# projects

application_id: 8688195
project_number: 5P50DA005312-24
project_title: Administrative Core
administering_ic: NIDA
award_notice_date: 2014-06-20
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1-EXL-T
subproject_number: 6584
contact_pi_person_id: 8535872
contact_pi: MILICH, RICHARD
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: 2014-07-01
budget_end_date: 2015-06-30
project_abstract:
The key functions of the Administrative Core in CDART are to: (1) provide thematic scientific integration ofthe different projects around the personality constructs under investigation; (2) create synergy across thethree proposed projects and other ongoing projects on campus; (3) facilitate interdisciplinary collaborationamong basic and prevention sciences using both neurobehavioral and psychosocial levels of analysis; and(4) oversee the long-range goal of translating our basic research into the development and implementation oftargeted prevention interventions. There are four specific aims in the Core: one scientific oneorganizational one that involves disseminating our research findings to practitioners in the field and one thatinvolves expanding leadership in the prevention science and drug abuse research communities.For the Scientific Aim the Core will provide the structure necessary to produce publications that extendbeyond the boundaries of the individual projects. The Core seeks to engender cross-cutting empiricaltheoretical and methodological articles that promote translation from basic science to prevention practice.For the Organizational Aimthe Core provides an intellectually stimulating and creative environment wherethe norm is to examine research questions and issues from a multilevel interdisciplinary perspective. Thiswill be accomplished by hosting a seminar series inviting nationally-prominent seminar speakers hosting anannual conference on issues relevant to CDART research and having an annual retreat of key personneland trainees. In terms of Dissemination of Results the Core will disseminate the research findings obtainedin the laboratory to the prevention/intervention being conducted by practitioners in the field. For theLeadership Aimthe Core will serve as a local regional national and international resource advocate andleader for the translation of basic science into efforts to prevent drug use/abuse. This will be accomplishedby building connections with other national NIDA-funded centers sponsoring workshops and trainingconferences and by having CDART faculty involved in professional organizations. The Core is alsocommitted to providing training to the next generation of drug abuse prevention researchers.RELEVANCE (See instructions):The Administrative Core is what makes the three proposed projects a Center rather than just a collection ofseparate grant proposals. The Core is the place where research questions are shared across projects ideasfor collaborative papers are generated and the actual translational research takes place.

project_terms:
Advocate;Applications Grants;Basic Science;Collection;Commit;Communities;Development;Drug abuse;Drug usage;Educational workshop;Environment;Faculty;Funding;Goals;Human Resources;Impulsivity;Individual;Individual Differences;Institution;Instruction;International;Investigation;Laboratories;Leadership;Mission;National Institute of Drug Abuse;Paper;Personality;Positioning Attribute;Prevention;Prevention Research;Preventive Intervention;Principal Investigator;Professional Organizations;Publications;Publishing;Research;Research Institute;Research Personnel;Resources;Science;Scientist;Series;Structure;Training;Translating;Translational Research;Translations;drug abuse prevention;evidence base;interdisciplinary collaboration;intervention program;neurobehavioral;next generation;outreach;psychologic;psychosocial;relating to nervous system;social;substance use prevention;symposium


application_id: 8687756
project_number: 5R01NS079507-04
project_title: Blood-brain barrier function in epilepsy: new targets for therapy
administering_ic: NINDS
award_notice_date: 2014-07-04
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: WHITTEMORE, VICKY R
project_start_date: 2012-09-30
project_end_date: 2017-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction and map key signaling proteins that can potentially serve as targets to repair the blood-brain barrier in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway thereby decreasing expression and activity of influx transporters and upregulating expression and activity of efflux transporters through the COX arm that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) Deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) Develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1 we will block cPLA2 and COX-2 to reverse seizure-induced changes in transporter expression and activity. We will monitor influx and efflux transporter expression and activity and determine AED brain uptake. In Aim 2 we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junction proteins and matrix metalloproteases and assess barrier leakage. In Aim 3 we will evaluate the therapeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity assessing barrier leakage and monitoring seizure frequency duration and severity. The proposed research is innovative because it is focused on a new integrated strategy that considers blood-brain barrier transporters as well as barrier leakage and it is designed specifically to repair te barrier to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development and our strategy has potential to be translated into the clinic.

project_terms:
Antiepileptic Agents;Blood;Blood - brain barrier anatomy;Blood capillaries;Brain;Chronic;Clinic;Clinical;Data;Development;Disease;Drug resistance;Epilepsy;Extravasation;Frequencies (time pattern);Functional disorder;Glutamates;Goals;Knowledge;LOX gene;Lead;Leukotrienes;Link;Maps;Matrix Metalloproteinases;Metalloproteases;Mining;Mission;Modeling;Molecular;Monitor;National Institute of Neurological Disorders and Stroke;Outcome;PTGS2 gene;Pathology;Pathway interactions;Patients;Pharmacotherapy;Proteins;Rattus;Research;Resistance;Seizures;Severities;Signal Pathway;Signal Transduction;Signaling Protein;Testing;Therapeutic;Tight Junctions;Translating;United States National Institutes of Health;Up-Regulation (Physiology);arm;capillary;design;improved;inhibitor/antagonist;innovation;nervous system disorder;novel strategies;prevent;protein expression;public health medicine (field);public health relevance;repaired;sis Genes;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will significantly advance our understanding of blood-brain barrier function in neurological diseases and potentially provide new treatment opportunities for epilepsy. Thus the proposed research is relevant to the mission of the NIH/NINDS which is to develop fundamental knowledge that will help reduce the burden of neurological diseases in people worldwide.


application_id: 8687694
project_number: 5P30GM106396-02
project_title: Animal Model Core
administering_ic: NIGMS
award_notice_date: 2014-07-25
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8530
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Animal Model;Animals;Antineoplastic Agents;Breast;Breeding;Centers of Research Excellence;Childhood Melanoma;Clinic;Colon;Core Facility;Detection;Diagnosis;Diagnostic Imaging;Genotype;Goals;Instruction;Laboratories;Lung;Malignant Neoplasms;Methods;Modality;Modeling;Molecular Target;Monitor;Neuroblastoma;Pancreas;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Prostate;Research Personnel;Resources;Safety;Services;Site;Specimen Handling;Techniques;Testing;Therapeutic Agents;Time;Toxic effect;Transgenic Mice;Translations;Universities;Xenograft Model;cancer prevention;cancer type;cost;efficacy testing;efficacy trial;human disease;human subject;mouse model;novel;novel strategies;novel therapeutics;pre-clinical;prevent;research study;response;safety testing;sample collection;success;tumor;tumor progression


application_id: 8687693
project_number: 5P30GM106396-02
project_title: Molecular Modelling Core
administering_ic: NIGMS
award_notice_date: 2014-07-25
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8529
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Biological;Cancer Center;Centers of Research Excellence;Chemicals;Code;Computational Biology;Computer Hardware;Computer Simulation;Computer software;Computers;Consult;Core Facility;Crystallography;Data;Data Analyses;Development;Discipline;Doctor of Philosophy;Drug Design;Environment;Equipment;Funding;Goals;Individual;Instruction;Maintenance;Mission;Modeling;Molecular;Molecular Models;Molecular Target;New Agents;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Rationalization;Research;Research Personnel;Resource Allocation;Resources;Route;Scientist;Structure;Students;System;Testing;Training;Translational Research;United States National Institutes of Health;Validation;base;computing resources;design;drug development;drug discovery;experience;meetings;molecular modeling;novel;operation;programs;research study;screening;structural biology;virtual


application_id: 8687692
project_number: 5P30GM106396-02
project_title: NMR and Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2014-07-25
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8528
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Animal Model;Animals;Automation;Binding (Molecular Function);Biochemical;Biochemistry;Cancer Center;Chemistry;Collaborations;Communities;Complement;Computer Simulation;Consultations;Core Facility;DNA;Data Analyses;Data Collection;Development;Drug Design;Drug Targeting;Enzymatic Biochemistry;Experimental Designs;Future;Goals;Image;Instruction;Label;Malignant Neoplasms;Metabolic Pathway;Metabolism;Methods;Mission;Modeling;Molecular Models;Molecular Target;Nucleic Acids;Pathway Analysis;Pharmaceutical Preparations;Phase;Procedures;Process;Proteins;Research;Research Infrastructure;Research Project Grants;Resolution;Running;Sampling;Spectrum Analysis;Stable Isotope Labeling;Structure;Students;Surface;Techniques;Technology;Tissues;Training;Transgenic Mice;Translational Research;Universities;Validation;base;cancer cell;data reduction;design;drug candidate;drug development;drug discovery;human subject;in vivo;instrumentation;macromolecule;member;metabolomics;molecular modeling;novel;research facility;research study;small molecule;stable isotope


application_id: 8687689
project_number: 5P30GM106396-02
project_title: Molecular Targets Phase III CoBRE
administering_ic: NIGMS
award_notice_date: 2014-07-25
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
program_official: CANTO, MARIA TERESA
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: ZGM1-TWD-C(C3)
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
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:
Accounting;Animal Model;Antineoplastic Agents;Area;Biostatistics Core;Cancer Center;Cell Separation;Centers of Research Excellence;Clinical Trials;Core Facility;Development;Ensure;Faculty;Flow Cytometry;Funding;Goals;Growth;Human;Institution;Leadership;Malignant Neoplasms;Molecular Models;Molecular Target;Phase;Research;Research Infrastructure;Research Personnel;Role;Testing;Training;Translating;Translational Research;United States National Institutes of Health;Universities;cancer therapy;career;drug development;drug discovery;inhibitor/antagonist;member;metabolomics;molecular modeling;novel;novel therapeutics;pre-clinical;programs;public health relevance;success;tumor metabolism


application_id: 8686732
project_number: 5R01AI095307-03
project_title: Alternative macrophage activation in acute Pseudomonas pneumonia
administering_ic: NIAID
award_notice_date: 2014-06-02
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 095307
program_official: DAVIDSON, WENDY F
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 8968639
contact_pi: FEOLA, DAVID
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): Alternative macrophage activation regulates inflammatory responses to pathogenic organisms. Most work to date has characterized their role in Th2-type immune responses. Alternatively activated macrophages (AAM) have been shown to inhibit classically activated macrophage proliferation and function as well as to suppress T cell mediated immune responses through the production of the type II cytokine transforming growth factor (TGF)- and arginase-1. While primarily functioning to orchestrate remodeling and repair mechanisms arginase-1 and TGF are also important in controlling lung homeostasis and suppressing inflammation. The function of AAM in regulating the inflammatory response to extracellular Gram-negative bacterial infection in the lungs has not been characterized. Understanding the role of AAM in this setting is critical for advancing our understanding of immune mechanisms affecting patients with cystic fibrosis (CF) and other chronic pulmonary inflammatory conditions. CF causes progressive life-threatening lung damage due in large part to repeated dysregulated inflammatory responses to Pseudomonas aeruginosa infection. Therefore this work will address the hypothesis that alternatively activatedmacrophages decrease pulmonary inflammation in P. aeruginosa infection and that this is dependent upon production of TGF and arginase-1. We will utilize a model of P. aeruginosa pneumonia in normal and genetically engineered mice to address 3 distinct aims. Aim 1 will determine whether regulation of inflammation caused by P. aeruginosa lung infection is dependent upon alternative macrophage activation. Aim 2 will address whether AAM regulation of T cell disposition can control inflammation and lung damage through the production of TGF. Aim 3 will determine whether arginase-1 expression by macrophages is required to prevent inflammation induced by P. aeruginosa pneumonia. Mouse models with genetically altered AAM TGF signaling and macrophage-specific arginase-1 production will be used along with adoptive transfer methodologies and complementary in vitro experiments. The impact of these alterations will be evaluated in terms of inflammation classical macrophage function and T cell subset activation and function to determine the important mechanisms employed by macrophages in regulating these responses. Highlighting the clinical relevance of this work is the use of the antimicrobial agent azithromycin as an immunomodulator in patients with CF. This drug has been shown to slow pulmonary function decline and decrease morbidity in CF patients infected with Pseudomonas but the beneficial mechanistic effect is unknown. Recently it has been shown in both in vitro and animal studies that azithromycin polarizes macrophages to an alternative-like phenotype dramatically increasing the expression of arginase-1. This data along with the successful long-term use of azithromycin in patients with CF make studying the role of alternative macrophage activation in response to Pseudomonas pneumonia attractive and likely to yield novel therapeutic targets for intervention to alter this destructive cycle of inflammation and airway damage.

