pathology not correlated with AD-type pathology nor with APOE genotype. HS-Aging affects 10-25% of persons above age 85 years. The PI of the current proposal has studied HS-Aging extensively including the first HS-Aging genome-wide association study (GWAS). A genetic polymorphism in the ABCC9 gene is linked to HS-Aging pathology. Importantly we recently (Jan 2015) published a paper that replicated this observation in a separate group of research volunteers. The ABCC9 mutation enables us to address a central as-yet unrealized promise of genomics studies: clinical relevance. Remarkably the GWAS-identified HS-Aging risk gene ABCC9 is a "druggable target"-both agonist and antagonist drugs are used widely in humans. In a prior published study we found that exposure to sulfonylureas (oral anti-diabetic drugs that antagonize ABCC9 protein function) is associated with increased risk for HS-Aging pathology in humans controlling for other factors. We need to assess the potential to target ABCC9 in a preclinical model for more rigorous control of experimental parameters. That will enable us to test the impact of an ABCC9 agonist drug with the opposite effects of sulfonylureas as a potential therapy for clinical HS-Aging. Overall Hypothesis: Pharmacologic ABCC9 regulation provides a therapeutic strategy for HS-Aging. We propose proof-of-concept preclinical studies to test the specific hypothesis that ABCC9 agonist nicorandil attenuates pathologic and behavioral features of HS-Aging in a mouse model. Specific Aims: 1. Characterize the first preclinical model of HS-Aging. In GRN knockout (GRN-KO) mice our studies indicate the presence of brain changes that model features of human HS-Aging including hippocampal P-TDP-43 pathology and hippocampus-related neurobehavioral deficits. 2. Based on studies in humans test in the GRN-KO mouse model the hypothesis that a sulfonylurea drug (glimepiride) which antagonizes ABCC9 exacerbates HS-Aging pathology and abnormal behavior. 3. Test in the GRN-KO mouse model the hypothesis that nicorandil which opens the potassium channel (the opposite activity as sulfonylureas) reduces HS-Aging-related abnormal pathology and behavior. Since there are similar pathologies and genetic susceptibilities the therapeutic strategy may also be relevant to a separate lethal neurodegenerative disease frontotemporal lobar degeneration (FTLD).

project_terms:
Address;Affect;Age;Aging;Agonist;Alzheimer's Disease;Amygdaloid structure;Animal Model;Antidiabetic Drugs;Apolipoprotein E;Astrocytosis;Attenuated;Autopsy;Behavior;Behavioral;Biochemical Markers;Biochemistry;Brain;Cells;Clinical;Clinical Data;Clinical Research;Clinical Trials;Controlled Study;Data;Development;Diabetes Mellitus;Disease;Drug usage;Elderly;Exposure to;Frontotemporal Lobar Degenerations;Genes;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Genotype;Glimepiride;Gliosis;Goals;Hippocampus (Brain);Human;Impaired cognition;Knockout Mice;Knowledge;Left;Life;Link;Modeling;Morbidity - disease rate;Mus;Mutation;Neurodegenerative Disorders;Neurofibrillary Tangles;Nicorandil;Oral;Paper;Pathologic;Pathology;Patients;Persons;Pharmaceutical Preparations;Potassium Channel;Pre-Clinical Model;Preclinical Testing;Proteins;Public Health;Publishing;Regulation;Research;Risk;Series;Sulfonylurea Compounds;Testing;Therapeutic;Transgenic Mice;age related;base;behavioral study;clinically relevant;genome wide association study;genome-wide;hippocampal sclerosis;mouse model;neurobehavioral;novel;novel therapeutics;pre-clinical;preclinical study;protein TDP-43;protein function;public health relevance;risk variant;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. A common and high-morbidity "AD mimic" is HS-Aging and here we propose the first animal model of HS-Aging to test a novel therapeutic strategy. We will treat transgenic mice with a drug nicorandil as a preclinical "proo of concept" to reverse the HS-Aging related pathology and behavioral changes and which may also be relevant to a therapeutic approach for frontotemporal lobar degeneration (FTLD).


application_id: 9054459
project_number: 1UH2DA041115-01
project_title: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2015-09-08
opportunity_number: RFA-DA-15-017
application_type: 1
activity_code: UH2
ic: DA
serial_number: 041115
program_official: SHIH, MING L
project_start_date: 2015-09-15
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZDA1 JXR-D (12)]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for cocaine addiction or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 M) we have recently designed and discovered a set of BChE -1 mutants known as cocaine hydrolases (CocHs) with at least 1000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy our recently designed discovered and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs) this investigation will focus on further optimization manufacturing process development formulation development and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing Investigational New Drug (IND)-enabling studies and subsequent clinical trials. Thus this investigation will move a promising therapeutic
candidate closer toward FDA approval for cocaine addiction treatment.

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


application_id: 9054119
project_number: 5R01ES024771-02
project_title: Community-Engaged Research and Action to Reduce Respiratory Disease in Appalachia
administering_ic: NIEHS
award_notice_date: 2016-02-03
opportunity_number: PA-12-153
application_type: 5
activity_code: R01
ic: ES
serial_number: 024771
program_official: FINN, SYMMA
project_start_date: 2015-04-15
project_end_date: 2020-01-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 1939811
contact_pi: BROWNING, STEVEN R
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Action Research;Address;Adult;Adult asthma;Affect;Age;Air;Air Pollutants;Appalachian Region;Area;Asthma;Back;Behavioral;Chronic Obstructive Airway Disease;Coal Mining;Collaborations;Communities;Community Participation;Data;Development;Diagnosis;Diet;Environmental Exposure;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epidemiology;Evaluation;Exposure to;Gender;Goals;Health;Health education;Healthcare;Home environment;Individual;Intervention;Kentucky;Knowledge;Lead;Lung diseases;Measurement;Measures;Modification;Nature;Neighborhoods;Occupations;Outcome;Outcome Assessment;Physical activity;Population;Process;Public Health;Quality of life;Randomized;Reporting;Research;Research Design;Research Personnel;Risk;Risk Factors;Role;Rural;Self Efficacy;Self Management;Smoking;Source;Symptoms;Testing;Voice;arm;base;community organizations;community partnership;design;efficacy testing;environmental justice;experience;health disparity;improved;innovation;low socioeconomic status;meetings;member;programs;pulmonary function;residence;respiratory;respiratory health;response;satisfaction;social


application_id: 9053483
project_number: 5R21EB020107-02
project_title: Immuno-vasculogenic hydrogels for islet engraftment and localized tolerance
administering_ic: NIBIB
award_notice_date: 2016-02-25
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: EB
serial_number: 020107
program_official: MAMAGHANI, SHADI
project_start_date: 2015-04-15
project_end_date: 2018-03-31
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: GARCIA, ANDRES J
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Type 1 diabetes (T1D) is an autoimmune disease caused by immune destruction of insulin-producing pancreatic  cells. T1D affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion. Allogeneic islet transplantation has proven effective in improving metabolic control/quality of life and in preventing severe hypoglycemia in patients with T1D. However broad clinical application of allogeneic islets is limited by i) immunerejection despite the chronic use of immunosuppression and its sequelae ii) transplantation into the liver which compromises immediate post-graft islet engraftment as well as long-term survival and iii) insufficient human islet supply from cadaveric pancreata. Thus there is a significant need for innovative strategies that overcome these limitations of islet transplantationfor a broader clinical practice.  This R21 application is formulated to overcome graft rejection without chronic use of immunosuppression and establish the small bowel mesentery as an extrahepatic site for islet transplantation thereby overcoming two critical barriers of islet transplantation. This will be achieved by engineering dual-action immunomodulatory and vasculogenic hydrogels for controlled delivery of a novel form of PD-L1 and VEGF for islet transplantation in the small bowel mesentery. PD-L1 (programmed death-ligand 1) is an important immunoregulatory molecule involved in tolerance to self-antigens and has extensively been exploited by chronic infections and cancer for immune evasion. PD-L1 interaction with PD-1 receptor on various adaptive and innate immune effector cells results in inhibition of effector function and/or physical elimination of these cells. Importantly PD-1/PD-L1 interaction is involved in the generation of tolerogenic DCs and induced CD4+CD25+FoxP3+ Treg cells that are critical to peripheral tolerance to self-antigens and acquired tolerance to foreign antigens invarious experimental settings. VEGF has recently been shown to confer a stable tolerogenic phenotype to DCs by inducing the expression of indoleamine 23-dioxygenase (IDO). IDO is an important immunoregulatory enzyme and signaling molecule that is involved in fetomaternal tolerance and generation of Treg cells. Our central hypothesis is that PD-L1 and VEGF delivered by biomaterials will work in synergy to induce localized tolerance and promote islet vascularization for long-term allogeneic islet survival and function without continuous use of immunosuppression. The overall objective will be accomplished by testing our central hypothesis through two Aims: 1) Engineer PD-L1/VEGF- presenting hydrogels to generate Treg cells in vitro and facilitate allogeneic islet engraftment vascularization and survival in short-erm in vivo studies; and 2) Test the efficacy of the PD-L1/VEGF hydrogels to support long-term engraftment vascularization tolerance induction and treatment of diabetes. Studies will be conducted to elucidate the mechanistic basis of graft failure and/or long-term survival with particular focus on innate and adaptive effector immune and regulatory (tolerogenic dendritic cells and Treg cells) responses.