project_terms:
Acute;Address;Adoptive Transfer;Affect;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Azithromycin;Bacterial Infections;Bacterial Pneumonia;Cell physiology;Cells;Characteristics;Chronic;Chronic lung disease;Cystic Fibrosis;Data;Disease;Exposure to;Future;Genes;Genetically Engineered Mouse;Goals;Gram-Negative Bacterial Infections;Homeostasis;Immune;Immune response;Immunomodulators;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Knowledge;Lead;Life;Lung;Lung Inflammation;Macrophage Activation;Methodology;Methods;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mouse Strains;Mus;Organism;Pathology;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Play;Pneumonia;Process;Production;Pseudomonas;Pseudomonas aeruginosa;Randomized Clinical Trials;Regulation;Role;Series;Signal Transduction;Staging;T cell differentiation;T cell regulation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Transforming Growth Factors;Up-Regulation (Physiology);Work;airway inflammation;antimicrobial drug;arginase;base;cell mediated immune response;clinically relevant;cystic fibrosis mouse;cystic fibrosis patients;cytokine;evidence base;experience;extracellular;functional decline;in vivo;macrophage;mouse model;neutrophil;new therapeutic target;pathogen;prevent;pulmonary function decline;repaired;research study;response;therapeutic target

public_health_relevance:
Cystic fibrosis and other chronic lung diseases cause progressive life-threatening lung destruction due in part to excessive inflammation with frequent exacerbations caused by repeated bacterial infections. This project will investigate the regulatory role that macrophages play in the immune response to Pseudomonas aeruginosa one of the most common bacterial pathogens in these patients. This work will lead to the identification of therapeutic targets for intervention to delay the rate of pulmonary decline in these patients.


application_id: 8686632
project_number: 5F31NS077750-03
project_title: Effects of spinal cord injury on vagal afferents from the rat bladder and colon.
administering_ic: NINDS
award_notice_date: 2014-06-11
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: NS
serial_number: 077750
program_official: JAKEMAN, LYN B
project_start_date: 2012-07-01
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 10717584
contact_pi: HERRITY, APRIL N
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): Secondary health complications present a major concern for people living with spinal cord injury (SCI). Furthermore deficits in urological functin rank high as one of the most important factors affecting quality of life for SCI patients 6. A common complication of SCI is the development of a neurogenic bladder which involves lower urinary tract dysfunction and a loss of voluntary control. Complications include overactivity of th detrusor muscle leading to urinary incontinence sustained high pressure within the bladder tissue walls and sphincter-detrusor dyssynergia resulting in a loss of coordination 26. In previous years the leading cause of death in SCI patients was due to renal failure 76. However improvements in urological management have reduced mortality rates in this area but current urological treatment options for patients are often difficult to sustain and have low patient compliance 33. Some of the problems with current treatment options include: repeated infections and scarring from frequent catheterization sexual dysfunction side effects following surgical procedures adverse reactions to pharmaceuticals and failure to establish recommended guidelines and protocols for bladder management. Equally important in chronic SCI is a loss of conscious control of defecation. Patients develop a neurogenic bowel that includes constipation fecal impaction and incontinence and increased pain from abdominal distention 66; 68; 60. Patients
are able to defecate by either digital ano-rectal stimulation to initiate reflexive contractions or
through digital evacuation 68. Both urinary bladder dysfunction and colorectal problems are causes of significant morbidity and mortality in the SCI population 29; 67. Therefore in order to improve and better assist patients with bladder and bowel dysfunction a better understanding of the anatomy and physiology following chronic injury is needed. Evidence from anatomical tracing studies as well as preliminary electrophysiology recordings from our lab indicates that the bladder and colon are not only innervated by spinal afferents but by the vagus nerve as well. In pathological conditions such as SCI where central pathways are compromised the vagus nerve may take on a faciliatory role and actually contribute to dysfunction. In order to assess the degree of vagal involvement the purpose of this study is 1) to evaluate using neuroanatomical tracing techniques in male rats the extent of urinary bladder and colon sensory afferents in nodose ganglia the degree convergence with the colon and the histochemical phenotype of such neurons and 2) to identify using in vitro and in vivo electrophysiological recordings plasticity-related changes in nodose ganglion neuronal response properties of traced urinary bladder and colon sensory afferents under conditions of tissue irritation and/or chronic spinal transection relative to normal controls. This project aims o demonstrate that vagal afferents are conveyed directly from the rat bladder and colon to the caudal medulla and can be characterized based upon their histochemical signature and response properties to tissue irritation and/or SCI. The ultimate goal is to identify the vagus nerve as a potential source of phantom sensations that arise from below the level of a "clinically" (ASIA criteria) as well as an "anatomically" complete SCI with the hope of providing a
novel therapeutic target for SCI patients.

project_terms:
Abdominal Pain;Acute;Adverse effects;Adverse reactions;Affect;Afferent Neurons;Anatomy;Area;Ataxia;Bladder;Bladder Dysfunction;Bladder Tissue;Catheterization;Cause of Death;Cells;Cervical;Cervix Uteri;Chemical Stimulation;Chemicals;Chronic;Cicatrix;Colon;Colorectal;Compliance behavior;Complication;Conscious;Constipation;Data;Defecation;Development;Devices;Disease;Distal;Electrophysiology (science);Esthesia;Exhibits;Failure (biologic function);Fecal Impaction;Fecal Incontinence;Female;Functional disorder;Genital system;Goals;Guidelines;Health;In Vitro;Individual;Infection;Injury;Intestines;Intractable Pain;Kidney Failure;Label;Life;Lower urinary tract;Mechanical Stimulation;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Neurogenic Bladder;Neurons;Nodose Ganglion;Nucleus solitarius;Operative Surgical Procedures;Orgasm;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Physiological;Physiology;Population;Procedures;Property;Protocols documentation;Quality of life;Rattus;Rectum;Relative (related person);Reporting;Rodent;Role;Sensory;Sexual Dysfunction;Source;Sphincter;Spinal;Spinal Cord transection injury;Spinal cord injury;Spinal cord injury patients;Structure;Sympathectomy;Techniques;Tissues;Urinary Incontinence;Vagina;Vagus nerve structure;Viscera;Visceral;Visceral pain;Woman;afferent nerve;base;clinically relevant;detrusor muscle;digital;improved;in vivo;irritation;male;nerve supply;new therapeutic target;novel therapeutics;patch clamp;pressure;public health relevance;rectal;relating to nervous system;reproductive;response;urinary;urologic

public_health_relevance:
The goal of this project is to study the role of the vagus nerve with respect to bladder and bowel function with an emphasis on its contribution in a clinically relevant rodent spinal cord injury model. Determining the anatomical connections and physiological responses of the vagus with respect to the bladder and distal colon will aide in the development of novel therapeutic devices for urinary/bowel disorders including dysfunction after chronic spinal cord injury.


application_id: 8686631
project_number: 5R01NS072302-04
project_title: Preclinical evaluation of IGF1 therapy for traumatic brain injury
administering_ic: NINDS
award_notice_date: 2014-06-13
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 072302
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2011-07-15
project_end_date: 2016-06-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI IGF-1 is a promising therapeutic candidate as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1 initiated at 15 min 3 hr or 8 hr postinjury improves motor and cognitive function in mice subjected to cortical impact brain injury in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells promote neuronal oligodendroglial and endothelial differentiation and increase angiogenesis in the brain. Therefore in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4 we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI.

project_terms:
Acute;Age;Attenuated;Behavioral;Blood Vessels;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Death;Cells;Cerebral Ischemia;Cessation of life;Clinical;Clinical Trials;Cognition;Cognitive;Complex;Contusions;Cortical Contusions;Data;Demyelinations;Enrollment;Evaluation;Functional disorder;Goals;Health;Hippocampus (Brain);Human;IGF1 gene;Individual;Infusion procedures;Injury;Insulin-Like Growth Factor I;Investigation;Isolectin;Label;Learning;Measurement;Memory;Motor;Mus;Myelin;Nerve Degeneration;Neurologic Dysfunctions;Neurons;Outcome;Patients;Perfusion;Personal Satisfaction;Productivity;Proliferating;Property;Quality of life;Rattus;Recombinants;Recovery of Function;Research;Silver Staining;Spinal cord injury;Staining method;Stains;Stem cells;Survivors;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Translations;Traumatic Brain Injury;angiogenesis;attenuation;axonal degeneration;brain repair;catalyst;cell injury;cell type;central nervous system injury;clinical application;clinically relevant;cognitive function;cognitive recovery;cognitive rehabilitation;controlled cortical impact;density;disability;functional outcomes;improved;injured;insight;knowledge base;myelination;neurobehavioral;neurogenesis;neuron loss;neuronal survival;neuroprotection;neurorestoration;novel;preclinical evaluation;rehabilitation strategy;repaired;response;stem;subventricular zone;tissue repair;tomato lectin


application_id: 8685860
project_number: 5R01AG046116-02
project_title: Pain and Well-being in Older Women: The Roles of Activity and Motivation
administering_ic: NIA
award_notice_date: 2014-06-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 046116
program_official: NIELSEN, LISBETH
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: CROFFORD, LESLIE J
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:
Adverse effects;Affect;Age;Aging;Area;Arthritis;Back Pain;Biological Markers;Elderly;Feeling;Female;Genetic Polymorphism;Genotype;Goals;Guilt;Headache;Health;High Prevalence;Hydrocortisone;Individual;Individual Differences;Inflammation;Interleukin 6 Receptor;Interleukin-6;Link;Literature;Longitudinal Studies;Measures;Modeling;Moods;Motivation;Musculoskeletal Pain;Neurosecretory Systems;Outcome;Pain;Pain interference;Pain management;Patients;Personal Satisfaction;Personality;Persons;Physical activity;Physiological;Physiology;Prevalence;Prevalence Study;Recruitment Activity;Registries;Relative (related person);Reporting;Role;Sensory;Severities;Testing;Time;Woman;aged;chronic pain;diaries;experience;fitness;heart rate variability;hedonic;improved;interest;older women;optimism;physical conditioning;prognostic;psychologic;psychosocial;public health relevance;receptor;resilience;satisfaction;sex;social

public_health_relevance:
As people age they are more likely to experience physical pain. However some older adults are able to maintain high feelings of well-being about themselves and their lives despite pain whereas some do not maintain well-being although they have little pain. This study tests whether daily activities determine whether pain does or does not result in decrements in well-being and whether activity and well-being affect immunological and neuroendocrine correlates of health.


application_id: 8685314
project_number: 5R01HL109501-05
project_title: Mechanisms of cardiac Ca dysregulation and arrhythmias in ankyrin B deficiency
administering_ic: NHLBI
award_notice_date: 2014-07-03
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 109501
program_official: KRULL, HOLLY
project_start_date: 2011-09-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-CVRS-F(02)M]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
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):  Ankyrin B (AnkB) is an "adaptor" protein that anchors several membrane proteins to the cytoskeleton. AnkB deficiency emerged as an important pro-arrhythmic factor a few years ago when it was found that AnkB loss- of-function mutations generate human long QT syndrome type 4 (LQT4) the only LQT produced by alterations in a protein other than an ion channel. Besides LQT4 humans with AnkB loss-of-function mutations display a complex cardiac phenotype that also includes bradycardia stress-induced ventricular arrhythmias and sudden cardiac death. The mechanisms responsible for such a phenotype are largely unknown. AnkB protein expression and distribution are drastically altered in the infarct border zone after myocardial infarction (MI). This may result in a mechanism for post-MI remodeling and arrhythmogenesis similar to that found in patients with AnkB loss-of-function mutations. Direct interaction with AnkB is required for the membrane targeting and stability of the Na/Ca exchanger (NCX) and Na/K-ATPase (NKA) which are essential in the regulation of cardiac [Na]i and [Ca]i and thus contractility and potential for triggered arrhythmias. The severity of the human cardiac phenotype generated by various AnkB loss-of-function mutants directly relates to the inability of those mutants to target NCX and NKA correctly to the cardiac myocyte sarcolemma. Thus altered NCX and NKA expression and membrane distribution are key to the cardiac phenotype generated by AnkB loss-of-function. This phenotype is largely reproduced in mice heterozygous for a null mutation in AnkB (AnkB mice). Myocytes from AnkB mice show modestly reduced NCX and NKA protein expression predominantly at the T-tubules larger cellular and sarcoplasmic reticulum (SR) Ca load and increased frequency of early afterdepolarizations (EAD) and delayed afterdepolarizations (DAD). Despite its physiological and pathophysiological significance the role of AnkB in regulating cardiac [Ca]i and arrhythmogenesis is poorly understood. The overall goal of this proposal is to decipher the mechanisms responsible for altered cardiac Ca regulation and triggered arrhythmias induced by AnkB loss-of-function (inherited and acquired). We will combine measurements of [Na]i and [Ca]i (in the bulk and junctional cleft) patch-clamp and molecular biology techniques in isolated cardiac myocytes in three Specific Aims. First I will test several specific hypotheses aimed at understanding how AnkB affects intracellular Ca in the heart. Aim 2 will focus on the mechanisms responsible for the occurrence of early and delayed afterdepolarizations in myocytes with AnkB deficiency. In the final aim I will test the hypothesis that AnkB proteolysis by calpain and the ensuing remodeling in NCX and NKA is a more general mechanism for triggered ventricular arrhythmias. These studies will both advance our understanding of how AnkB affects cardiac [Ca]i regulation and will provide key mechanistic information that could lead to the development of new treatments for patients with ventricular arrhythmias associated with inherited or acquired AnkB loss-of-function.

project_terms:
ATP phosphohydrolase;Action Potentials;Adaptor Signaling Protein;Affect;Ankyrins;Arrhythmia;Bradycardia;Caffeine;Calpain;Cardiac;Cardiac Myocytes;Cations;Cells;Characteristics;Cleaved cell;Complex;Cytoskeleton;Death Sudden Cardiac;Dependence;Development;Frequencies (time pattern);Functional disorder;Genetic;Goals;Heart;Human;Infarction;Inherited;Ion Channel;Ischemia;Lead;Long QT Syndrome;Measurement;Measures;Mediating;Membrane;Membrane Proteins;Messenger RNA;Molecular Biology Techniques;Mus;Muscle Cells;Myocardial Infarction;Na(+)-K(+)-Exchanging ATPase;Patients;Phenotype;Physiological;Protein Isoforms;Proteins;Proteolysis;Regulation;Reperfusion Therapy;Role;Sarcolemma;Sarcoplasmic Reticulum;Severities;Stress;Testing;Time;Ventricular;Ventricular Arrhythmia;Western Blotting;Wild Type Mouse;Work;cell injury;density;immunocytochemistry;loss of function;loss of function mutation;mutant;novel;null mutation;patch clamp;protein distribution;protein expression;sensor;voltage

public_health_relevance:
The proposed work will identify the main factors responsible for altered Ca regulation and triggered ventricular arrhythmias generated by ankyrin B deficiency. This project will also determine to what extent calpain- mediated proteolysis of ankyrin B which occurs in pathophysiological conditions such as ischemia/reperfusion leads to a mechanism for cardiac dysfunction and arrhythmogenesis similar to that seen with genetic loss-of- function of ankyrin B. Thus these studies will both advance our understanding of how ankyrin B affects cardiac Ca regulation and will provide key mechanistic information that could lead to the development of new treatments for patients with ventricular arrhythmias associated with inherited or acquired loss-of-function of ankyrin B.


application_id: 8685097
project_number: 5R33AI088585-05
project_title: Plant-produced Actinohivin as a Candidate HIV Microbicide
administering_ic: NIAID
award_notice_date: 2014-06-16
opportunity_number: RFA-AI-09-021
application_type: 5
activity_code: R33
ic: AI
serial_number: 088585
program_official: TURPIN, JIM A
project_start_date: 2010-06-10
project_end_date: 2016-09-30
study_section: ZAI1-EC-A(J1)
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
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):  Safe effective and inexpensive topical microbicides are urgently needed to curb the global human immunodeficiency virus type-1 (HIV-1) epidemic. Actinohivin (AH) is an actinomycete-derived lectin. This lectin specifically binds to high-mannose clusters uniquely found on the HIV-1 envelope (Env) thereby eliciting nanomolar antiviral activity against multiple HIV strains. Preliminary analyses revealed that AH has a high safety profile in human peripheral blood mononuclear cells (PBMCs) and in the rabbit vaginal irritation assay. Meanwhile a translational AH-AH fusion protein (recombinant dimer [rd] AH) was suggested to have stronger and broader anti-HIV-1 activity than the original monomer. Given these high potentials we hypothesize that rAH and/or rdAH (r/rdAH) are excellent HIV-1 microbicide candidates. This project's goal is to reveal the feasibilities of r/rdAH in terms of manufacture antiviral efficacy and safety upon use as a vaginal microbicide. In the R21 phase we will initially focus on developing a highly efficient scalable production system for r/rdAH that allows for extensive efficacy and safety studies and possible global use. We will utilize recombinant plant virus-based expression systems and various molecular biological approaches for rapid and high-level expression of high-quality r/rdAH. Upon obtaining bulk r/rdAH active pharmaceutical ingredients with high purity standards we will analyze HIV-1 neutralization effects against selected R5-type viruses in two in vitro HIV neutralization assays based on Env-pseudotyped virus-reporter gene expression and primary isolate- PBMC infection systems. Next r/rdAH' cytotoxic mitogenic and inflammatory potentials will be tested in PBMCs and/or human cervicovaginal (CV) epithelial cell lines to establish the minimal safety profile. Our success criteria in the R21 phase are: (1) establishing the bulk preparation procedure; (2) demonstrating cross- clade antiviral effects to R5 viruses; and (3) demonstrating no apparent in vitro cytotoxicity mitogenic activity or inflammatory potential at >100 times above an average anti-HIV IC50 for plant-made r/rdAH. Upon approval of our transition to the R33 phase we will comprehensively analyze anti-HIV-1 efficacy of r/rdAH for various modes of HIV-1 infection and transmission using various in vitro assay systems. In addition we will investigate potential overlap complementation synergy and antagonism of anti-HIV activities between r/rdAH and other inhibitors toward potential microbicide combination strategies. Finally we will perform extensive evaluations of r/rdAH upon vaginal application in rabbit and mouse models. We will thoroughly evaluate r/rdAH' vaginal toxicity inflammatory potential and stability. Upon determining the maximal tolerated dose of r/rdAH we will examine their potential immunogenicity and toxicity after a long-term exposure. Potential toxicity to the symbiotic vaginal commensal bacteria the Lactobacillus species will be examined. In summary the proposed studies should answer the question of whether r/rdAH is justified for advanced next-stage preclinical studies. . The proposed studies will analyze the feasibilities of the novel HIV-1-binding lectin Actinohivin and its derivative recombinant dimer as a candidate vaginal HIV-1 microbicide. The proposed studies should generate a comprehensive data set that will reveal their large-scale producibility anti-HIV-1 efficacy and broad toxicity profile upon vaginal application thereby providing criteria of whether Actinohivin and its derivative are justified for further extensive preclinical and clinical studies.

project_terms:
Affinity;Animal Model;Antiviral Agents;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Cell Line;Cells;Clinical Research;Data Set;Dendritic Cells;Development;Dose;Drug Formulations;Drug Kinetics;Epidemic;Epithelial Cells;Evaluation;Gene Expression;Giant Cells;Goals;HIV;HIV-1;Human;Immune;In Vitro;Infection;Inflammatory;Inhibitory Concentration 50;Integration Host Factors;Lactobacillus;Lectin;Local Microbicides;Macaca;Mannose;Maximum Tolerated Dose;Methods;Modeling;Molecular;Mus;Oligosaccharides;Oryctolagus cuniculus;Peripheral Blood Mononuclear Cell;Pharmacodynamics;Pharmacologic Substance;Phase;Pilot Projects;Plant Viruses;Plants;Play;Polysaccharides;Preclinical Testing;Preparation;Procedures;Production;Proteins;Rage;Recombinant Fusion Proteins;Recombinants;Reporter Genes;Role;Safety;Seminal Plasma;Solutions;Specificity;Staging;System;T-Lymphocyte;Testing;Time;Toxic effect;Vagina;Viral;Virus;base;cervicovaginal;commensal microbes;cytotoxic;cytotoxicity;dimer;immunogenicity;improved;in vitro Assay;inhibitor/antagonist;irritation;meetings;microbicide;monomer;mouse model;novel;preclinical study;safety study;success;sugar;transmission process;vaginal microbicide

public_health_relevance:
Project Narrative. The proposed studies will analyze the feasibilities of the novel HIV-1-binding lectin Actinohivin and itsderivative recombinant dimer as a candidate vaginal HIV-1 microbicide. The proposed studies shouldgenerate a comprehensive data set that will reveal their large-scale producibility anti-HIV-1 efficacy and broadtoxicity profile upon vaginal application thereby providing criteria of whether Actinohivin and its derivative arejustified for further extensive preclinical and clinical studies.


application_id: 8684189
project_number: 1R21HL120050-01A1
project_title: MicroRNAs as Biomarkers for Tobacco Exposure and Heart Disease
administering_ic: NHLBI
award_notice_date: 2014-05-20
opportunity_number: PAR-12-266
application_type: 1
activity_code: R21
ic: HL
serial_number: 120050
suffix: A1
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 AARR-G (56)]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
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
project_abstract:
DESCRIPTION (provided by applicant): Smoking is a major cause of heart disease for both men and women. Measuring urinary nicotine metabolite cotinine is a popular and established method of biologically monitoring exposure to tobacco smoke. Lipid profile blood pressure cardiac-specific troponins etc. have been successfully used as biomarkers to help diagnose evaluate and monitor individuals suspected of having heart problems or carrying the risk of atherosclerosis. However the development of a single biological important and clinically validated biomarker remains an unmet challenge for measuring exposure to tobacco smoke and for assessing cardiac function at the same time. MicroRNAs (miRNAs) are short 20-25 nucleotide RNA molecules that negatively regulate gene expression. Over 1000 human miRNA genes have been identified. Recently altered miRNA expression has been reported in various tobacco-related diseases such as cardiovascular dysfunction and the profiles of tissue miRNAs exhibit great potential for diagnostic applications. Moreover miRNAs are remarkably stable in human plasma or serum. Differential levels of circulating miRNAs have been associated with ischemic heart disease heart failure and coronary artery disease. However there are limited studies on circulating miRNAs upon tobacco exposure. Our hypothesis is that miRNAs can serve as blood-based biomarkers for linking tobacco exposure to heart disease. In this proposal we propose one specific aim to determine whether there is a signature of circulating miRNAs that can link tobacco smoke to heart disease. We will first profile miRNAs differentially present in the plasma in four groups of human subjects: smokers with or without heart disease and non-smokers with or without heart disease using miRNA deep-sequencing and quantitative real-time PCR. We will then examine the circulating miRNA changes in smokers with or without myocardial infarction who are asked to quit smoking. We will also profile circulating miRNAs in mice following exposure to acute or chronic tobacco smoke with or without induced myocardial infarction. Finally we will analyze the miRNA alterations in both humans and mice compare them to reported circulating miRNA profiles in various human cardiovascular pathologies and formulate a miRNA signature that can be used as biomarkers to associate heart disease with tobacco exposure. Data generated from this research will directly assess biologically relevant changes associated with tobacco use in both humans and mice and will contribute to the science base to inform the FDA's regulation of tobacco products.

project_terms:
Acute;Affect;American;Atherosclerosis;Biological;Biological Markers;Blood;Blood Pressure;Cardiac;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cessation of life;Chronic;Computing Methodologies;Coronary Arteriosclerosis;Cotinine;Data;Development;Diagnosis;Diagnostic;Disease;Environmental Exposure;Environmental Tobacco Smoke;Exhibits;Exposure to;Functional disorder;Gene Expression;Genes;Health;Heart;Heart Diseases;Heart Injuries;Heart failure;Human;Individual;Lead;Link;Lipids;Measures;Methods;MicroRNAs;Molecular Profiling;Monitor;Mus;Myocardial Infarction;Myocardial Ischemia;Nicotine;Non-smoker;Nucleotides;Patients;Physiological;Plasma;Prevalence;RNA;Regulation;Reporting;Research;Risk;Science;Serum;Smoker;Smoking;Therapeutic Intervention;Time;Tissues;Tobacco;Tobacco smoke;Tobacco use;Troponin;United States;Woman;base;cardiovascular disorder risk;cigarette smoking;deep sequencing;disability;human subject;men;premature;public health relevance;smoking cessation;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cigarette smoking is the number one preventable cause of premature death and illness in the United States. This project will directly assess circulating miRNA changes associated with tobacco use in both humans and mice and will present miRNAs as pathophysiological biomarkers that are predictive of tobacco-related adverse heart conditions.