project_terms:
Abdomen;Adult;Affect;Allogenic;Antigens;Apoptosis;Autoantigens;Autoimmune Diseases;Beta Cell;Biocompatible Materials;Biotin;Cells;Child;Chronic;Dendritic Cells;Development;Diabetes Mellitus;Diabetic mouse;Effector Cell;Encapsulated;Engineering;Engraftment;Enzymes;Extrahepatic;Formulation;Generations;Goals;Graft Rejection;Graft Survival;Health;Health Care Costs;Homeostasis;Human;Hydrogels;Hypoglycemia;IL2RA gene;Immune;Immune Tolerance;Immune response;Immune system;Immunology;Implant;In Vitro;Infection;Inflammatory Infiltrate;Insulin;Insulin-Dependent Diabetes Mellitus;Islets of Langerhans;Islets of Langerhans Transplantation;Label;Lead;Lectin;Life;Liver;Longitudinal Studies;Maintenance;Malignant Neoplasms;Mesentery;Metabolic Control;Monitor;Mus;Natural immunosuppression;Nature;PDCD1LG1 gene;Pancreas;Patients;Performance;Phenotype;Population;Proteins;Quality of life;Regulatory T-Lymphocyte;Research;Signaling Molecule;Sirolimus;Site;Small Intestines;Source;Streptavidin;Structure of beta Cell of islet;Testing;Therapeutic;Transplantation;Tryptophan 23 Dioxygenase;Vascular Endothelial Growth Factors;Vascularization;Work;base;clinical application;clinical practice;cytokine;density;efficacy testing;graft failure;improved;in vivo;innovation;islet;novel;novel strategies;peripheral tolerance;prevent;receptor;response;standard care

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of population worldwide. Insulin as a standard treatment although effective in treating T1D has major long-term complications. Therefore the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. In this application we propose the engineer hydrogels with vasculogenic and immunomodulatory proteins to deliver allogeneic pancreatic islets (a source of insulin producing beta cells) into the abdomen ofdiabetic mice to treat T1D by enhancing islet engraftment of and controlling rejection for indefinite graft survival in the absence of chronic use of immunosuppression. If effective this approach may have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9053452
project_number: 6R44CA139791-03
administering_ic: NCI
award_notice_date: 2016-05-06
opportunity_number: PA-14-071
application_type: 6
activity_code: R44
ic: CA
serial_number: 139791
program_official: KURTZ, ANDREW J
project_start_date: 2009-04-01
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZRG1-OTC-T(12)B]
contact_pi_person_id: 9542261
contact_pi: AGARWAL, MUKESH KUMAR
other_pis: WALD, DAVID
congressional_district: 06
department: Unavailable
primary_duns: 830682089
primary_uei: CUJMD4EH1V21
duns_number: 830682089
uei: CUJMD4EH1V21
fips: US
organization_id: 10023555
organization_name: MIRX PHARMACEUTICALS, LTD
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
project_title:
Original Phase 1 Title: Identifying Small Molecule Inhibitors of HdmX using Cell-based Screening Revised Title: Development of a Novel HdmX Inhibitor for Leukemia

project_abstract:
DESCRIPTION (provided by applicant): Despite advances in cancer therapy the majority of cancer therapeutics in use still exhibit significant toxicity and induce DNA damage. The DNA damage though toxic to non-malignant cells often plays an important role in killing cancer cells through the induction of p53. Recently in order to develop less toxic and more targeted cancer therapies alternative strategies to induce p53 have been proposed. One strategy involves disrupting p53 interactions with its negative regulators HdmX and/or Hdm2. In our phase 1 grant we identified CTX1 a novel small molecule inhibitor of HdmX/p53 that can disrupt HdmX/p53 interactions and lead to p53 induction and cancer cell death in a non-DNA damage dependent fashion. CTX1 can directly interact with HdmX and preferentially kill cancer cells expressing p53. As expected the activity of CTX1 is enhanced by concurrent Hdm2 inhibition. Nonetheless this compound demonstrates promising activity even as a single agent in a mouse model of circulating primary human AML. The goal of this proposal is to develop an optimized version of our HdmX inhibitor that we identified during our phase 1 grant towards clinical trials. The aims of this proposal are to assess the clinical potential of this agent through mouse efficacy pharmacokinetic and toxicity studies. It is hoped that this work will lead to the initiaton of IND-enabling studies and the initiation of a phase 1 clinical trial.

project_terms:
Acute Myelocytic Leukemia;Adverse effects;Animals;Apoptosis;Binding;Biological Models;Blood;Bone Marrow;Cell Death;Cells;Clinical;Clinical Research;Clinical Trials;Complex;DNA Damage;Development;Disease;Dose;Drug Kinetics;Exhibits;Future;Goals;Grant;Health;Hematopoietic;Homologous Gene;Human;Immunodeficient Mouse;In Vitro;Killings;Lead;Leukemic Cell;Malignant Neoplasms;Modeling;Mus;Mutation;Non-Malignant;Normal Cell;Organ;Pathway interactions;Patient Selection;Patients;Pharmaceutical Chemistry;Phase;Phase I Clinical Trials;Play;Property;Public Health;Rattus;Regimen;Reporting;Rodent;Role;Safety;Sampling;Specificity;TP53 gene;Testing;Therapeutic;Toxic effect;Work;acute toxicity;animal efficacy;base;cancer cell;cancer therapy;cancer type;cell transformation;chemotherapy;clinically relevant;companion diagnostics;human disease;inhibitor/antagonist;leukemia;mouse model;mutational status;novel;novel therapeutics;overexpression;prevent;screening;small molecule inhibitor;targeted cancer therapy;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to lead to the development of novel therapies for patients with Acute Myeloid Leukemia that are both efficacious and have low toxicity. As the current AML therapeutics have low efficacy and high toxicities there is a significant need for new therapies.


application_id: 9052203
project_number: 5R01HL073085-12
project_title: Angiotensin - A link between obesity and hypertension
administering_ic: NHLBI
award_notice_date: 2016-04-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-VH-F(02)M]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The prevalence of obesity is rising in Kentucky and the nation. Prior to the obesity epidemic hypertension prevalence was lower in females than males until menopause when both obesity and hypertension increase. The most recent NHANES data demonstrate the surprising finding that the prevalence of hypertension is rising at a faster rate in females than males. This competing renewal focuses on mechanisms contributing to obesity-induced hypertension in males versus females a highly significant topic since obesity is a primary cause of hypertension in both genders. We have examined whether an activated adipocyte renin-angiotensin system (RAS) is a link between obesity and hypertension. During the current period we demonstrated that deficiency of adipocyte-derived angiotensinogen (AGT) prevented elevations in adipose and systemic angiotensin II (Ang II) concentrations and abolished the development of hypertension in obese male mice. We also demonstrated that adipocytes express angiotensin converting enzyme 2 (ACE2) which cleaves Ang II to form the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). In male obese hypertensive mice exhibiting increased adipose-derived systemic Ang II adipose ACE2 expression was reduced and systemic Ang-(1-7) concentrations plummeted. These results suggest that reductions in ACE2 in an expanded adipose mass make Ang II the predominant adipose-derived RAS peptide contributing to hypertension in obese male mice. In contrast to males obese female mice were totally resistant to the development of hypertension despite greater adiposity. Remarkably female normotensive obese mice exhibited increased adipose ACE2 activity associated with elevated plasma Ang-(1-7) concentrations. Deficiency of ACE2 converted obese females to a hypertensive phenotype. Removal of ovarian sex hormones reduced adipose ACE2 activity and plasma Ang- (1-7) concentrations and resulted in robust obesity-induced hypertension. Moreover estrogen markedly stimulated ACE2 mRNA abundance in 3T3-L1 adipocytes. We hypothesize that differential regulation of adipocyte ACE2 in obese males versus females determines whether adipose tissue produces Ang II or Ang-(1- 7) in the development of hypertension. Aim 1 tests the hypothesis that adipocyte ACE2 deficiency promotes hypertension in obese female mice while ACE2 activation prevents hypertension in obese males through an adipocyte ACE2-dependent mechanism. Aim 2 tests the hypothesis that estrogen promotes adipocyte ACE2 expression and protects male and ovariectomized female obese mice from hypertension. Aim 3 tests the hypothesis that DIZE-induced ACE2 activation reduces blood pressure in male and ovariectomized female obese hypertensive mice through an Ang-(1-7)/MasR-dependent mechanism. The impact of these studies is definition of mechanisms for the development of hypertension in obese males versus females. We will also develop ACE2 activation as a novel therapy to treat hypertension in obese males and/or menopausal females.

project_terms:
Adipocytes;Adipose tissue;Angiotensin II;Angiotensinogen;Angiotensins;Blood Pressure;Body mass index;Castration;Cleaved cell;Data;Development;Epidemic;Equilibrium;Estrogen Therapy;Estrogens;Excision;Exhibits;Female;Gender;Gonadal Steroid Hormones;Health;Hypertension;Kentucky;Knock-out;Left;Link;Mediator of activation protein;Menopause;Messenger RNA;Modeling;Mus;NHANES;Obese Mice;Obesity;Ovarian;Peptides;Peptidyl-Dipeptidase A;Phenotype;Plasma;Prevalence;Production;Regulation;Renin-Angiotensin System;Resistance;Source;Testing;Translating;Vasodilator Agents;Women's Rights;angiotensin I (1-7);blood pressure reduction;male;normotensive;novel;novel therapeutics;prevent;receptor;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is at epidemic proportions in the US and may eventually overcome previously ascribed protection of females against the development of hypertension. These studies focus on the renin-angiotensin system of adipocytes as a mediator of obesity-hypertension in males versus females. Since obesity is the primary cause of hypertension in the US and the prevalence of hypertension is increasing more rapidly in females than males our studies will define mechanisms for these differences and uncover novel targets for drug therapy.