application_id: 8683763
project_number: 3R01AR060964-02S1
project_title: Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds
administering_ic: NIAMS
award_notice_date: 2013-08-30
opportunity_number: PA-10-009
application_type: 3
activity_code: R01
ic: AR
serial_number: 060964
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2012-09-01
project_end_date: 2016-07-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration but for large defects slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring thatcan create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory anti-oxidant pro-resolution and anti-fibrotic biomolecules. With respect to this Aim it is hypothesized that the devices can be tailored to deliver anti-inflammatory anti-oxidant pro-resolution and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled localized sequential release of anti-inflammatory anti- oxidant pro-resolution and anti-fibrotic components to enhance structural/histological biochemical and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices i.e. materials that resolve inflammation and then prevent fibrosis will not only enhance muscle regeneration but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed.

project_terms:
Adhesions;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biochemical;Biocompatible Materials;Biological Response Modifier Therapy;Chronic;Cicatrix;Contracture;Data;Defect;Devices;Disease;Event;Excision;Fibroblasts;Fibrosis;Film;Gel;Generations;Goals;Healed;Home environment;Homeostasis;Inflammation;Inflammation Mediators;Inflammatory;Injury;Killings;Kinetics;Laceration;Lead;Light;Location;Mechanics;Membrane;Methods;MicroRNAs;Military Personnel;Modeling;Muscle;Musculoskeletal;Natural regeneration;Operative Surgical Procedures;Outcome;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Polymers;Process;Property;Recovery;Resolution;Rodent;Sequential Treatment;Site;Skeletal muscle structure;Surface;System;Testing;Tissues;Trauma;Ursidae Family;Vent;Work;Workplace;Wound Healing;base;combat;controlled release;design;experience;flexibility;healing;in vivo;microorganism;multidisciplinary;muscle regeneration;prevent;repaired;response;satellite cell;stem cell population;tissue regeneration;tissue repair;vehicular accident;wound

public_health_relevance:
Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.


application_id: 8682884
project_number: 5R01AR061578-03
project_title: BISPHOSPHONATE USE AND BONE QUALITY
administering_ic: NIAMS
award_notice_date: 2014-06-18
opportunity_number: PA-10-009
application_type: 5
activity_code: R01
ic: AR
serial_number: 061578
program_official: LESTER, GAYLE E
project_start_date: 2012-07-01
project_end_date: 2016-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Bisphosphonates (BP) have been used to halt bone loss and prevent osteoporosis-related fractures but recent reports and our experience indicate that their long-term use may be related to "atypical" bone fractures. This poses a great public health concern because it could indicate a rising tide of difficult to treat costly atypical bonefractures now in the making. An understandable consequence of these reports is the growing mistrust from the public and physicians regarding use of BPs to treat bone loss. Thus additional "typical" osteoporosis-related fractures could result due to reluctance to use BPs. This scenario emanating from two different reasons for increasing fractures creates an urgent need to clarify the relationship between long-term BP use and bone quality. Bone quality is important because it is widely regarded that alterations in this parameter are linked to bone fragility. The central hypothesis to be evaluated is that long-term BP use is associated with slow but progressive abnormalities in bone quality. The specific aims of the proposed study are to use an engineering-based approach to: 1) quantify bone quality abnormalities associated with no short medium and long-term BP treatment and to evaluate the contributions of low bone turnover and/or osteoporosis as a disease per se and 2) analyze the relationship between bone quality parameters and the continuous duration of BP use to determine the nature of these relationships (linear second-order exponential etc.) with time. The availability of an unrivaledarchive of bone biopsy specimens (8000+) and the collaborative experience of our clinical laboratory and engineering-based research team offers the unique opportunity to efficiently achieve these specific aims. The proposed study will measure the microstructural material and mechanical parameters of cortical and cancellous bone quality in bone samples from: a) patients with osteoporosis or no short medium and long-term BP therapy and b) healthy age-matched volunteers. These measurements will be made by using histomorphometry Fourier Transform Infrared Spectroscopy and nanoindentation. The proposed research offers a strong prospect to provide a substantial and sustained benefit to patients with osteoporosis. The findings will generate new information regarding the relationship between the duration of BP treatment and bone quality. If bone quality abnormalities are observed with BP treatment then a basis will exist for reformulation of BP treatment guidelines. If no bone quality abnormalities areobserved with BP treatment then the findings will provide reassurance to patients and physicians allowing confident use of BPs. Thus either outcome will provide valuable information regarding the therapeutic use of BPs. This will result in improved health for millions of patients with osteoporosis.

project_terms:
Activities of Daily Living;Address;Advocate;Affect;Age;Archives;Biopsy;Biopsy Specimen;Carbonates;Caucasians;Caucasoid Race;Clinical;Collagen;Competence;Control Groups;Diagnostic;Disease;Distress;Drug usage;Engineering;Fracture;Fright;Goals;Guidelines;Hardness;Health;Health Care Costs;Human;Knowledge;Laboratories;Laboratory Study;Life;Link;Measurement;Measures;Mechanics;Minerals;Morbidity - disease rate;Mortality Vital Statistics;Nature;Osteoporosis;Outcome;Patients;Pharmaceutical Preparations;Physicians;Porosity;Postmenopause;Quality of life;Reporting;Research;Research Personnel;Resolution;Sampling;Specimen;Spectroscopy Fourier Transform Infrared;Stress;Therapeutic Uses;Thick;Time;Tissues;Woman;base;bisphosphonate;bone;bone loss;bone mass;bone quality;bone turnover;crosslink;experience;improved;inorganic phosphate;meetings;nanoindentation;prevent;public health medicine (field);treatment duration;volunteer

public_health_relevance:
Bisphosphonates (BPs) are commonly used drugs that improve bone mass in millions of patients with osteoporosis but recent reports link long-term BP use with atypical bone fractures. This suggests that an abnormality in bone quality must accompany long-term BP use. The proposed laboratory study uses the PI's unrivaled archive of human diagnostic bone biopsy specimens to determine how long-term BP use affects bone quality. Knowledge gained from this study should provide a substantial and sustained benefit to human life by allowing the public to use bisphosphonates without fear of drug-related complications thereby reducing the morbidity mortality and healthcare costs linked to osteoporosis.


application_id: 8680609
project_number: 1R21EY024347-01
project_title: Impact of EOM specific myosin loss on extraocular muscle structure and function
administering_ic: NEI
award_notice_date: 2014-03-14
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: EY
serial_number: 024347
program_official: ARAJ, HOUMAM H
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
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):  Strabismus is a common condition in children that frequently leads to permanent visual impairment. Available treatment options target the extraocular muscles when they are not fully developed. The extraocular muscles are different from other muscles; they even have their own tissue-specific myosin isoform EOM-specific myosin which appears soon after birth during a period of postnatal extraocular muscle development linked to visual experience: absence of vision during this time disrupts EOM-specific myosin expression and alters the contractile properties of the extraocular muscles perhaps permanently. The same changes occur in strabismus patients and may explain the need for multiple surgeries to restore normal eye position in many of them. This project will answer two questions: to what extent EOM-specific myosin defines normal extraocular muscle function and how eye muscle function changes when the expression of this tissue-specific myosin is altered. To address these issues we will ablate or restore the EOM-specific myosin gene to test the relevance of this myosin isoform to extraocular muscle function and integrity. The experimental approach relies on our recently developed mouse strains that permit control of the expression of the EOM-specific myosin gene and will test the hypothesis that EOM-specific myosin is necessary for normal development of extraocular muscle structure and function and its appearance after its normal postnatal window does not restore muscle function. Specific Aim 2 will determine the consequences of EOM-specific myosin gene ablation on the postnatal development of mouse extraocular muscle structure and function. Specific Aim 2 will test whether the recovery of EOM-specific myosin expression in the adult mouse restores extraocular muscle function. The answers that will result from the completion of this project will inform the timing of surgical and medical treatment for congenital strabismus.

project_terms:
6 year old;ATP phosphohydrolase;Ablation;Address;Adult;Affect;Amblyopia;Appearance;Biochemical;Birth;Characteristics;Child;Data;Defect;Depth Perception;Development;Esotropia;Eye;Eye Movements;Failure (biologic function);Genes;Goals;Human;Incidence;Intervention;Knockout Mice;Limb structure;Link;Medical;Messenger RNA;Mouse Strains;Mus;Muscle;Muscle Development;Muscle Fibers;Muscle function;Myosin ATPase;Myosin Heavy Chains;Operative Surgical Procedures;Pathway interactions;Patients;Phenotype;Physiological;Positioning Attribute;Property;Protein Isoforms;Proteins;Recovery;Respiratory Muscles;Specimen;Strabismus;Structure;Testing;Therapeutic;Time;Tissues;Vision;Visual;Visual impairment;Work;base;experience;interest;mouse development;muscle form;muscular structure;novel;orbit muscle;postnatal;public health relevance;research study

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The extraocular muscles are the small muscles that move the eyes to keep them on the visual target of interest; one of their defining characteristics is tht they have a unique form of myosin EOM-specific myosin a special protein that influences how these muscles work. This protein is lost in patients with strabismus (crossed eyes). This project will determine what happens to eye muscle function when this protein is absent. The results from these studies will be important for our understanding of extraocular muscle function and how it is affected in congenital and acquired strabismus.


application_id: 8680457
project_number: 1R03DK101705-01
project_title: Reducing Diabetes Risk for Rural Appalachian Grandparent Headed Households
administering_ic: NIDDK
award_notice_date: 2014-06-24
opportunity_number: PAR-13-074
application_type: 1
activity_code: R03
ic: DK
serial_number: 101705
program_official: MCBRYDE, KEVIN D
project_start_date: 2014-07-01
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZDK1 GRB-9 (J1)]
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 of
the 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 Services Accessibility;Health behavior;Health behavior outcomes;Household;Household Heads;Household and Family;Hypertension;Intervention;Interview;Kentucky;Life;Life Style;Literature;Measures;Medical;Mental Depression;Methods;Minority;Non-Insulin-Dependent Diabetes Mellitus;Phase;Physical activity;Physical environment;Population;Poverty;Predisposing Factor;Prevalence;Preventive;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;disability;experience;grandchild;grandparent;health disparity;informant;innovation;member;nutrition;peer;phase 2 study;prevent;public health medicine (field);public health relevance;rural area;sedentary;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: 8679129
project_number: 1K99EY024336-01
project_title: Non-canonical NLRP3 Inflammasome Activation in Geographic Atrophy
administering_ic: NEI
award_notice_date: 2014-03-03
opportunity_number: PA-11-197
application_type: 1
activity_code: K99
ic: EY
serial_number: 024336
program_official: AGARWAL, NEERAJ
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZEY1 VSN (02)]
contact_pi_person_id: 11044965
contact_pi: KERUR, NAGARAJ
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: 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:
AbstractThis K99/R00 grant will facilitate the applicant's (Dr. Nagaraj Kerur) long-term goal to develop as anindependent investigator in vision research. Geographic atrophy (GA) is an advanced form of age-relatedmacular degeneration (AMD) characterized by central loss of vision due to retinal pigmented epithelium (RPE)degeneration. Currently there is no therapy available for GA because of its unclear etiology. We recentlydiscovered that DICER1 deficit causes a pathologic accumulation of Alu RNA transcripts in the RPE of humanGA eyes and that the accumulated Alu RNAs activate the NLRP3 inflammasome which in turn leads to IL-18/MyD88-dependent RPE cell death (Kaneko et al. Nature 2011; Tarallo et al. Cell 2012). In exciting newpreliminary studies we have discovered that Alu RNA-induced NLRP3 inflammasome activation occurs in anon-canonical fashion- a newly described pathway in which caspase 4 (aka caspase 11 in mouse) is requiredfor the NLRP3 inflammasome activation (in contrast the canonical inflammasome activation is independent ofcaspase 4). The central goal of the proposed research is to define role of caspase 4-mediated non-canonicalNLRP3 inflammasome activation in the context of GA and to identify critical signaling pathways regulatingcaspase 4 activation via the following aims: (1) Define the signaling pathways that regulate caspase 4 (akacaspase 11 in mouse) activation by Alu RNA; (2) Elucidate the mechanisms of caspase 4 (aka caspase 11 inmouse) activation of the NLRP3 inflammasome; and (3) Measure the activation of these non-canonicalinflammasome signaling pathways in human GA. These studies will illuminate the molecular foundation of GAunravel novel regulatory checkpoints of NLRP3 inflammasome activation and provide a strong molecularfoundation for exploiting new therapeutic targets in AMD.During the mentored phase (K99) the applicant will carry out the proposed studies under direct supervision ofthe mentor Dr. Jayakrishna Ambati at the University of Kentucky. In addition an advisory committee consistingof co-mentor Dr. Katherine Fitzgerald and the faculty members at the Department of Ophthalmology andVisual Sciences will monitor the applicant's research progress and offer assistance in advancing theapplicant's transition towards independent investigator. The Ambati Group at the University of Kentucky as wellas the Fitzgerald Laboratory at the University of Massachusetts Medical School both offer scientificallyenriching environments and resources necessary for the advancement of the applicant's scientific career. Themajor focus of K99 phase will include: (1) mentored research to define molecular insights into the caspase 4activation mechanism and to optimize experimental conditions for studies to be carried out in the R00 phase;and (2) training activities consisting of formal course work seminars workshops on grant writing andacquisition of other skill-sets required for successfully developing and leading an independent researchprogram. During the R00 phase the focus will be on: (1) deciphering the mechanisms by which caspase 4regulates NLRP3 inflammasome activation; and (2) quantifying the activation of non-canonical inflammasomesignaling pathways in human GA eyes. Overall this proposal will not only unravel the novel molecularmechanisms of RPE degeneration in GA but will also equip the applicant with suitable skills to transition intoan independent career in vision research.

project_terms:
Advisory Committees;Age related macular degeneration;Atrophic;Blindness;CASP1 gene;Caspase-1;Cell Culture Techniques;Cell Death;Cells;Cellular biology;Cessation of life;DICER1 gene;Dependency (Psychology);Development;Disease;Educational workshop;Environment;Etiology;Eye;Faculty;Foundations;Goals;Grant;Human;IL18 gene;Immune;Interferons;Interleukin-1;Interleukin-18;Investigation;Kentucky;Laboratories;Massachusetts;Measures;Mediating;Mentors;Modeling;Molecular;Monitor;Mus;Nature;Ophthalmology;Pathogenesis;Pathologic;Pathway interactions;Phase;Pilot Projects;Play;Proteomics;RNA;Regulation;Regulatory Pathway;Research;Research Personnel;Resources;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Structure of retinal pigment epithelium;Supervision;Therapeutic;Tissue Model;Training Activity;Transcript;Universities;Vision research;Work;Writing;age related;career;caspase;cytokine;geographic atrophy;human CASP4 protein;human DICER1 protein;human tissue;insight;macula;medical schools;member;mouse model;new therapeutic target;novel;procaspase-1;programs;public health relevance;skills;vision science

public_health_relevance:
Project NarrativeRecently we have discovered that the over-activation of the NLRP3 inflammasome pathwayplays an essential role in the development of geographic atrophy (GA) an untreatable cause ofblindness. However the mechanisms that govern inflammasome activation in GA are poorlyunderstood. Our proposed research will help gain a deeper understanding of theseinflammasome-regulatory pathways to identify novel critical molecules that can be targeted fortreating GA and other inflammasomopathies.


application_id: 8678991
project_number: 5R01HL111040-03
project_title: Epigenetic Regulation of Inflammatory Gene Expression by Telomerase
administering_ic: NHLBI
award_notice_date: 2014-06-19
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 111040
program_official: HASAN, AHMED A K
project_start_date: 2012-09-27
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-VH-D(02)]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
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): Innate immune responses are central to the pathogenesis of atherosclerotic cardiovascular disease and are orchestrated through transcriptional networks involving epigenetic modification of the chromatin architecture. There is now increasing evidence that the chromatin state is affected by telomerase. In addition to its well- established function to synthesize telomere repeats at the ends of chromosomes telomerase reverse transcriptase (TERT) serves a direct role in facilitating the activation of geneexpression programs. This second activity of TERT in permitting gene transcription appears to operate independently of its role in telomere homeostasis but may involve modification of the higher-order chromatin structure. Although TERT is expressed in macrophages of human atherosclerotic lesions a physiological role of this non-canonical activity of TERT in inflammation and atherosclerosis remains to be discovered. Our recent studies confirmed that TERT activates gene promoters in macrophages. Conversely TERT-deficiency alters macrophage inflammatory gene expression by inducing chromatin modifications reminiscent of gene silencing. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that TERT promotes inflammatory gene expression in macrophages through epigenetic chromatin modifications and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize a combination of cellular and molecular approaches to determine the transcriptional mechanisms by which TERT regulates macrophage inflammatory gene expression programs. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis and test the hypothesis that TERT-dependent activation of inflammatory gene expression in macrophages constitutes an important mechanism for the development of the disease. Ultimately the results of these studies will not only characterize TERT as a chromatin modifier and novel regulatory protein orchestrating macrophage inflammatory gene expression but also advance our understanding of the inflammatory mechanisms contributing to the development of atherosclerosis.

project_terms:
Adult;Affect;American;Architecture;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Cause of Death;Cell physiology;Cells;Chromatin;Chromosomes;DNA;Data;Development;Developmental Process;Disease;Environment;Epigenetic Process;Exhibits;Feeds;Funding;Gene Activation;Gene Expression;Gene Silencing;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Higher Order Chromatin Structure;Histones;Homeostasis;Human;Immune response;Inflammation;Inflammatory;Inflammatory Response;Lead;Modification;Molecular;Nucleosomes;Pathogenesis;Pathway interactions;Physiological;Promotor (Genetics);Property;Recovery;Recruitment Activity;Regulation;Relative (related person);Role;Signal Transduction;Somatic Cell;Staging;Telomerase;Telomere Maintenance;Telomere Shortening;Testing;Tissues;United States;Vascular Diseases;base;chromatin modification;chromatin remodeling;genetic regulatory protein;in vivo;innate immune function;macrophage;novel;novel therapeutics;programs;protein complex;research study;response;telomerase reverse transcriptase;telomere;vascular inflammation

public_health_relevance:
Atherosclerotic cardiovascular disease is the leading cause of death in the United States and inflammatory pathways contribute to all stages of the disease. This application will investigate novel mechanisms that control the activation of inflammation during atherosclerosis formation. The results of these studies may ultimately characterize novel pathways contributing to vascular diseases and lead to new therapeutic opportunities.


application_id: 8677240
project_number: 1K23NR014883-01
project_title: Interventions in Nutrition Education and Skills
administering_ic: NINR
award_notice_date: 2014-04-18
opportunity_number: PA-11-194
application_type: 1
activity_code: K23
ic: NR
serial_number: 014883
program_official: ROARY, MARY
project_start_date: 2014-04-18
project_end_date: 2017-03-31
study_section: National Institute of Nursing Research Initial Review Group[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 effect
of 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) assessing
nutritional 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;Disadvantaged;Discipline of Nursing;Eating;Economically Deprived Population;Economics;Effectiveness;Environment;Environmental Risk Factor;Exhibits;Food;Food Preservation;Frequencies (time pattern);Funding;Goals;Grant;Habits;Health Food;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;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;programs;public health medicine (field);public health relevance;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: 8675800
project_number: 5R21AI106260-02
project_title: Borrelia burdorferi Ebfc regulon
administering_ic: NIAID
award_notice_date: 2014-05-15
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 106260
program_official: ILIAS, MALIHA R
project_start_date: 2013-06-15
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-A(80)S]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Successful infection of a host requires that the invading pathogen control production of its virulence determinants. The infectious agent must sense its environment then respond by increasing production of appropriate factors and repressing production of unnecessary ones. These features are especially critical for vector-borne pathogens which must not only efficiently infect two extremely different host types but also be transmitted back and forth between hosts. Deciphering the regulatory pathways used by pathogens to control production of infection-associated proteins will provide significant insight into the infectious nature of those organisms. Moreover regulatory pathways are attractive candidates for development of novel preventative and curative therapies. We discovered that the Lyme disease spirochete Borrelia burgdorferi utilizes a site-specific DNA-binding protein named EbfC to regulate expression of over 50 different genes (>5% of its genome). The EbfC regulon includes genes known to be differentially expressed during the bacteria's infectious cycle and to be associated with mammalian infection. We hypothesize that EbfC is critical for global regulation of bacterial gene expression and that dysregulation of the EbfC regulon will prevent efficient mammalian infection. To address that hypothesis we will critically examine the effects of EbfC on all aspects of the borrelial mammal-tick infectious cycle           The vast majority of other bacteria species including many pathogens encode homologs of EbfC. Almost nothing is known about those other bacteria's homologs so our studies will have impacts upon almost the entire domain Eubacteria. Thus our continued studies will focus efforts toward production of improved preventative and curative therapies for not only Lyme disease but also many other significant human infectious diseases.

project_terms:
Address;Animal Model;Animals;Back;Bacteria;Bacterial Gene Expression Regulation;Biochemical;Biology;Borrelia;Borrelia burgdorferi;Communicable Diseases;DNA-Binding Proteins;Data;Development;Disease;Environment;Eubacterium;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genome;Homologous Gene;Human;Infection;Infectious Agent;Invaded;Investigation;Lyme Disease;Mammals;Molecular Biology;Molecular Profiling;Names;Nature;Order Spirochaetales;Organism;Pathogenesis;Plasmids;Play;Preparation;Process;Production;Proteins;Publications;RNA Sequences;Recombinants;Regulation;Regulatory Pathway;Regulon;Role;Site;Staging;Techniques;Testing;Ticks;Virulence;Work;genetic regulatory protein;graduate student;human disease;improved;insight;mutant;novel;pathogen;pathogenic bacteria;prevent;protein expression;public health relevance;research study;transcriptome sequencing;vector

public_health_relevance:
Pathogens must regulate expression of their genes to produce factors necessary for human infection while repressing synthesis of unnecessary factors so we hypothesize that disruption of essential regulatory networks will impair the abilityof pathogenic bacteria to infect and cause disease. We discovered a new type of regulatory protein EbfC which exerts significant effects on gene expression in the Lyme disease agent Borrelia burgdorferi. In addition almost every other bacterial pathogen encodes a homolog of EbfC so our studies are important for understanding a great number of human diseases.


application_id: 8675214
project_number: 5K02DA031766-04
project_title: Medications Development for Cannabis-Use Disorders: Clinical Studies
administering_ic: NIDA
award_notice_date: 2014-06-26
opportunity_number: PA-10-057
application_type: 5
activity_code: K02
ic: DA
serial_number: 031766
program_official: HAMPSON, AIDAN
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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):  Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. The overarching goal of my career is to develop a clinical research program in which I am able to screen potential medications for cannabis-use disorders using an efficient evidence-based progression of laboratory procedures followed by an evaluation of the efficacy of promising leads in dependent treatment-seeking individuals. My graduate and post-doctoral training and K01 and R01 support have enabled me to build an independent research program in which rational targets for medications development are identified based on the neuropharmacology of 9-THC. My research has identified compounds that could represent major breakthroughs in cannabis-use treatment. The goal of this K02 award is to continue my career development trajectory by acquiring the additional skills and experience needed to move my research into the next steps of the screening process. In order to achieve this goal I have formulated a career development plan that includes additional coursework training with expert preceptors relevant research and data publication/presentation activities further grant development and the receipt and delivery of training in the responsible conduct of research. The research to be conducted during the funding period consists of a three-step screening process to 1) identify targets and/or specific compounds for subsequent screening; 2) test the safety and tolerability of cannabis administration during maintenance on candidate medications; and 3) test the ability of maintenance on putative pharmacotherapies to attenuate the reinforcing effects of cannabis under controlled laboratory conditions while simultaneously monitoring changes in cannabis use in the natural ecology. Importantly this last step represents an innovative approach that will enhance the efficiency of early phase clinical trial research direct the choice of candidate medications for full scale clinical efficacy testing and facilitate my eventual transition to clinical trials research. This research will be carried out in the Department of Behavioral Science at the University of Kentucky which is an exceptional environment having the necessary physical and intellectual resources for successful completion of the proposed career development plan. Moreover this institution is committed to my scientific development and has acknowledged that my research program is an integral part of its scientific community. I have a solid foundation of training and research experience have established a strong record of productivity and independent funding and have demonstrated a commitment to mentoring the next generation of scholars interested in the treatment of cannabis-use disorders. The career development activities supported by the K02 award will allow me to sustain and expand these efforts and thus meet my career goals which will directly impact the field of cannabis-use treatment.