application_id: 9052132
project_number: 5R01AI120244-02
project_title: Molecular and Cellular Pathogenesis of Legionella
administering_ic: NIAID
award_notice_date: 2016-04-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 120244
program_official: ERNST, NANCY L
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alveolar Macrophages;Amoeba genus;Ankyrin Repeat;Asparagine;Bacterial Proteins;Binding;Biogenesis;Bioinformatics;Biological Process;Cell physiology;Cells;Chemicals;Complex;Computer Simulation;Data;Disease;Endoplasmic Reticulum;Environment;Enzymes;Genomics;Genus Mycobacterium;Health;Human;Hydroxylation;Hypoxia;Infection;Inflammatory;Killings;Legionella;Legionella pneumophila;Lysosomes;MMP14 gene;Mediating;Membrane;Mixed Function Oxygenases;Modification;Molecular;Morbidity - disease rate;Organism;Pathogenesis;Phagocytes;Pneumonia;Post-Translational Protein Processing;Proliferating;Proteins;Proteome;RNA Interference;Recruitment Activity;Reporting;Role;Shigella;System;Testing;Type IV Secretion System Pathway;Ubiquitination;Vacuole;Yersinia;genome-wide;innovation;knock-down;liquid chromatography mass spectrometry;macrophage;microbial;monocyte;mortality;novel;pathogen;protein protein interaction;transmission process


application_id: 9052102
project_number: 5R01AG033649-07
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2016-04-06
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: WISE, BRADLEY C
project_start_date: 2009-08-01
project_end_date: 2020-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
21 year old;Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Formulation;Functional disorder;Funding;Gap Junctions;Glucose;Health;Healthcare Systems;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathway interactions;Patients;Peripheral;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Research Design;Risk;Risk Factors;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging hippocampus;aging population;animal tissue;base;blood glucose regulation;clinically relevant;cognitive function;cognitive performance;cognitive process;feeding;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;molecular imaging;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy


application_id: 9050994
project_number: 1F31NS092202-01A1
project_title: MMPs in microhemorrhage occurrence in cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2015-09-18
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: NS
serial_number: 092202
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2015-09-28
project_end_date: 2017-09-27
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 12104649
contact_pi: WEEKMAN, ERICA MARIE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Dementia is defined as cognitive loss severe enough to affect daily living and unlike other leading causes of death the number of persons afflicted with dementia is increasing. The two most common forms of dementia are Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID). Although they have different etiologies these two forms of dementia share some similar pathologies such as vasogenic edema and microhemorrhages. These pathologies were also exacerbated when anti- amyloid beta (A) immunotherapy was used for treatment of AD causing termination of the clinical trials. Matrix metalloproteinases (MMPs) are proteases that can break down the blood brain barrier leading to vasogenic edema and microhemorrhage. The specific goals of this proposal are to determine the contribution of two specific MMPs MMP2 and MMP9 to the occurrence of vasogenic edema and microhemorrhage and to evaluate whether the presence of VCID will reduce the efficacy of anti-A treatment. The overall goal of this proposal is to provide possible targets for adjunct therapies with anti-A immunotherapy and improve AD clinical trials by screening for VCID co-morbidities.  To achieve these goals this proposal will utilize in vivo (Aim 1) and in vitro (Aim 2) methods. In Aim 1 the effect of VCID on the efficacy f anti-A immunotherapy vasogenic edema and microhemorrhages will be determined. Transgenic mice with amyloid deposition will be placed on the hyperhomocysteinemia diet to induce VCID and then treated with an anti-A immunotherapy. When VCID is pre-existing in a model of amyloid deposition treatment with anti-A immunotherapy will increase activation of the MMP2 and MMP9 systems exacerbate microhemorrhages and vasogenic edema and have reduced efficacy on cognition. Vasogenic edema microhemorrhages cognitive changes and MMP2 and MMP9 activity will be determined for Aim 1. Aim 2 will evaluate the role of MMP9 in the degradation of tight junctions in endothelial and astrocyte co-culture. The effect of inhibitio of MMP9 on tight junction degradation will also be assessed. Inflammatory- mediated activation of MMP9 will degrade tight junctions between cerebrovascular endothelial cells leading to vasogenic edema and microhemorrhages and inhibition of MMP9 will reduce tight junction degradation. Tight junction permeability and MMP9 activity will be assessed for Aim 2. Together these aims will offer valuable information on the contribution of MMP2 and MMP9 to vasogenic edema and microhemorrhage occurrence and the effect VCID has on anti-A immunotherapy.  These studies will provide training in new techniques. Specifically the applicant will learn how t execute cell biology based assays such as the sodium fluorescein assay and the isolation of primary astrocytes along with data analysis and interpretation skills. These aims and the training potential provided by them will aid the applicant in achieving their long term career goals.

project_terms:
Affect;Alzheimer disease screening;Alzheimer's Disease;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Amyloid deposition;Animal Husbandry;Antibodies;Astrocytes;Biological Assay;Blood - brain barrier anatomy;Brain;Cause of Death;Cell Culture Techniques;Cells;Cellular biology;Cerebrovascular Disorders;Clinical Trials;Coculture Techniques;Cognition;Comorbidity;Data Analyses;Dementia;Diet;Edema;Endothelial Cells;Etiology;Gelatinase A;Gelatinase B;Goals;Hyperhomocysteinemia;Immunotherapy;Impaired cognition;In Vitro;Inflammatory;Inhibition of Matrix Metalloproteinases Pathway;Injection of therapeutic agent;Interleukin-1 beta;Knockout Mice;Learning;Life;Manuscripts;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediating;Methionine;Methods;Modeling;Mus;Pathology;Patients;Peptide Hydrolases;Permeability;Persons;Population;Proteins;Role;SB 3CT compound;Sodium Fluorescein;System;TIMP1 gene;Techniques;Testing;Tight Junctions;Training;Transgenic Mice;Tumor Necrosis Factor-alpha;Vitamin B6;Writing;aged;base;behavioral outcome;career;cerebrovascular;cognitive change;design;extracellular;improved;in vivo;inhibitor/antagonist;mouse model;presenilin-1;public health relevance;screening;skills;therapeutic target;vascular contributions

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID) are the two most common forms of dementia affecting 55% and 20% of dementia patients respectively. This proposal is designed to offer valuable information on the contribution of specific proteins to pathologies common to Alzheimer's disease and VCID (vasogenic edema and microhemorrhage) and the effect VCID has on therapies for Alzheimer's disease (anti-A immunotherapy). With this information we will provide possible targets for adjunct therapies with anti-A immunotherapy and improved clinical trials of Alzheimer's disease by screening more closely for patients with VCID co-morbidities.


application_id: 9050804
project_number: 1R01CA203257-01
project_title: Natural product-based modulators of 4E-BP1 phosphorylation
administering_ic: NCI
award_notice_date: 2016-03-21
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 203257
program_official: FU, YALI
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1 BCMB-D (02)]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: SHE, QING-BAI
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Antineoplastic Agents;Binding;Biological Assay;CCI-779;Colorectal Cancer;Complex;Development;Disease;Disease Progression;Drug Kinetics;Drug resistance;EIF4EBP1 gene;FRAP1 gene;Generations;Genetic;Genetic Translation;Goals;In Vitro;Knowledge;MEKs;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Messenger RNA;Modeling;Molecular;Molecular Probes;Mutation;Naphthoquinones;Natural Products;Neoplasm Metastasis;Oncogenes;Oncogenic;PI3K/AKT;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phosphorylation;Phosphotransferases;Production;Property;Protein Inhibition;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Reactive Oxygen Species;Reporter;Research;Resistance;Signal Pathway;Signal Transduction;Staging;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translation Initiation;Translational Regulation;Translations;Work;Xenograft procedure;analog;base;cancer cell;cancer therapy;cell growth;clinical efficacy;drug development;effective therapy;expectation;in vitro Assay;in vivo;inhibitor/antagonist;interest;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;mouse model;mutant;novel;novel strategies;novel therapeutic intervention;pre-clinical;prevent;public health relevance;targeted treatment;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;upstream kinase


application_id: 9050592
project_number: 4R01AG027297-10
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2016-03-31
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: AG
serial_number: 027297
program_official: OPANASHUK, LISA A
project_start_date: 2006-09-01
project_end_date: 2018-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this project use innovative gene delivery techniques and a multipronged approach to assess the fundamental role of astrocyte activation in neurologic function in an intact mouse model of Alzheimer's disease (AD). Studies use adeno-associated virus vectors (AAV) bearing the astrocyte-specific promoter Gfa2 to target the protein phosphatase calcineurin (CN) and NFAT transcription factors in astrocytes of wild-type and APP/PS1 mice. AAV-Gfa2 vectors are bilaterally delivered to the hippocampus at different ages/disease stages and mice are assessed on different AD biomarkers. In Aim 1 cognitive status is assessed using the active avoidance task while synaptic function is evaluated using hippocampal slice electrophysiology and Western blot measures of synaptic proteins. In Aim 2 hippocampal glutamate regulation is investigated using ceramic enzyme-based microelectrode arrays and measures of glutamate transporter levels. In Aim 3 levels of glial activation and neuroinflammation are determined with immunohistochemical (IHC) analyses and assessment of cytokine levels using Multiplex ELISAs. In Aim 4 IHC is used to determine the extent of A deposition while ELISAs are used to quantify levels of A40 and A42 in soluble and insoluble hippocampal tissue fractions and Westerns used to assess BACE protein expression. AAV-Gfa2 vectors encode either potent inhibitors or activators of CN/NFAT signaling and therefore will determine the necessity and sufficiency of this astrocytic pathway in driving and/or maintaining neurologic dysfunction in AD mice. These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions.