project_terms:
Abstinence;Address;Admission activity;Adopted;Adverse effects;Agonist;Area;Attenuated;Baclofen;Behavioral Sciences;Biological Assay;Brain;Cannabinoids;Cannabis;Cannabis Smoking;Clinical;Clinical Data;Clinical Research;Clinical Treatment;Clinical Trials;Commit;Communities;Controlled Clinical Trials;Data;Dependence;Development;Development Plans;Diagnostic;Disease;Dose;Drug Combinations;Drug usage;Ecology;Environment;Foundations;Funding;Future;Goals;Gold;Grant;Hybrids;Illicit Drugs;Independent Scientist Award;Individual;Inpatients;Institution;Kentucky;Knowledge;Laboratories;Laboratory Procedures;Laboratory Research;Link;Maintenance;Measures;Mediating;Mentors;Methods;Monitor;Nabilone;Neurons;Neuropharmacology;Outpatients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Phase;Population;Procedures;Process;Productivity;Publications;Receptor Cannabinoid CB1;Relapse;Reporting;Research;Research Training;Resistance;Resources;Risk;Safety;Sampling;Screening procedure;Self Administration;Series;Solid;Stimulus;System;Testing;Therapeutic;Time;Toxicology;Training;Treatment Efficacy;Treatment outcome;United States;Universities;Urine;Withdrawal;absorption;base;career;career development;clinical efficacy;clinical practice;cost effective;drug discrimination;drug of abuse;efficacy evaluation;efficacy testing;endogenous cannabinoid system;evidence base;experience;gabapentin;gamma-Aminobutyric Acid;improved;innovation;interest;meetings;next generation;post-doctoral training;post-market research;programs;public health medicine (field);responsible research conduct;safety testing;screening;skills;tiagabine

public_health_relevance:
Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. Five years of funding is requested to support full-time (100% effort) research and training to support the development of an efficient evidence-based medication screening process.


application_id: 8674218
project_number: 1R01AR066082-01
project_title: Molecular clock and skeletal muscle weakness
administering_ic: NIAMS
award_notice_date: 2014-08-21
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AR
serial_number: 066082
program_official: BOYCE, AMANDA T
project_start_date: 2014-08-25
project_end_date: 2015-07-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
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):  Skeletal muscle weakness has long been known to contribute to morbidity and mortality in aging and other diseases. Single fiber studies from different models of weakness in humans and rodents have demonstrated reduced force implicating alterations in myofilament protein expression post-translational modifications and sarcomere organization. Our recent work in the emerging area of circadian rhythms and the molecular clock in skeletal muscle holds potential to provide insight into mechanisms of weakness. Most recently we generated an inducible line of mice in which Bmal1 is deleted only in adult skeletal muscle following tamoxifen treatment (iMSBmal1-/-). We observed progressive declines in cage activity and voluntary wheel activity and we determined that the muscles were weak with significant declines in maximum force and passive tension. To begin to identify the molecular mechanism(s) underlying weakness in this model we have identified circadian expression of transcription factors important for muscle (Srf Sox6 and Tead1) and we found that expression of these genes was disrupted in the muscle of iMSBmal1-/- mice. These observations support our hypothesis that the molecular clock in skeletal muscle directly regulates expression of a network of important transcription factors (muscle clock controlled genes) and when the molecular clock is disrupted this leads to downstream effects on sarcomere gene expression sarcomere structure and muscle mechanical function. In addition to work on the molecular clock my lab and others have demonstrated that scheduled physical activity can function as an environmental non-photic time cue for the skeletal muscle molecular clock. This discovery highlights a new mechanism for physical activity and provides the basis for our second hypothesis: Time of exercise will act as a therapeutic intervention to slow the progression of muscle weakness in aging. These two hypotheses will be tested in the following three specific aims. Specific Aim 1: To determine whether the myogenic transcription factors Srf Sox6 Tead1 are direct molecular clock controlled genes in skeletal muscle. Specific Aim 2: To determine the sarcomeric changes through which active and passive tension is reduced in skeletal muscle fibers of iSMBmal1-/- mice. Specific Aim 3: To determine whether time of exercise modifies the rate of progression of muscle weakness with aging. The results of these studies will provide new insight into mechanisms that link disrupted circadian rhythms and muscle weakness. Since aging and many chronic diseases are known to disrupt molecular clock function these findings may also provide novel new targets for therapeutic strategies.

project_terms:
Adult;Age-Months;Aging;Area;Binding (Molecular Function);Biochemical;Biological Assay;Bioluminescence;Cells;Chronic Disease;Circadian Rhythms;Cis Tests;Collection;Computer software;Cues;Data;Disease;Electrons;Elements;Enhancers;Exercise;Exhibits;Fiber;Gene Expression;Gene Silencing;Genes;Genetic;Genetic Recombination;Grant;Health system;Human;Leg;Light;Link;Maintenance;Measures;Mechanics;Microfilaments;Modeling;Molecular;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Mutate;Myosin Heavy Chains;Nuclear Extract;Phase;Physical activity;Physiological;Population;Post-Translational Protein Processing;Promotor (Genetics);Property;Proteins;Regulation;Rehabilitation therapy;Rodent;Role;Running;Sarcomeres;Schedule;Skeletal muscle structure;Tamoxifen;Techniques;Testing;Therapeutic Intervention;Time;Training;Transcriptional Regulation;Work;base;chromatin immunoprecipitation;connectin;gel electrophoresis;grasp;insight;mouse model;muscle form;muscular structure;mutant;nebulin;new therapeutic target;novel;programs;protein expression;public health relevance;research study;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Skeletal muscle weakness has long been known to contribute to morbidity and mortality in aging and other diseases. The experiments outlined in this grant will test the hypothesis that the molecular clock in skeletal muscle regulates a network
of important transcription factors that are important for maintenance of muscle structure and function. Additionally we will test whether time of exercise will act as a therapeutic intervention
to slow the progression of muscle weakness in aging.


application_id: 8673308
project_number: 1R01HL122581-01
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2014-05-27
opportunity_number: PA-11-260
application_type: 1
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_abstract:
DESCRIPTION (provided by applicant): Myocardial ischemia and reperfusion (I/R) results in increased glycolysis changes in internal pH inflammation and elevated levels of reactive oxygen species (ROS) that contribute to I/R injury and its clinical outcomes. However a common biochemical feature of myocardial I/R is increased formation of reactive carbonyls which are generated in high abundance in the ischemic heart and their concentration is further increased upon reperfusion. Previous work has shown that increased enzymatic detoxification of these carbonyls decreases myocardial I/R injury. Nevertheless it remains unclear which carbonyls are generated during I/R and how they contribute to tissue injury. As a result the general contribution of carbonyls to myocardial I/R injury remains unclear and no specific carbonyl quenching interventions have been developed to limit I/R injury. The current project is designed to understand the role of endogenous histidyl dipeptides synthesized by the heart in preventing carbonyl toxicity during I/R. Histidyl dipeptides such as carnosine and anserine react avidly with structurally-diverse carbonyls we propose that these peptides represent a general carbonyl detoxification pathway. To test this hypothesis we will elucidate the role of histidyl dipeptides in myocardial I/R injury. Using both in situ and ex vivo models of myocardial I/R injury we will examine whether increasing myocardial levels of histidyl dipeptides either by overexpression of histidyl dipeptide synthase (HDS) in the heart or exogenous delivery will diminish tissue injury. To assess whether the cardioprotective effects of these peptides are due to increased carbonyl detoxification we will determine whether increased myocardial levels of these peptides are associated with increased carbonyl removal and excretion Our studies will also delineate the mechanism by which histidyl dipeptides affect myocardial I/R injury. Specifically we will examine whether histidyl dipeptides generated during I/R inhibit the proteasome and induce ER stress and that histidyl dipeptides decrease myocardial damage by preventing protein carbonylation and thereby attenuating proteasomal dysfunction and ER stress. Finally we will examine the relative efficacy of endogenous and synthetic histidyl dipeptides against myocardial I/R injury. For this we will compare the relative efficacy of differet endogenous histidyl dipeptides and their synthetic analogs against carbonyl toxicity and investigate whether enhanced carbonyl quenching properties of these peptides result in greater protection against myocardial I/R injury. Completion of this project will lead to the identificatio and assessment of a novel antioxidant system present in the heart and how components of this system (histidyl peptides HDS) prevent critical features of ischemia injury (carbonyl toxicity). We expect that these studies will lead to the identification of specific carbonyls that mediate I/R
injury and how they contribute to myocardial damage. These findings might lead to the development of robust and effective interventions that could be used clinically to limit ischemic and oxidative injury in the heart as well as in other tissues.

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;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;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Role;Skeletal muscle structure;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 infarct sizing;novel;overexpression;oxidation;prevent;protein aggregation;public health relevance;sugar


application_id: 8671540
project_number: 1R21EY024313-01
project_title: Hypoxia-induced reprogramming to RPE stem cells
administering_ic: NEI
award_notice_date: 2014-03-06
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: EY
serial_number: 024313
program_official: NEUHOLD, LISA
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In urodeles and anurans a major component of retinal regeneration is transdifferentiation of RPE to neural retina. But regeneration is limited in mammals leaving them susceptible to retinal injury and blinding diseases. Recent studies identified a population of RPE stem cells (RPESC) among cultures of human RPE. These RPESC show unrestricted proliferation and their differentiation potential closely resembled mesenchymal stem cells (MSC) which share a common neuroepithelial origin with RPE. Although RPESC differentiated to express neuronal markers they failed to induce photoreceptor markers such as RHO. Thus these RPESC may not represent an intermediate in transdifferentiation of mammalian RPE into photoreceptors. We examined cultures of adult mouse RPE for cells with the differentiation capacity of RPESC but we failed to identify such cells. However we found that cells with properties of RPESC can be efficiently and stably induced from RPE (iRPESC) through a hypoxia-dependent pathway similar to that described for maintenance and induction of MSC. Hypoxia causes RPE damage and is linked to neovascularization and AMD. Key to this iRPESC reprogramming pathway is superinduction of hypoxia inducible factor 1a (Hif1a) to a threshold sufficient to bind and activate the Oct4 stem cell gene promoter. Oct4 in turn induces Dnmt1 which silences cell cycle blocking cyclin dependent kinase inhibitors leading to unrestricted proliferation. These iRPESC are resistant to hypoxia and importantly as opposed to human RPESC they differentiate into Rho+ cells-indeed this differentiation to Rho+ cells is more efficient than seen with embryonic stem cells or induced pluripotent stem cells. Furthermore iRPESC do not undergo the typical epithelial-mesenchymal transition (EMT) seen when RPE are placed in culture providing the potential for retaining an RPE phenotype as the cells are expanded. Because blinding diseases such as AMD are highlighted by loss of both functional RPE and photoreceptors the ability of the iRPESC to undergo photoreceptor differentiation and to resist EMT-initiated loss of phenotype suggest a unique therapeutic potential for the cells. During the two year period of this R21 proposal we aim to investigate the iRPESC reprogramming pathway on a molecular level. The purpose of these studies is to provide a foundation for experiments designed to optimize photoreceptor differentiation from iRPESC and to maintain a function RPE phenotype as iRPESC are expanded so in the future we can begin testing the effectiveness of the differentiated iRPESC in transplantation experiments. A second point of this molecular analysis is to identify pathway markers that can ultimately be used for detection of iRPESC in vivo and to understand factors that might be used in the future to stimulate iRPESC generation from RPE in situ.

project_terms:
Adult;Binding (Molecular Function);Cell Aging;Cell Cycle;Cell Differentiation process;Cells;Cessation of life;Cyclin-Dependent Kinase Inhibitor;Detection;Development;Disease;Effectiveness;Embryo;Environment;Epithelial;Foundations;Future;Generations;Genes;Goals;Hemostatic function;Human;Hypoxia;Hypoxia Inducible Factor;In Situ;Injury;Knowledge;Left;Link;Maintenance;Mammals;Mesenchymal;Mesenchymal Stem Cells;Mitotic;Molecular;Molecular Analysis;Mus;Natural regeneration;Neural Retina;Neuroepithelial;Neuronal Differentiation;Neurons;Newts;Optics;Organ;Pathway interactions;Phenotype;Photoreceptors;Play;Population;Proliferating;Promotor (Genetics);Property;Protocols documentation;Rana (genus);Repression;Resistance;Retinal;Retinal Diseases;Rodent;Rods (Retina);Role;Salamander;Stem cells;Structure of retinal pigment epithelium;Suspension substance;Suspensions;Testing;Therapeutic;Tissues;Transplantation;adult stem cell;design;diencephalon;embryonic stem cell;in vivo;induced pluripotent stem cell;inhibitor/antagonist;monolayer;neovascularization;neuroepithelium;pluripotency;prevent;progenitor;public health relevance;repaired;research study;response;restoration;retinal regeneration;rho;senescence;toad;transdifferentiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Retinal pigment epithelium (RPE) can efficiently transdifferentiate to replace damaged neural retina in newts and frogs and to a more limited degree in embryonic chick and rodents. However RPE transdifferentiation does not occur in adult mammals and regeneration is limited leaving mammals susceptible to retinal injury and blinding diseases. Recent studies have provided the first evidence of RPE stem cells (RPESC) in cultures of human RPE. This important finding raises the possibility that these RPESC may serve as a reservoir for replacement of damaged RPE in diseases such as AMD and they may represent an intermediate in transdifferentiation of RPE to photoreceptor in mammals. However even though these human RPESC closely resembled mesemchymal stem cells (MSC) in their differentiation potential and they showed evidence of neuronal differentiation they failed to induce markers of photoreceptor differentiation. We have examined adult mouse RPE for cells with properties of RPESC. Although we did not detect RPESC we found instead that cells with properties of RPESC could be stably and efficiently induced from RPE (iRPESC) through a hypoxia-dependent pathway similar to that described for maintenance and induction of MSC. Key to this iRPESC reprogramming pathway is superinduction of hypoxia inducible factor 1a (Hif1a) to a threshold sufficient to bind and activate the Oct4 stem cell gene promoter. Oct4 in turn induces Dnmt1 which silences cell cycle blocking cyclin dependent kinase inhibitors leading to unrestricted proliferation. These iRPESC are resistant to hypoxia and importantly as opposed to human RPESC they differentiate into Rho+ cells-indeed this differentiation to Rho+ cells is more efficient than seen with embryonic stem cells or induced pluripotent stem cells. These results with iRPESC demonstrate induction of RPESC under hypoxic conditions that have been linked to RPE damage in retinal disease (e.g. neovascularization and AMD). Because iRPESC can efficiently differentiate to express rod photoreceptor makers they can act as a stable intermediate for transition of mammalian RPE to cells expressing markers of photoreceptors. We propose studies of the molecular pathway leading to iRPESC reprogramming during the two year period of the R21.


application_id: 8670733
project_number: 5R44DK089892-05
project_title: BIOMARKER FOR EARLY DETECTION OF CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2014-06-25
opportunity_number: PA-11-096
application_type: 5
activity_code: R44
ic: DK
serial_number: 089892
program_official: MOXEY-MIMS, MARVA M
project_start_date: 2010-09-20
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-L(11)B]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: COUGHLIN, RICHARD THOMAS
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There are an estimated 26 million Americans with early chronic kidney disease (CKD). Early diagnosis and treatment are the only cost-effective means to reverse this growing problem. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD. Current methods and biomarkers that are used to assess CKD are effective once the disease is well established but are not reliable for the detection of early disease. Further many patients initially determined tohave a mild decline in kidney function by the current methods may actually be misclassified and possibly under-diagnosed resulting in a patient having undiagnosed moderate to severe kidney damage. We will produce a new ELISA for CKD to be employed as a diagnostic test based upon the use of a novel biomarker that reflects early events in the pathophysiology of kidney disease. Detection of this biomarker for CKD will give laboratory results and clinical insight thatare complementary to creatinine-based glomerular filtration rate (GFR) estimates as well as tests for urine albumin. This should result is a more reliable and earlier identification of CKD.  n addition our CKD-Assay would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension or diabetes. In Phase I we evaluated the feasibility and proof-of principal of this test and found that the prototype assay in both populations was highly sensitive and specific. In Phase II we will look for the influence of comorbid conditions and medications on assay performance compare our results to the gold standard assay of GFR and follow up patients over at least 3 years to evaluate the ability of this biomarker to follow progression of CKD. Lastly we will evaluate whether patient characteristics such as age gender BMI ethnicity and other factors impact on assay performance. We request Phase II support so that we can evaluate the prototype assay and further test its feasibility to help identiy at-risk patients for early kidney disease and monitor therapy with the ultimate goal of obtaining FDA approval and reducing the societal impact of under-diagnosed CKD.

project_terms:
Affect;Age;Albumins;American;Antibodies;Archives;Biological Assay;Biological Markers;Blood Circulation;Cardiovascular Diseases;Characteristics;Chronic Kidney Failure;Clinical;Clinical Trials;Complement;Creatinine;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic tests;Disease;Early Diagnosis;Early identification;Early treatment;Enzyme-Linked Immunosorbent Assay;Ethnicity aspects;Event;Filtration;Functional disorder;Gender;Glomerular Filtration Rate;Goals;Gold;Health;Hemodialysis;Homeostasis;Hypertension;Impairment;Individual;Kidney;Kidney Diseases;Laboratories;Linear Models;Measures;Medical;Methods;Microalbuminuria;Monitor;NHANES;Patients;Performance;Pharmaceutical Preparations;Phase;Physicians;Play;Population;Prevalence;Race;Reagent;Renal function;Risk;Role;Sampling;Serum;Sodium Chloride;Specificity;Staging;Testing;United States;United States National Institutes of Health;Urine;Variant;Water;base;cardiovascular risk factor;case control;commercialization;cost effective;economic impact;follow-up;high risk;insight;novel;phase 1 study;post gamma-globulins;prevent;prohormone;prototype;prouroguanylin;research and development;research clinical testing;salt sensitive hypertension;scale up

public_health_relevance:
Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease and hemodialysis. We will develop an assay for the identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8670678
project_number: 5R01AA020051-03
project_title: RAX PKR and ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2014-05-21
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 020051
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2012-09-01
project_end_date: 2017-05-31
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 (Molecular Function);Brain;Cells;Cerebellum;Child;Congenital Abnormality;Cytoplasmic Granules;Development;Disease;Dominant-Negative Mutation;Double-Stranded RNA;Down Syndrome;Ethanol;Ethanol toxicity;Exposure to;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;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;cell type;cost;disability;eIF-2 Kinase;effective therapy;inhibitor/antagonist;innovation;mouse model;neuron apoptosis;neuron loss;neurotoxicity;novel;novel strategies;postnatal;public health medicine (field);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: 8669044
project_number: 5R00HL095769-05
project_title: Metabolic Stress-Induced Fatty Acid Nitration and Cardiovascular Function
administering_ic: NHLBI
award_notice_date: 2014-05-22
opportunity_number: PA-07-297
application_type: 5
activity_code: R00
ic: HL
serial_number: 095769
program_official: DESVIGNE-NICKENS, PATRICE
project_start_date: 2010-07-01
project_end_date: 2016-05-31
study_section: NSS
contact_pi_person_id: 7162747
contact_pi: COLE, MARSHA P
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractHyperglycemic and hyperlipidemic conditions lead to dysregulation of insulin mediated cell signaling andmetabolic abnormalities. A pro-oxidative milieu exists in type II diabetes which results in increased cardiacmitochondrial production of reactive oxygen species and nitric oxide synthase activity. This proposal focuseson the central hypothesis that one class of NO-dependent oxidation and nitration products nitrated fatty acids(NO2-FA) are generated in heart mitochondria under hyperglycemic conditions and can mediate reactions thatbeneficially modify mitochondrial function. NO2-FA derivatives are present endogenously and mediate anti-inflammatory effects through predominately cGMP-independent mechanisms that include electrophilic post-translational protein modification and potent peroxisome proliferator-activated receptor (PPARg) ligand activity.As a result of robust thiol reactivity NO2-FA also activate phase II enzyme expression in vitro (e.g. hemeoxygenase 1 HO-1) through nuclear factor E2-related factor 2 (Nrf2) activation of antioxidant responseelement (ARE) dependent gene expression. Current knowledge supports that in type II diabetes a pro-oxidative milieu exists that promotes fatty acid nitration. Three specific aims are designed to test thehypothesis that mitochondrial fatty acid nitration occurs and that these species may beneficially modifymitochondrial and cardiovascular function in type II diabetes: 1) quantify the mitochondrial production of NO2-FA in hyperglycemic wildtype and diabetic Lepob mice 2) determine whether administered OA-NO2 modulatesmitochondrial function in a diabetic-leptin deficient (ob/ob) murine model and 3) assess changes in cardiaccontractility function and oxygen consumption following OA-NO2 administration in Lepob diabetic mice.Completion of the proposed aims will lend insight into how NO2-FA can impact mitochondrial respiratoryfunction myocardial efficiency and cardiac contractility in a murine model of diabetes. This work is ofsubstantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as anadaptive cell signaling mediator in hyperglycemic-induced myocardial injury.

project_terms:
Action Potentials;Age;Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Appointment;Biological Assay;Biology;Cardiac;Cardiovascular Physiology;Chemicals;Complex;Cyclic GMP;DNA;Data;Diabetes Mellitus;Diabetic mouse;Diastolic blood pressure;Diet;Electrospray Ionization;Enzymes;Fatty Acids;Gene Expression;Heart;Heart Mitochondria;Heart Rate;Heme Oxygenase (Decyclizing);High Pressure Liquid Chromatography;Homeostasis;Hyperglycemia;Hyperglycemic Mice;In Vitro;Individual;Inflammation Mediators;Inflammatory;Injection of therapeutic agent;Injury;Insulin;Ions;Knowledge;Lead;Left;Leptin;Ligands;Linoleic Acids;Lipids;Measurement;Measures;Mediating;Mediator of activation protein;Mentorship;Metabolic;Metabolic stress;Mitochondria;Mitochondrial Proteins;Modeling;Molecular Weight;Monocyte Chemoattractant Protein-1;Mus;Myocardial;Myocardial dysfunction;NF-kappa B;Nitrates;Nitric Oxide;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Nuclear;Obesity;Oleic Acids;Oxidation-Reduction;Oxidative Stress;Oxygen Consumption;PPAR gamma;Peroxisome Proliferator-Activated Receptors;Peroxonitrite;Pharmacologic Actions;Phase;Play;Polyunsaturated Fatty Acids;Positioning Attribute;Post-Translational Protein Processing;Preparation;Production;Property;Proteins;Pump;Reaction;Reactive Oxygen Species;Research;Respiration;Respiratory physiology;Response Elements;Risk;Role;Signal Transduction;Spectrometry Mass Electrospray Ionization;Sulfhydryl Compounds;Superoxides;Testing;Time;Tissues;Treatment Efficacy;Tumor Necrosis Factor-alpha;Universities;Up-Regulation (Physiology);Ventricular;Work;Workload;abstracting;adduct;cardiovascular injury;clinically relevant;cytokine;design;diabetic;falls;feeding;heart preservation;in vivo;insight;nitration;oxidation;pressure;protein complex;receptor;respiratory;response;transcription factor

public_health_relevance:
This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury.


application_id: 8668908
project_number: 5R01CA166327-02
project_title: Regulation of Tumor Metabolism by Retinoblastoma Protein
administering_ic: NCI
award_notice_date: 2014-05-09
opportunity_number: PA-11-260
application_type: 5
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;Histones;Human;Knock-out;Knockout Mice;Lipids;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Molecular Target;Mus;Neoplasm Metastasis;Neoplasms;Normal Cell;Normal tissue morphology;Nucleotide Biosynthesis;Oncogenes;Oxygen Consumption;Pathway interactions;Phenotype;Polychlorinated Biphenyls;Positron-Emission Tomography;Process;Production;Promotor (Genetics);Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Relative (related person);Retinoblastoma;Retinoblastoma Protein;Role;TOCSY;Testing;Transcription Repressor/Corepressor;Tumor Suppressor Proteins;Wild Type Mouse;Withdrawal;angiogenesis;base;bcr-abl Fusion Proteins;c-myc Genes;cancer cell;cell transformation;chromatin remodeling;enzyme pathway;glucose uptake;in vivo;macromolecule;neoplastic;neoplastic cell;public health relevance;small molecule;tumor;tumor initiation;tumor metabolism;tumor progression;tumorigenesis;uptake