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

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


application_id: 9049500
project_number: 5R01ES024478-02
project_title: The role of chromatin structural and epigenetic changes in arsenic-induced gene expression
administering_ic: NIEHS
award_notice_date: 2016-01-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 024478
program_official: TYSON, FREDERICK L
project_start_date: 2015-04-07
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adhesions;Affect;Arsenic;Binding;Biochemical;Bioinformatics;Cell Adhesion;ChIP-seq;Chromatin;Chromatin Structure;Cues;DNA;DNA Binding;DNA Methylation;DNA Sequence;Data;Development;Diagnostic;Disease;Ensure;Epigenetic Process;Etiology;Eukaryotic Cell;Exposure to;Failure;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Structure;Generations;Genes;Genetic Transcription;Genome;Goals;Growth and Development function;Health;Heavy Metals;Histones;Human;ITGB4 gene;In Vitro;Integrins;Lead;Location;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Mediating;Modification;Molecular Profiling;Molecular Target;NCAM1 gene;Neoplasm Metastasis;Nucleosomes;Organism;Outcome;Pathogenesis;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Process;Proteins;Reactive Oxygen Species;Research;Risk;Role;Site;Specific qualifier value;Stimulus;Structure;System;To specify;Toxin;World Health Organization;Zinc Fingers;base;carcinogenesis;cell transformation;chromatin protein;chromatin remodeling;clinical biomarkers;contaminated water;differential expression;drinking;epigenome;epigenomics;epithelial to mesenchymal transition;genome-wide;in vivo;insight;metaplastic cell transformation;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;pollutant;promoter;response;single-molecule FRET;targeted treatment;tool;transcription factor;tumorigenesis


application_id: 9048514
project_number: 2R44DE023523-02A1
project_title: Mouth barrier rinse of sustained-release poly(curcumin) to treat oral mucositis
administering_ic: NIDCR
award_notice_date: 2016-07-29
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: DE
serial_number: 023523
suffix: A1
program_official: WANG, CHIAYENG
project_start_date: 2013-09-24
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1 MOSS-K (11)]
contact_pi_person_id: 12547606
contact_pi: BHANDARI, ROHIT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Oral mucositis (OM) is one of the most common side effects of most anti-cancer therapies affecting nearly 100% of head and neck cancer patients (5-6% of the 12.7 million new cancer cases worldwide annually). OM manifests by deep and extremely painful mouth ulcers that can force patients to halt life-saving anti-cancer treatments and experience increased emergency room visits and longer hospital stays. Lubricating and analgesic mouth rinses are the primary treatment options but provide only palliative care and have shown poor efficacy. Palifermin (recombinant keratinocyte growth factor) is the only approved drug for treating OM in patients with hematological malignancies but is not approved for solid tumors and carries the risk of neoplasia. Clearly an unmet need exists for effective and
safe drugs to treat this condition. Curcumin a multi-action antioxidant and anti-inflammatory compound derived from turmeric has been shown to reduce the incidence and severity of OM in preclinical studies and a recent human trial. Unfortunately the trial required an aggressive dosing regimen of 4 mouth rinses every 4 hours likely due to the known poor bioavailability of curcumin. Our innovation is a polymeric formulation that provides local and prolonged delivery of curcumin to buccal tissues which will increase its efficacy in treating OM. Bluegrass Advanced Materials' product to treat OM will be a drug-device combination composed of (1) a sachet containing a single dose of poly(curcumin) powder and (2) a wide-mouth bottle containing 5 ml of mucoadhesive solution. In Phase I we demonstrated that biodegradable microparticles of poly(curcumin) can provide a sustained release of curcumin for 24 hours under physiological conditions while retaining antioxidant activity. In a preclinical study we demonstrated that once-daily treatment with a poly(curcumin) oral rinse reduced the severity of OM in the Syrian hamster model. In Phase II we propose to: 1. Optimize efficacy of poly(curcumin) oral rinse to treat radiation-induced OM. 2. Scale up manufacturing to produce pilot preclinical batch. 3. Develop combination product packaging in sachets and bottles and perform stability testing. 4. Demonstrate safety of poly(curcumin) oral rinse in GLP preclinical studies. Successful completion of Phase II will accomplish the key tasks necessary to prepare for Phase I human clinical trials and enable us to approach the FDA to begin the approval process.

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

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


application_id: 9047702
project_number: 1R43OD020304-01A1
administering_ic: OD
award_notice_date: 2016-04-07
opportunity_number: PA-14-071
application_type: 1
activity_code: R43
ic: OD
serial_number: 020304
suffix: A1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2016-04-15
project_end_date: 2018-04-14
study_section: Special Emphasis Panel[ZRG1 EMNR-W (10)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_title:
An Innovative Device Integrating Cryopreservation Storage and Artificial Insemination of Mouse Sperm

project_abstract:
DESCRIPTION (provided by applicant): ParaTechs Corporation aims to provide researchers with advanced technology and methods to simplify procedures for laboratory animal models. While actively supporting efforts to `reduce replace and refine' animal use ParaTechs provides safe and efficient alternatives for surgical procedures. We have already brought to market a nonsurgical embryo transfer device (NSETTM) which replaces surgical embryo transfers with a nonsurgical method that takes only seconds and does not require anesthesia. We have developed a new protocol for nonsurgical artificial insemination (AI) of mice which replaces existing protocols for surgical AI and is a technical advancement for existing nonsurgical AI protocols. We plan to use this newly developed protocol to revolutionize the process of archiving and global distribution of mouse models through a novel sperm cryopreservation and strain recovery system. The use of mouse strains in research is one of the most important tools used to study mammalian gene function. While hundreds of thousands of mouse strains have been catalogued and cryopreserved sharing of strains is becoming increasingly difficult as regulatory constraints and the cost of shipping live animals increase. We can solve this problem and provide a technically superior alternative with the cryopreservation and insemination (C&I) device. This system will integrate storage and shipment of cryopreserved sperm with nonsurgical artificial insemination. The device will be suitable for storage of cryopreserved sperm will be shippable will allow viable sperm recovery upon thawing and then will be used directly for nonsurgical artificial insemination. This device will eliminate the need to perform in
vitro fertilization (IVF) upon thawing of cryopreserved sperm; greatly reducing the number of mice required for the procedure and replacing a surgical method of artificial insemination both of which promote animal health and welfare. Therefore the goals of this project are to design manufacture and test a C&I device for mice. The goals will be accomplished in two aims. First a C&I device prototype will be designed and produced. Second the feasibility of using the C&I device prototype for sperm cryopreservation and mouse strain recovery will be tested. This new technological breakthrough will provide an alternative to cryorecovery of mouse strains by in vitro fertilization methods the currently preferred but technically challenging and labor intensiv strain recovery method. In doing so the C&I device will provide a substantial cost savings to researchers and a convenient method for shipping and strain recovery.

project_terms:
Address;Age;Anesthesia procedures;Animal Experimentation;Animal Model;Animal Welfare;Animals;Archives;Artificial Insemination;Breeding;Cataloging;Catalogs;Cohort Studies;Collaborations;Contracts;Core Facility;Cost Savings;Cryopreservation;Devices;Disease;Embryo Transfer;Fertilization in Vitro;Genetic Drift;Goals;Health;Housing;Individual;Insemination;Institution;Laboratories;Laboratory Animal Models;Laboratory Animals;Laboratory Research;Laboratory mice;Lasers;Life;Marketing;Methodology;Methods;Modeling;Mouse Strains;Mus;Natural Disasters;One-Step dentin bonding system;Operative Surgical Procedures;Polypropylenes;Price;Problem Solving;Procedures;Process;Protocols documentation;Recovery;Research;Research Personnel;Resources;Sampling;Services;Shipping;Ships;Social Welfare;System;Technology;Testing;Thick;Time;Transgenic Organisms;Workload;cost;design;gene function;human disease;innovation;mouse model;novel;prototype;public health relevance;repository;sperm cell;sperm quality;tool;ultraviolet

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The ability to genetically modify the laboratory mouse is now producing an ever-rising number of increasingly valuable and unique strains to investigate human disease. While maintaining these mouse strains has become a significant and recurring effort and budgetary commitment cryopreservation of strains in sperm repositories has proven successful as a means to permanently and economically preserve them. ParaTechs proposes to design manufacture and test a cryopreservation and insemination (C&I) device for the purpose of integrating cryopreservation storage shipping and strain recovery of mice through a newly developed nonsurgical artificial insemination method.


application_id: 9047634
project_number: 9R42AG055375-03
project_title: Development of An Integrated High Throughput Imaging and Image Analysis Platform for Muscle
administering_ic: NIA
award_notice_date: 2016-09-20
opportunity_number: PA-14-072
application_type: 9
activity_code: R42
ic: AG
serial_number: 055375
program_official: WILLIAMS, JOHN
project_start_date: 2013-07-15
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1 MOSS-Q (14)]
contact_pi_person_id: 12598388
contact_pi: YANG, LIN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078357046
primary_uei: LA54LAMKQ5A6
duns_number: 078357046
uei: LA54LAMKQ5A6
fips: US
organization_id: 10032028
organization_name: CYTOINFORMATICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568852
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  There is growing awareness that weakness of muscle is a significant biomedical health issue associated with many different chronic diseases and aging. There are a variety of different diseases that affect muscle including muscular dystrophy fibromyalgia cerebral palsy amyotrophic lateral sclerosis and myasthenia gravis each of which carries its own unique set of symptoms accompanied by a myriad of genetic and molecular abnormalities. There is agreement within the basic research and clinical communities that important morphological characteristics of muscle fibers such as fiber cross sectional area fiber type the number and position of myonuclei cellular infiltration and fibrosis are among many critical factors that determine the health and functionality of the muscle. Until now the imaging equipment available is relatively low throughput and the quantification is still largely based on manual or at best semi-automatic methods that require extensive human intervention. In Phase I CytoInformatics LLC has developed a software called CytoQuant which can accurately perform automatic segmentation and provide accurate boundaries of each muscle fiber for a cropped image patch. The goal of CytoInformatics LLC in Phase II is to 1) deliver the first version of the CytoQuant software to the market 2) develop the second version of CytoQuant by continuously improving its performance especially in handling large scale whole slide images and also 3) develop an integrated multiplexing imaging hardware and analysis software framework as a seamless solution for high throughput automated image analysis of muscle specimens. After careful investigation in Phase I (please refer to the details in business plan) we conclude that this integrated software/hardware platform with cutting-edge technologies in advanced imaging large scale machine learning and big data is commercially attractive to the entire muscle community including research institutes hospitals and pharmaceutical and athletic companies demonstrated by strong enthusiasm among end users and many supporting letters. The specific aims are: 1) Deliver the first version of CytoQuant developed in Phase I to the market continue to develop the second version of CytoQuant which will focus on improving the robustness and speed in handling whole slide images; 2) Develop an integrated platform that provides unified imaging hardware and image analysis software to handle whole slide images labeled with multiple bio-relevant markers. This unified whole-slide based software and hardware solution will deliver an efficient and specialized imaging platform that seamlessly integrates with a high throughput multi-marker and automatic image analysis software specifically designed for muscle.

project_terms:
Affect;Aging;Agreement;Amyotrophic Lateral Sclerosis;Area;Athletic;Awareness;Basic Science;Big Data;Biological Markers;Biology;Businesses;Cellular Infiltration;Cerebral Palsy;Characteristics;Chronic Disease;Clinical;Communities;Computer software;Development;Discipline;Disease;Doctor of Philosophy;Educational process of instructing;Eosine Yellowish;Equipment;Exhibits;Feedback;Fiber;Fibromyalgia;Fibrosis;Fluorescence;Future;Genetic;Goals;Health;Hematoxylin;Hospitals;Human;Image;Image Analysis;Imagery;Immunofluorescence Immunologic;Immunohistochemistry;Institutes;Intervention;Investigation;Label;Laboratory Research;Learning;Learning Module;Letters;Machine Learning;Manuals;Marketing;Methods;Microscopy;Molecular Abnormality;Muscle;Muscle Fibers;Muscle Weakness;Muscular Dystrophies;Myasthenia Gravis;Noise;Performance;Pharmacologic Substance;Phase;Positioning Attribute;Principal Investigator;Process;Qi;Recruitment Activity;Reporting;Research Institute;Research Personnel;Scanning;Signal Transduction;Slide;Software Design;Software Framework;Specimen;Speed;Staining method;Stains;Symptoms;Technology;Tissue Sample;Tissue imaging;Universities;Update;Variant;Yang;adaptive learning;base;bioimaging;commercialization;design;experience;gigabyte;graphical user interface;image processing;image visualization;imaging Segmentation;imaging modality;imaging platform;imaging system;improved;interest;member;muscle form;novel;optic imaging;programs;public health relevance;quantitative imaging;success;technology development;user-friendly

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  In Phase II CytoInformatics is proposing a unified whole-slide multispectral imaging (MSI) system that seamlessly integrates with a high throughput accurate and automated software to provide fast and efficient multiplexed imaging and quantitative muscle image analysis simultaneously. This will be the first integrated hardware/software solution that is specifically designed for muscle.


application_id: 9045757
project_number: 3R01DA033866-04S1
project_title: Brief intervention for drug-using rural women at high-risk for HIV/HCV
administering_ic: NIDA
award_notice_date: 2015-06-16
opportunity_number: PA-12-149
application_type: 3
activity_code: R01
ic: DA
serial_number: 033866
suffix: S1
program_official: JONES, DIONNE
project_start_date: 2012-07-15
project_end_date: 2016-06-30
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
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 SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high-risk for HIV and HCV. This project has potential to make a significant contribution to science by advancing knowledge about the health disparities high-risk behaviors (injection drug use sex risk) and service utilization of this high-risk vulnerable an understudied group of women during a time of emerging and significant public health risk in an Appalachian rural setting. This project will incorporate standardized screening (NIDA-modified ASSIST) to identify high-risk rural women drug users from jails including injectors. Consenting women (N=350) will be asked to participate in a baseline interview and will then be randomly assigned to one of two study groups: (1) HIV Education (HIV- Ed n=175) which includes the NIDA standard pre and post-test counseling HIV and HCV rapid testing and an information packet on existing community drug abuse and HIV/HCV resources; or (2) Motivational Interviewing- based HIV Risk Reduction (MI-HIV n=175) which in addition to what is received in the HIV-Ed group also includes an evidence-based brief intervention for high-risk women focused on an individualized plan for enhancing motivation to reduce risk behaviors and to use health and behavioral health services in the community. Specific aims include: (1) to compare the effectiveness of an evidence-based HIV risk reduction intervention (MI-HIV) to HIV Education (NIDA Standard) in reducing sex risk behaviors injection practices and drug use among a culturally unique sample of disadvantaged drug-using rural women at high-risk for HIV and HCV; and (2) to examine MI-HIV Intervention engagement as a predictor of community health and behavioral health service utilization (including drug treatment and mental health) at follow-up among disadvantaged drug- using rural women at high risk for HIV and HCV. This project is innovative because it 1) targets a high-risk and understudied group of women 2) uses brief intervention to not only reduce risk behavior but also to enhance motivation for using community health and behavioral health resources and 3) utilizes a real-world setting to identify high-risk women drug users. The long-term goal of this study is to increase access to health and behavioral health services in order to improve the quality of health of high-risk rural women.

project_terms:
AIDS/HIV problem;Address;Appalachian Region;Area;Centers for Disease Control and Prevention (U.S.);Communities;Community Health;Community Services;Consent;Counseling;Country;Criminal Justice;Disadvantaged;Drug abuse;Drug usage;Drug user;Educational Intervention;Educational aspects;Evidence based intervention;Goals;HIV;HIV risk;Health;Health Resources;Health Services;Healthcare;Hepatitis C virus;High Risk Woman;Injection of therapeutic agent;Intervention;Interview;Jail;Kentucky;Knowledge;Mental Health;Motivation;National Institute of Drug Abuse;Opiates;Participant;Pattern;Pharmaceutical Preparations;Pre-Post Tests;Prevalence;Random Allocation;Randomized;Reporting;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Sampling;Science;Services;Staging;Testing;Time;United States National Institutes of Health;Vulnerable Populations;Walkers;Woman;Women's Group;base;behavioral health;brief intervention;compare effectiveness;comparison group;cost;design;drug resource;evidence base;follow-up;health care service utilization;health disparity;high risk;high risk behavior;improved;injection drug use;innovation;motivational enhancement therapy;outreach;prescription opiate;public health medicine (field);response;rural area;screening;service utilization;sex risk;treatment planning

public_health_relevance:
The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high risk for HIV and HCV. This project has potential to make a significant contribution to science by providing knowledge about the health risk behaviors and service utilization of a vulnerable and understudied group of women during a time of emerging and significant public health risk in a rural Appalachian setting. Successful completion of the aims ofthis project will advance the delivery of a low-cost potentially high impact intervention with implications for a number of other real world settings (such as criminal justice venues) where other disadvantaged high-risk drug users can be identified and targeted for intervention.


application_id: 9045659
project_number: 5R01HD064993-07
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2016-01-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2020-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
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_terms:
Adult;Age;Age-Years;Aging;Alzheimer's Disease;Amyloid beta-Protein;Antigen-Antibody Complex;Attenuated;Autopsy;Behavior;Biological Markers;Blood;Brain;Case Series;Chromosomes Human Pair 21;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive aging;Data;Dementia;Dependency;Development;Diagnosis;Diffuse;Down Syndrome;Employee Strikes;Encephalitis;Event;Functional disorder;Future;Genes;Goals;Health;Hereditary Disease;Human;Image;Impaired cognition;Individual;Inflammation;Inflammatory;Intellectual functioning disability;Intervention Studies;Link;Liquid substance;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Molecular;Molecular Target;Nerve Degeneration;Neurobiology;Neurofibrillary Tangles;Outcome;Parietal Lobe;Pathology;Pathway interactions;Pattern;Phenotype;Plasma;Play;Predisposition;Proteins;Quality of life;RNA;Recovery;Recruitment Activity;Reporting;Research;Research Design;Role;Senile Plaques;Signal Transduction;Spin Labels;Syndrome;Testing;United States;United States National Institutes of Health;Variant;Weight;abeta accumulation;abeta deposition;age related;aging brain;brain tissue;cerebrovascular;cognitive function;cohort;functional decline;imaging modality;improved;middle age;neurobiological mechanism;neuroinflammation;neuropathology;novel;prevent;white matter


application_id: 9045658
project_number: 5R01HD070792-05
project_title: Indomethacin and delayed umbilical cord clamp for preterm infant IVH
administering_ic: NICHD
award_notice_date: 2016-06-01
opportunity_number: PAR-11-246
application_type: 5
activity_code: R01
ic: HD
serial_number: 070792
program_official: REN, ZHAOXIA
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-R(55)R]
contact_pi_person_id: 6654912
contact_pi: GIANNONE, PETER J
other_pis: BAUER, JOHN ANTHONY
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence long term consequences and enormous medical and social costs mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined especially for extremely premature infants. Only one medical therapy prophylactic indomethacin during the first 3 days of life has been shown to prevent or decrease the severity of IVH in preterm infants but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. We will therefore conduct a randomized blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin with respect to survival IVH or PVL incidence and severity neurodevelopmental outcomes and relevant mechanistic effects. Our Specific Aims are: Aim 1) Compare efficacy and safety of prophylactic indomethacin DCC and their combination in affecting the incidence and severity of IVH/PVL in infants <28wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups) and longer term neurocognitive function; Aim 2) Investigate mechanistic effects of prophylactic indomethacin DCC and their combination in infants less than 28wks gestational age (blood volume/circulatory status inflammatory stress progenitor cells); and Aim 3) Determine relationships between clinical outcomes and mechanistic measurements among treatment groups (n=400 total cases). With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi-disciplinary project addresses an important medical problem for an understudied patient population where the current practice has clear limitations.

project_terms:
Address;Adverse effects;Affect;Apoptotic;Biological Markers;Birth;Birth Weight;Blinded;Blood;Blood Volume;Brain;Brain Injuries;Brain imaging;Caring;Case Study;Cephalic;Cerebral Palsy;Child;Clinical;Cognitive;Communities;Costs and Benefits;Data;Developmental Delay Disorders;Developmental Disabilities;Disabled Persons;Effectiveness;Evaluation;FDA approved;Frequencies;Gestational Age;Goals;Head;Health;Health Care Costs;Hemorrhage;Incidence;Indomethacin;Infant;Inflammatory;Intervention;Intestinal Perforation;Investigation;Kidney;Lesion;Life;Link;Magnetic Resonance Imaging;Measurement;Medical;Medical center;Mental Retardation;Mothers;Neonatology;Neurocognitive;Neurologic;Neurons;Newborn Infant;Organ failure;Outcome;Outcome Measure;Patient Care;Patients;Pediatric Hospitals;Performance;Periventricular Leukomalacia;Phenotype;Premature Infant;Prevalence;Prevention;Prevention therapy;Protocols documentation;Randomized;Research;Risk;Safety;Severities;Site;Stem cells;Stress;Surveys;Survivors;Testing;Toxic effect;Ultrasonography;Umbilical cord structure;clinical care;comparative efficacy;cost;design;disability;extreme prematurity;follow-up;handicapping condition;hemodynamics;high risk;improved;intraventricular hemorrhage;patient population;prevent;primary outcome;prophylactic;social;treatment group;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is designed to improve the medical care of extremely premature infants and to determine improved strategies to prevent intracranial bleeding that often occurs in the first few days of life. Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related neurological disabilities later in life. We will conduct a randomized blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) delayed umbilical cord clamp (DCC) alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin with respect to survival IVH or PVL incidence and severity neurodevelopmental outcomes and relevant mechanistic effects (n=400 total cases). With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi-disciplinary project addresses an important medical problem for an understudied patient population where current medical practice has clear limitations.


application_id: 9045635
project_number: 5P42ES007380-19
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7485
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Adsorption;Aftercare;Attention;Benign;Biological Sciences;Carbon;Chemicals;Chemistry;Chlorine;Collaborations;Development;Diffusion;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Free Radicals;Funding;Generations;Health;Heating;High temperature of physical object;Human;Hydrogen Peroxide;Hydroxyl Radical;Individual;Inflammatory;Iron;Kentucky;Knowledge;Laboratories;Laboratory Research;Lead;Ligands;Manufacturer Name;Medical;Membrane;Metals;Methods;Modeling;Mono-S;Nature;Outcome Study;Palladium;Pathway interactions;Phase;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Production;Public Health;Reaction;Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solvents;Source;Structure;Superfund;System;Techniques;Technology;Temperature;Testing;Toxic effect;Toxicity Tests;Translational Research;Trichloroethylene;United States Environmental Protection Agency;Vinyl Chloride;Water;Work;base;chemical stability;contaminated water;cost effective;dechlorination;demineralization;design;drinking;drinking water;global environment;hazard;hydrodynamic flow;innovation;iron oxide;metal oxide;microbial;nanoparticle;nanoscale;nanosized;nanostructured;novel;nutrition;oxidation;particle;pollutant;prevent;remediation;scaffold;sensor;superfund chemical;superfund site;technology validation;treatment strategy


application_id: 9045634
project_number: 5P42ES007380-19
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7484
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Affinity;Antibodies;Binding;Binding Proteins;Biodistribution;Biological;Biomimetics;Chemistry;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetic nanoparticles;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Reporting;Research;Resources;Risk;Sampling;Sensitivity and Specificity;Soil;Solubility;Specificity;Superfund;Surface;System;Techniques;Technology;Testing;Thick;Time;Toxic effect;Tryptophan;Tyrosine;Universities;Work;aqueous;base;bisphenol A;chemical stability;design;disorder prevention;evidence base;exposed human population;exposure route;fundamental research;global environment;imprint;nanocomposite;nanomaterials;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site;tool


application_id: 9045633
project_number: 5P42ES007380-19
project_title: Polychlorinated Biphenyls Nutrition and Diabetes - Project 3
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7483
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Acute;Adipocytes;Adipose tissue;Affect;Antioxidants;Body Burden;Body Weight decreased;Community Health;Consumption;Data;Development;Diabetes Mellitus;Diabetic Diet;Dioxins;Environmental Exposure;Exhibits;Exposure to;Fatty acid glycerol esters;Female;Glucose;Health Surveys;High Fat Diet;Impairment;Insulin;Insulin Resistance;Intervention;Laboratories;Link;Lipids;Mediating;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Odds Ratio;Overweight;Oxidative Stress;Plasma;Polychlorinated Biphenyls;Population;Research;Resveratrol;Risk;Role;Serum;TNF gene;Testing;Therapeutic;Toxic Environmental Substances;Toxic effect;Weight;Work;World Health Organization;aryl hydrocarbon receptor ligand;aryl hydrocarbons;blood glucose regulation;clinically significant;cytokine;experience;feeding;glucose tolerance;glucose uptake;impaired glucose tolerance;improved;insulin signaling;insulin tolerance;lipophilicity;male;nutrition;persistent organic pollutants;polyphenol;prevent;receptor;superfund chemical


application_id: 9045632
project_number: 5P42ES007380-19
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7482
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Adipose tissue;Adult;Adult Children;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Breast;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Discipline of Nursing;Disease;Dose;Environment;Environmental Health;Environmental Pollutants;Environmental Pollution;Epidemic;Erythroid;Euglycemic Clamping;Exercise;Exercise intervention;Exposure to;Fatty acid glycerol esters;Female;Fostering;Functional disorder;Funding;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Health;High Fat Diet;Human Milk;Impairment;Inflammation;Inflammatory;Insulin;Insulin Resistance;Intervention;Laboratories;Life;Life Cycle Stages;Lipids;Long-Term Effects;Measures;Messenger RNA;Metabolism;Methods;Molecular;Mus;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Paper;Partner in relationship;Perinatal;Perinatal Exposure;Placenta;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevalence;Principal Investigator;Public Health;Research;Risk;Role;Running;Serum;Source;Staging;Techniques;Testing;Time;Tissues;Toxic effect;Toxin;United States;Weaning;Work;base;blood glucose regulation;chemical stability;cost effective;critical period;cytokine;exposed human population;fasting glucose;feeding;fetal;glucose tolerance;impaired glucose tolerance;improved;in utero;in vivo Model;innovation;insight;insulin sensitivity;insulin signaling;lifestyle intervention;liver inflammation;mouse model;novel;nutrition;offspring;perinatal complications;pollutant;postnatal;pregnant;prenatal;prenatal exposure;programs;sedentary;superfund chemical;trait;trend


application_id: 9045631
project_number: 5P42ES007380-19
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction - Project 1
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7481
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Affect;Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Arterial Fatty Streak;Aryl Hydrocarbon Receptor;Atherosclerosis;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Catechin;Cause of Death;Caveolae;Cells;Chemicals;Chronic;Complement;Data;Development;Diet;Dietary Fats;Dietary Intervention;Dietary Polyphenol;Disease;Ecology;Endocrine disruption;Endothelial Cells;Endothelium;Environment;Environmental Health;Environmental Pollutants;Epigallocatechin Gallate;Erythroid;Event;Exposure to;Flavonoids;Foundations;Functional disorder;Genes;Green tea;Hazardous Waste Sites;Health;Health Food;Human;Hypertriglyceridemia;In Vitro;Inflammation;Inflammatory;Investigation;Kentucky;Knockout Mice;Link;Lipids;Mediating;Membrane;Methodology;Modeling;Nuclear;Nutritional;Nutritional status;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidation-Reduction;Plants;Play;Poisons;Polychlorinated Biphenyls;Preventive measure;Process;Proteins;Public Health;Regulation;Research;Risk;Risk Assessment;Risk Factors;Role;Severities;Signal Pathway;Signal Transduction;Small Interfering RNA;Structural Genes;Superfund;Technology;Testing;Time;Toxic effect;United States;Universities;Vascular Diseases;Vascular Endothelial Cell;Work;bioactive food component;caveolin 1;chemical stability;design;disorder risk;exposed human population;genetic manipulation;global environment;heme oxygenase-1;in vivo;mouse model;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;protective effect;remediation;response;stressor;superfund chemical;superfund site;toxicant;trafficking;vascular inflammation


application_id: 9045630
project_number: 5P42ES007380-19
project_title: Training Core - Core E
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7480
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Affect;Clinical Sciences;Communication;Communities;Complex;Detection;Dimensions;Discipline;Ecology;Education;Educational workshop;Environment;Environmental Health;Ethics;Fostering;Foundations;Future;Generations;Goals;Grant;Health;Human;Individual;Institution;Interdisciplinary Study;Internships;Intervention;Kentucky;Knowledge;Leadership;Life;Link;Measures;Medical Ethics;Mentors;Methods;Mission;Policies;Problem Solving;Public Health;Public Health Education;Qualifying;Recruitment Activity;Research;Research Personnel;Research Training;Science;Scientific Advances and Accomplishments;Series;Signal Recognition Particle;Skills Development;Solid;Students;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Translational Research;Translations;Underrepresented Groups;Universities;Writing;base;biomedical scientist;career;career development;college;graduate student;health knowledge;improved;interdisciplinary collaboration;meetings;nutrition;outreach;pollutant;programs;remediation;responsible research conduct;skill acquisition;skills;skills training;social;socioeconomics;success;superfund chemical;superfund site;symposium;tool;web page


application_id: 9045629
project_number: 5P42ES007380-19
project_title: Community Engagement Core - Core D
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7479
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Affect;Appalachian Region;Area;Attitude;Chronic Disease;Collaborations;Communication;Communities;Community Actions;Community Services;County;Diet;Dietitian;Environmental Health;Environmental Pollutants;Evaluation;Exposure to;Family;Feedback;Food;Fostering;Funding;Hazardous Waste Sites;Health;Health Professional;Health Status;Health behavior;Human Resources;Individual;Kentucky;Knowledge;Life Style;Location;Methods;Nurses;Nutritional;Outcome;Outcome Measure;Outcomes Research;Physicians;Poisons;Population;Prevalence;Process;Public Health;Recommendation;Research;Research Personnel;Resources;Risk;Services;Site;Superfund;Toxic effect;Translating;Trust;United States Environmental Protection Agency;Work;base;design;disease registry;empowered;evidence base;health knowledge;improved;interest;meetings;nutrition;programs;response;superfund chemical


application_id: 9045628
project_number: 5P42ES007380-19
project_title: Research Translation Core - Core C
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7478
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Advisory Committees;Appalachian Region;Area;Behavior Therapy;Chemicals;Clinical Sciences;Collaborations;Communication;Communities;County;Decision Making;Department of Energy;Diffusion;Documentation;Educational workshop;Electronic Mail;Engineering;Ensure;Environment;Environment and Public Health;Environmental Health;Event;Exercise;Exposure to;Family health status;Fostering;Future;Goals;Health;Home environment;Housing;Human Resources;Information Dissemination;Interdisciplinary Study;Kentucky;Laboratory Research;Lead;Leadership;Maintenance;Medicine;Mentors;Mentorship;National Institute of Environmental Health Sciences;Outcome;Outcomes Research;Output;Pharmacology and Toxicology;Physiological;Plants;Poisons;Polychlorinated Biphenyls;Positioning Attribute;Printing;Process;Productivity;Program Development;Public Health;Public Health Practice;Public Policy;Reporting;Research;Research Activity;Research Infrastructure;Research Institute;Research Project Grants;Research Support;Resources;Risk;Risk Management;Role;Scientist;Series;Services;Site;Superfund;Targeted Research;Toxic effect;Training;Translating;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;University resources;Water;Work;base;cardiovascular pharmacology;community center;disease registry;experience;health science research;implementation science;innovation;meetings;nano;new technology;nutrition;pollutant;practice-based research network;program dissemination;programs;success;superfund chemical;technology validation;web site


application_id: 9045627
project_number: 5P42ES007380-19
project_title: Research Support Core - Core B
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7477
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Advanced Development;Animal Model;Animals;Area;Basic Science;Bioinformatics;Biological Markers;Biology;Biomedical Research;Biometry;Calibration;Cardiovascular Diseases;Cell model;Cells;Center for Translational Science Activities;Clinical;Clinical Research;Cultured Cells;Data;Data Analyses;Data Base Management;Data Set;Detection;Development;Dose;Drug Metabolic Detoxication;Ecology;Ensure;Experimental Designs;Funding;Gene Expression Profiling;Generations;Health Hazards;Health Services Research;High Pressure Liquid Chromatography;Individual;Inflammation;Informatics;Intervention;Investments;Kentucky;Laboratories;Life Style;Mass Fragmentography;Mass Spectrum Analysis;Mediator of activation protein;Metabolic;Metabolic Diseases;Methods;Monitor;Nutritional;Nutritional Study;Nutritional Toxin;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Polychlorinated Biphenyls;Productivity;Proteomics;Public Health;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Services;Superfund;Suspension substance;Suspensions;Systems Biology;Technology;Toxic effect;Toxin;Training;Universities;Validation;base;biomarker discovery;biomarker identification;case control;computer infrastructure;data acquisition;data management;design;diphenyl;exposed human population;instrumentation;metabolomics;nutrition;programs;remediation;research study;sensor;sharing data;small molecule;superfund chemical


application_id: 9045626
project_number: 5P42ES007380-19
project_title: Administrative Core - Core A
administering_ic: NIEHS
award_notice_date: 2016-04-06
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7476
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
budget_end_date: 2017-03-31
project_terms:
Address;Advisory Committees;Area;Benign;Chemicals;Collaborations;Communication;Communities;Discipline;Documentation;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Health;Environmental Pollution;Event;Exercise;Exposure to;Federal Government;Fostering;Future;Goals;Health;Housing;Human Resources;Individual;Inflammatory;Information Centers;Interdisciplinary Study;Kentucky;Leadership;Life Style;Maintenance;Medicine;Mentors;Mentorship;Modeling;National Institute of Environmental Health Sciences;Outcome;Output;Pharmacology and Toxicology;Physiological;Polychlorinated Biphenyls;Positioning Attribute;Private Sector;Process;Productivity;Program Development;Public Health;Reporting;Research;Research Activity;Research Infrastructure;Research Project Grants;Research Support;Research Training;Resources;Risk;Role;Science;Scientist;Superfund;Targeted Research;Technology;Toxic effect;Training;Translational Research;Translations;Universities;base;cardiovascular pharmacology;experience;health science research;innovation;meetings;nano;nutrition;pollutant;programs;remediation;superfund chemical;superfund site;training project


application_id: 9045375
project_number: 5F30AI114194-02
project_title: Elucidating binding fusion and entry of HMPV in cell culture and host tissue
administering_ic: NIAID
award_notice_date: 2016-04-13
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: AI
serial_number: 114194
program_official: KIM, SONNIE
project_start_date: 2015-05-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-F13-C(20)L]
contact_pi_person_id: 12024712
contact_pi: KLIMYTE, EDITA MARIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen in the Paramyxoviridae family that infects nearly 100% of the world population. This enveloped virus causes severe viral respiratory disease in infants the elderly and immunocompromised patients worldwide. In fact HMPV is estimated to be the second most common cause of pediatric lower respiratory illness following the closely related respiratory syncytial virus. Furthermore the rate of hospitalization for respiratory disease caused by HMPV in adults over the age of 65 is near that of influenza. Despite its clinical significance there is no antiviral treatment or vaccine available at this time. Since its discovery several key factors have been identified to play a role in HMPV entry but much of the mechanisms of binding fusion and entry remain unsolved. It has been previously shown by our group that heparan sulfate is a required moiety for HMPV binding and infectivity; however it is not known if heparan sulfate proteoglycans (HSPGs) serve as a receptor or mediate other necessary cellular factors on the plasma membrane. Furthermore the route of entry has not been identified for HMPV. Thus to elucidate the role of HSPGs we will utilize a collection of currently available HMPV strains from laboratory strains and clinical isolates to determine the effects of heparan sulfate blocking molecules and knockdown studies on specific HSPGs; in order to identify the route of entry we will utilize viral particles with fluorescent labeled envelopes to track if membrane fusion is occurring at the plasma membrane or within intracellular compartments. Finally we propose to study HMPV entry in the context of traditional cell culture utilizing physiologically relevant cell lines derived from human lung tissue such as Beas-2B Calu-3 and A549 as well as novel human airway epithelial tissue to elucidate important details about its life cycle in this model and identify potential factors that may affect
HMPV infection in vivo. We hypothesize heparan sulfate proteoglycans specifically the syndecan moieties serve as an attachment factor for HMPV which is required for internalization and membrane fusion occurs in intracellular compartments. We expect heparan sulfate is also critical for viral infectivity in human airway epithelium. We also anticipate tissus derived from patients with chronic respiratory disease will show an increased permissibility to HMPV infection.

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

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


application_id: 9044124
project_number: 3R01NS070899-06S2
project_title: Regulation signaling and dynamics of glucan phosphatases
administering_ic: NINDS
award_notice_date: 2015-04-23
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: NS
serial_number: 070899
suffix: S2
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2016-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Affect;Aminoglycosides;Binding (Molecular Function);Biochemical;Biochemistry;Biological Assay;Biology;Carbohydrates;Cell Culture Techniques;Cells;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Energy Metabolism;Enzymes;Epilepsy;Event;Family;Fibroblasts;Genes;Glucans;Glycogen;Glycogen Phosphorylase;Glycogen Storage Disease;Goals;Health;Inherited;Lafora Disease;Lead;Life;Link;Liver;Metabolism;Methods;Missense Mutation;Modeling;Molecular;Mus;Muscle;Mutagenesis;Mutation;Mutation Spectra;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Nonsense Codon;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Proteome;Protocols documentation;Reading;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Symptoms;Testing;Therapeutic;Tissues;Translating;Ubiquitin;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;cell type;design;disease-causing mutation;glycogen metabolism;in vivo;insight;loss of function mutation;member;mouse model;neuron apoptosis;neurotoxicity;novel;novel therapeutics;particle;potency testing;screening;tool;ubiquitin-protein ligase


application_id: 9043917
project_number: 5R01HD075829-02
project_title: The development of emotion processing in infancy
administering_ic: NICHD
award_notice_date: 2016-01-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 075829
program_official: FREUND, LISA S
project_start_date: 2015-04-01
project_end_date: 2020-02-29
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Affect;Age-Months;Age-Years;Anger;Autistic Disorder;Behavior;Categories;Conduct Disorder;Cues;Development;Disease;Emotional;Emotions;Face;Feeling;Fright;Gestures;Health;Human;Human body;Infant;Infant Development;Intention;Knowledge;Learning;Life;Literature;Mental disorders;Modality;Modeling;Motor;Movement;Nature;Organism;Perception;Perceptual learning;Persons;Play;Posture;Process;Psychopathology;Research;Role;Scanning;Signal Transduction;Social Functioning;Social Interaction;Social Perception;Sorting - Cell Movement;Source;Testing;Visual;Visuospatial;Walkers;Work;autism spectrum disorder;base;cognitive function;developmental disease/disorder;emotional behavior;experience;infancy;negative affect;object perception;research study;showing emotion;social;theories


application_id: 9043832
project_number: 5R01CA188118-02
project_title: Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2016-04-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188118
program_official: AULT, GRACE S
project_start_date: 2015-04-01
project_end_date: 2020-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program which provides cells with the increased phenotypic and cellular plasticity required during embryonic development tissue remodeling wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail due to protein stabilization contribute significantly to theincreased invasion therapeutic resistance CSC-like properties and tumor recurrence. However the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines which contain no detectable endogenous Dub3 and Snail induces transformation to a basal-like phenotype; whereas Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail durig EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate th molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.

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


application_id: 9043210
project_number: 5R21NS091096-02
project_title: Small G-protein signaling in brain injury
administering_ic: NINDS
award_notice_date: 2016-03-21
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 091096
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-04-01
project_end_date: 2018-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of death and permanent disability in the United States with TBI being a contributing factor to a third of all injury-related deaths. Long-term TBI-related disability results in reduced quality of ife for the patient and prolonged medical social and economic effects on society. TBI is a heterogeneous disease. Mechanisms of brain damage underlying focal contusion are associated with localized regions of necrotic neuron death driven by oxidative damage and excitotoxicity. In contrast axonal injury and persistent tissue inflammation are thought to be major contributors to morbidity with diffuse mild TBI (mTBI). Due to the diversity of brain damage mechanisms that play a role in TBI therapeutic interventions that target multiple mechanisms are likely to have a maximal impact for improving the quality of life of patients. The long-term objective of these studies is to understand novel signaling pathways that promote acute neuron survival and limit axonal injury and neuroinflammatory processes following TBI with the hypothesis that manipulation of these pathways will have broad therapeutic potential. Our preliminary data indicates that Rin GTPase directed signaling plays a unique and critical role in functional recovery following TBI. First Rin deficiency promotes cell survival including activation of the Akt pathway to reduce neurodegeneration and cognitive dysfunction after contusion TBI. Second loss of Rin attenuates axonal degeneration and improves cognition after diffuse mild TBI. These data motivate the central hypothesis that: (1) Rin signaling plays a central role in cellular and functional recovery over a spectrum from mild to severe brain trauma and (2) that inhibition of Rin signaling will therefore have broad therapeutic potential in the setting of TBI. Using clinically-relevant mouse models of contusive brain injury and diffuse mTBI we will evaluate our hypothesis using two specific aims. Aim 1 will use Rin-/- mice to determine whether Rin deficiency protects against contusive TBI by reducing neuron death and improving cognitive function in part via modulation of a novel Akt signaling pathway. Aim 2 will examine whether Rin loss protects against inflammation and/or attenuates axonal injury to lessen neurobehavioral dysfunction following repeated mTBI. This innovative multi-system approach will generate insights into the molecular mechanisms of recovery and may lead to novel strategies to rescue or replace damaged or lost neurons after brain trauma.

project_terms:
Acute;Animal Model;Attenuated;Behavioral;Brain;Brain Injuries;Cause of Death;Cell Survival;Cessation of life;Clinical;Cognition;Contusions;Data;Diffuse;Diffuse Brain Injury;Disease;Economics;Functional disorder;GTP-Binding Proteins;Guanosine Triphosphate Phosphohydrolases;Health;Hippocampus (Brain);Impaired cognition;Inflammation;Injury;Lead;Life;Mediating;Medical;Molecular;Molecular Analysis;Monomeric GTP-Binding Proteins;Morbidity - disease rate;Mus;Necrosis;Nerve Degeneration;Neurons;Pathology;Pathway interactions;Patients;Persons;Play;Population;Process;Quality of life;Recovery;Recovery of Function;Role;Signal Pathway;Signal Transduction;Societies;System;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Tissues;Transgenic Animals;Traumatic Brain Injury;United States;axon injury;axonal degeneration;clinically relevant;cognitive function;design;disability;economic cost;effective therapy;excitotoxicity;improved;improved outcome;in vivo;innovation;insight;mild traumatic brain injury;mouse model;neurobehavioral;neuroinflammation;neuron loss;new therapeutic target;novel;novel strategies;novel therapeutics;oxidative damage;relating to nervous system;research study;social;therapeutic development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States often resulting in persistent deficits for which there are no effective treatments. The long-term objective of these studies is to understand Rin G-protein signaling mechanisms that promote acute neuron survival and limit axonal injury and neuroinflammatory processes following TBI with the hypothesis that manipulation of these pathways will have broad therapeutic potential in the setting of TBI.


application_id: 9043168
project_number: 4R01HL112788-04
project_title: BIOACTIVE LIPIDS IN STEM CELL HOMING AND MOBILIZATION
administering_ic: NHLBI
award_notice_date: 2016-03-15
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: HL
serial_number: 112788
program_official: YANG, YU-CHUNG
project_start_date: 2013-06-01
project_end_date: 2019-03-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): A tug-of-war concept has been proposed to explain how a chemotactic stromal derived factor-1 (SDF-1) gradient between bone marrow (BM) and peripheral blood (PB) determines whether cells will be released and mobilized from BM into PB or home back from PB to the BM microenvironment. This concept however needs reappraisal because plasma SDF-1 levels do not consistently correlate with mobilization of hematopoietic stem/progenitor cells (HSPCs). At the same time it is becoming clear that SDF-1 does not play an exclusive role in the homing of HSPCs into BM implying the existence of additional factors. New data from our laboratory and supported by recent observations from other researchers identify a potentially important role for the bioactive sphingolipids sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) in trafficking of HSPCs. S1P and C1P are i) strong chemoattractants for HSPCs ii) resistant to proteolytic enzymes and iii) exhibit markedly increased levels in PB during mobilization and in BM after myeloablative conditioning for transplantation. Based on these data we propose three interrelated aims to reappraise the role of SDF-1 in stem cell trafficking and address our central hypothesis that the bioactive lipids S1P and C1P play an important and presently unappreciated role in homing and mobilization of HSPCs. In addition to clinical studies our approach will exploit small molecule- and genetics-based strategies in mouse models. Specific Aim 1. Bioactive lipids S1P and C1P as executors of HSPC mobilization. Our recently published data support a pivotal role for the S1P- S1P receptor type 1 (S1P1) axis in egress of HSPCs from BM into PB. We will investigate the impact of mobilization on the distribution of S1P between blood compartments and determine whether the level of S1P in PB correlates with mobilization efficacy in patients. In parallel we will address the role of C1P and investigate whether one or both bioactive lipids (which are stored in circulating red blood cells) are responsible for mobilization of HSPCs in patients with hemolytic syndromes. Finally we will mechanistically define which mobilization steps are promoted by S1P and C1P. Specific Aim 2. Bioactive lipids as a novel homing factors for HSPCs. Myeloablative conditioning for transplantation induces a proteolytic microenvironment in BM leading to a decrease in chemotactically active SDF-1. We have found that BM levels of S1P and C1P are increased during conditioning and that antagonism of S1P1 impairs engraftment of HSPCs. Since these lipids are strong HSPC chemoattractants for HSPCs we will focus on their potential role in homing of HSPCs and elucidate the molecular and cellular basis for this phenomenon. Specific Aim 3. Develop strategies to improve mobilization and homing of hematopoietic stem cells by modulating S1P and C1P signaling. Based on our preliminary data we propose to develop new strategies that will improve both mobilization and homing of HSPCs. These strategies will be tested first in mice and subsequently validated in chimeric human HSPCs/immunodeficient mouse xenotransplant models.

project_terms:
AMD3100;Address;Adult;Affect;Back;Blood;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell surface;Cells;Chemotactic Factors;Clinical Research;Complement Activation;Data;Development;Engraftment;Erythrocytes;Exhibits;Fetal Liver;Fibroblasts;Genetic;Growth;Health;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Human;Immunodeficient Mouse;Injection of therapeutic agent;Integrin alpha4beta1;Integrins;Laboratories;Life;Ligands;Lipids;Mediating;Modeling;Molecular;Mus;Osteoblasts;Patients;Peptide Hydrolases;Plasma;Play;Process;Publishing;Refractory;Research Personnel;Resistance;Role;Signal Transduction;Sphingolipids;Sphingosine-1-Phosphate Receptor;Stem cell transplant;Stem cells;Syndrome;Testing;Time;Transplantation Conditioning;Vascular Cell Adhesion Molecule-1;War;base;ceramide 1-phosphate;conditioning;improved;knock-down;mouse model;novel;peripheral blood;receptor;reconstitution;small molecule;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With new data from our laboratory we have identified an important potential role for bioactive sphingolipids in trafficking of HSPCs. Bioactive sphingolipids are i) strong chemoattractants for HSPCs ii) resistant to proteolytic enzymes and iii) markedly increased in level in PB during mobilization and in BM after myeloablative conditioning for transplantation. Based on these findings we propose three interrelated aims to reappraise the role of SDF-1 in stem cell trafficking and address our central hypothesis that the bioactive lipids play an important and presently unappreciated role in homing and mobilization of HSPCs.


application_id: 9042751
project_number: 3T32CA165990-03S2
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2015-04-07
opportunity_number: PA-11-184
application_type: 3
activity_code: T32
ic: CA
serial_number: 165990
suffix: S2
program_official: LIN, ALISON J
project_start_date: 2013-04-01
project_end_date: 2016-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
project_abstract:
DESCRIPTION (provided by applicant): This multi-disciplinary program will focus on training pre-doctoral students and post-doctoral fellows in Cancer Biology so that they can effectively decipher important research questions associated with human Cancer. To accomplish this objective we have integrated the already established and successful programs in Signal Transduction and Mechanisms of Cancer Cell Survival Cancer Progression and Metastasis Tumor Microenvironment and Oxidative Stress and DNA Damage with clinical exposure into one cohesive program. The trainees will receive both didactic and non-didactic instruction laboratory-based basic science research training in cancer research and cutting edge clinical applications and career development as independent cancer biologists. The students and fellows will receive ample training to articulate their ideas and communicate them effectively evaluate biomedical research and mentor others in scientific excellence and thus function as important members of the scientific community.  This program assembles a cohesive group of basic science and clinical faculty from 6 different departments at the College of Medicine. In the past 10 years our program faculty has trained 90 doctoral students and over 100 post-doctoral fellows and has the experience and the interdisciplinary focus to guide this group of trainees to function in research teams pursuing multidisciplinary investigations. We mentor our trainees to be proficient at utilizing hypothesis-driven approaches as well as discovery-oriented research design to address key problems. All trainees are required to complete the foundation courses in graduate level Genetics Biochemistry Immunology Pharmacology Physiology Cell Biology Molecular Biology Biostatistics Ethics and the Cancer Biology and Therapy course which emphasizes cancer in the context of human disease. Training also involves participation in the Markey Cancer Center Seminar Series and a Cancer Biology Journal Club. A unique feature of this program is the interdisciplinary training opportunity that will emphasize bench to bedside (and vice versa) research topics to provide a bridge between the fundamental biology of cancer and clinical cancer. The ultimate objective is to develop a cadre of future scientists who can become leaders in integrative team approaches to understand the complex issue of cancer as it relates to potential prevention and treatment strategies. Moreover to help ensure our commitment to the clinical-translation of basic science discoveries Markey Cancer Center Associate Director Vivek Rangnekar Ph.D. and Director Mark Evers M.D. will be PIs for this team-based training program. The University of Kentucky places a significant emphasis on training of minority students post-doctoral researchers and physicians and therefore this program will ensure the inclusion of individuals with under-represented racial and ethnic background to better serve our diverse society. Accordingly this training program will train the next generation of cancer researchers to better understand and treat cancers using an interdisciplinary team approach.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       This multidisciplinary training program represents a team-approach involving multiple PIs to mentor pre- doctoral students and post-doctoral fellows in fundamental aspects of cancer biology translational science of cancer and therapeutics and prepare them as independent investigators who can become fully integrated in multidisciplinary cancer care teams.