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: 8668173
project_number: 5T32NS077889-03
project_title: Neurobiology of CNS Injury and Repair
project_terms: Neurobiology;central nervous system injury;injury and repair
administering_ic: NINDS
award_notice_date: 2014-06-12
opportunity_number: PA-11-184
application_type: 5
activity_code: T32
ic: NS
serial_number: 077889
program_official: KORN, STEPHEN J
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: ZNS1-SRB-P(63)
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: GEDDES, JAMES W.
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
public_health_relevance:
PROJECT NARRATIVE This project will involve the development of a new training program to prepare 4 predoctoral fellows/year for neurological research careers directed at the discovery and translation of novel neuroprotective and neurorestorative therapies for the treatment of traumatic spinal cord and brain injuries. The training will be directed by basic science and clinical faculty of the University of Kentucky Spina Cord & Brain Injury Research Center.


application_id: 8667195
project_number: 2T32DA016176-11
project_title: Training in Drug Abuse Related Research
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2014-06-20
opportunity_number: PA-11-184
application_type: 2
activity_code: T32
ic: DA
serial_number: 016176
program_official: BABECKI, BETH
project_start_date: 2004-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZDA1 EXL-T (02)]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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
public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal of this training program is to prepare promising predoctoral and postdoctoral trainees for productive and successful careers in drug abuse research a critical endeavor for current and future public health challenges associated with drug addiction. The program fosters the development of essential experimental and critical thinking skills and focused expertise on the interrelationships of cellular and molecular aspects of receptors and signaling mechanisms involved in the response to drugs of abuse within the context of drug discovery and development of novel treatments for drug abuse. Our program provides a highly collaborative environment of interdisciplinary and translational training in drug
abuse research coupled with opportunities for networking and collaboration to advance our trainees towards independent investigator status in drug abuse research.


application_id: 8666710
project_number: 5R21AI097608-02
project_title: Identification of host factors required for Yersinia pestis macrophage infection
administering_ic: NIAID
award_notice_date: 2014-05-07
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 097608
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2013-06-01
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-A(80)S]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Plague is an acute infection caused by Yersinia pestis a Gram-negative facultative intracellular bacterium that infects and survives in macrophages. Growing evidence suggests that intracellular growth is important for mammalian colonization by Y. pestis. Upon entry into macrophages Y. pestis remains in a membrane-bound compartment called the Yersinia-containing vacuole (YCV) but it is not killed by the macrophage. Furthermore the bacterium actively inhibits acidification of the YCV. We hypothesize that Y. pestis interacts with specific host factors in order to alter YCV maturation and acidification. While bacterial factors important for intracellular survival have been identifie the molecular mechanisms used by the bacterium to survive within macrophages have not been defined. To identify these factors/pathways we have built a novel Y. pestis bioreporter to monitor Y. pestis survival in macrophages. Using this bioreporter we have developed an inhibitory RNA-based assay to specifically identify host factors that alter Y. pestis intracellularsurvival. With this assay we will perform a genome wide screen to identify host factors/pathways required for Y. pestis survival in macrophages (Aim 1). Using a combination of in silico and microscopy analysis we will also specifically identify host factors identified in our screen that alter phagosome maturation to the benefit of Y. pestis (Aim 2). These studies will be the first to target the host cell to understand the mechanisms used by Y. pestis to survive in host cells.

project_terms:
Acute;Antibiotic Resistance;Antibiotics;Bacteria;Binding (Molecular Function);Biological;Biological Assay;Cell Communication;Cell Survival;Cells;Computer Simulation;Confocal Microscopy;Data;Dendritic Cells;Development;Disease;Federal Government;Future;Growth;Human;Immune;Immune system;Infection;Integration Host Factors;Killings;Membrane;Microscopy;Molecular;Monitor;Mus;Nature;Pathway interactions;Phagocytosis;Phagosomes;Pharmaceutical Preparations;Plague;Plague Vaccine;Process;RNA;RNA Interference;Reagent;Small Interfering RNA;Specificity;Staging;Testing;Vacuole;Virulence;Work;Yersinia;Yersinia pestis;base;cell killing;combat;design;genome wide association study;genome-wide;human disease;innovation;insight;macrophage;novel;novel therapeutic intervention;novel therapeutics;novel vaccines;pathogen;public health relevance;resistant strain;screening;tool;weapons

public_health_relevance:
Yersinia pestis is the causative agent of plague an acute human disease and potential bioweapon. The work proposed here will identify host targets required by Y. pestis to infect cells of the innate immune system. Understanding the interactions between Y. pestis and the host immune system will allow us to design new vaccine and therapeutic approaches to combat plague infections.


application_id: 8666702
project_number: 5R21AG042699-02
project_title: Cyclic compressive loading as an intervention for skeletal muscle atrophy and imp
administering_ic: NIA
award_notice_date: 2014-05-22
opportunity_number: PAS-11-280
application_type: 5
activity_code: R21
ic: AG
serial_number: 042699
program_official: WILLIAMS, JOHN
project_start_date: 2013-06-01
project_end_date: 2016-05-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aging is associated with a decreased ability to recover muscle mass and strength after periods of inactivity to which elderly are often subjected resulting in frailty and functional dependence. Skeletal muscle is not only critically important for the development of force but also serves as a major protein reservoir and is an important predictor of mobility susceptibility to injury and mortality. Therefore it is criticaly important to design interventions to attenuate the decrease in muscle size during periods of disuse and to aid in the regrowth of atrophied muscle. Underlying mechanisms for the diminished capacity of muscle to regrow after disuse in the elderly are still largely unknown but could be related to alterations in the inflammatory processes associated with recovery from atrophy. Massage therapy is used in clinical settings to aid in the repair of inflammatory conditions in muscles and we have found that massage in the form of cyclic compressive loading (CCL) positively modulates the immune response in muscle and aids in the repair of muscle injury and restoration of function in young animals. However the effect of massage therapy on muscle atrophy and regrowth in the aged is completely unexplored. Therefore we hypothesize that CCL is beneficial for the maintenance of muscle size during disuse-induced atrophy and will improve the impaired regrowth response in aged rats. We will investigate this hypothesis with two specific aims. In Aim 1 we hypothesize that CLL attenuates muscle mass lost during disuse-induced atrophy through actions on protein turnover pathways. Male Fischer 344/Brown Norway rats at 10 and 30 months of age will be hind limb suspended for 14 days to induce atrophy. CCL will be applied at two different loads in different groups of rats to gastrocnemius muscles of one leg during hind limb suspension. Changes in muscle size protein synthesis markers of muscle protein synthesis and degradation and force generating capacity will be measured. In Aim 2 we hypothesize that CCL will improve regrowth of muscle in aged rats through its immunomodulatory actions. Rats at 10 and 30 months of age will be hindlimb suspended for 14 days followed by ambulation for 1 2 4 or 14 days. CCL will be applied at two different loads to gastrocnemius muscle of one leg starting immediately after reambulation to assess the effect of CCL on recovery of muscle size after atrophy. Muscles will be assessed for size immune cell infiltration degradation and regeneration and protein synthesis and degradation markers as well as force generating capacity. The experiments proposed in this application will indicate whether massage therapy is beneficial for muscle maintenance in general and muscle size and strength restoration in the aged in particular. The age- associated diminished capacity to recover muscle mass lost during disuse is of great clinical importance and it is critically important to develop strategies that can prevent inactivity-induced atrophy oraid in the recovery of muscle mass lost during disuse. If our results prove beneficial massage can be directly applied clinically for the maintenance and restoration of muscle size and strength.

project_terms:
Activities of Daily Living;Address;Age;Age-Months;Aging;Animals;Atrophic;Attenuated;Cells;Cellular Infiltration;Clinical;Data;Dependence;Development;Disease;Elderly;Energy Metabolism;Exercise;Exhibits;Frequencies (time pattern);Gastrocnemius muscle structure;Goals;Hindlimb;Immune;Immune response;Infiltration;Inflammatory;Inflammatory Response;Injury;Intervention;Leg;Limb structure;Maintenance;Massage;Measures;Modeling;Mortality Vital Statistics;Muscle;Muscle Proteins;Muscle function;Muscular Atrophy;NIH Program Announcements;Natural regeneration;Necrosis;Operative Surgical Procedures;Pathway interactions;Predisposition;Preventive Intervention;Process;Protein Biosynthesis;Proteins;Rattus;Rattus norvegicus;Recovery;Research;Signal Pathway;Skeletal muscle structure;Suspension substance;Suspensions;Testing;Time;Translating;age related;aged;clinical practice;frailty;improved;juvenile animal;male;muscle form;muscle strength;novel;prevent;protein degradation;public health relevance;repaired;research study;response;restoration;sarcopenia;therapy design

public_health_relevance:
Elderly exhibit a decreased ability to recover muscle mass and strength after periods of inactivity which can result in frailty and functional dependence. Thi research application proposes the use of massage to decrease muscle atrophy during disuse and to increase the ability to regrow muscle size after inactivity in the aged in a rat model. If or results prove beneficial massage can be directly applied clinically for the maintenance and restoration of muscle size and strength.


application_id: 8666634
project_number: 5R21DE023633-02
project_title: SGK1 is a Central Regulator of P. gingivalis-Induced Inflammation
administering_ic: NIDCR
award_notice_date: 2014-06-24
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: DE
serial_number: 023633
program_official: MELILLO, AMANDA A
project_start_date: 2013-07-01
project_end_date: 2016-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 16064057
contact_pi: WANG, HUIZHI
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Porphyromonas gingivalis (P. gingivalis) is a Gram-negative anaerobic bacterium and a causative agent of periodontitis.  Studies assessing the host inflammatory response to P. gingivalis have demonstrated that Toll-like receptor (TLR)-2 is the predominant TLR involved in the recognition of LPS and various other microbe-associated molecular patterns of P. gingivalis.  However the underlying cell-signaling pathways especially the intracellular regulatory molecules regulating the P. gingivalis (TLR2)-mediated inflammatory response are not fully understood. Using  siRNA  and  Cre/loxP  system  we have  for the first time  identified  that  serum-  and glucocorticoid-inducible kinase 1 (SGK1) suppresses P. gingivalis-mediated inflammatory responses in innate immune cells.  SGK1 is a ubiquitous serine/theronine kinase belonging to AGC kinase family (Protein kinase A -G and -C family) and can be activated by PI3 kinase.  Whereas the PI3K-Akt-GSK3- pathway has been demonstrated to play a critical regulatory role in TLR-mediated inflammatory responses the functional role of SGK1 in TLR-mediated immune responses is entirely unknown.  Therefore the studies proposed here are intend to identify and characterize how SGK1 regulates P. gingvalis induced inflammatory mediators as well as to delineate how the TLRs are involved in the phosphorylation and activation of SGK1. We hypothesize SGK1 is a critical kinase that controls inflammation of innate immune cells upon stimulation with P. gingivalis by regulating activation of Forkhead box protein O1 (FoxO1) and its downstream CCAAT/enhancer-binding protein beta (C/EBP-). This hypothesis is further substantiated by (i) the prediction of phosphorylation sites (by the software NetworKIN) identified FoxO1 as the optimum substrate of SGK1; (ii) our preliminary data showing that P. gingivalis stimulation phospho-activates SGK1 and abolishes the binding of FoxO1 to the promoter of C/EBP- in BMDC; and (iii) our recent publication demonstrating that PDK2 inhibition mediates FoxO1 nuclear sequestration and enhances TLR4 mediated inflammatory responses in innate immune cells (15). These observations provide a strong rationale for SGK1 in modulating P. gingivalis mediated inflammatory response via the TLR2-SGK1-FoxO1-C/EBP- axis.  The specific aims will establish the role for SGK1 as an endogenous inhibitor of the P. gingivalis-mediated inflammatory response and delineate how SGK1 is activated in response to P. gingivalis stimulation as well as determine if SGK1 negatively regulates P. gingivalis induced pro-inflammatory cytokines production via modification of the activity of FoxO1 and its downstream C/EBP- . Successful completion of this project will result in the isolation a novel and potentiall critical signaling pathway (TLR2-PI3K-SGK1-FoxO1-C/EBP- ) and greatly aid in the understanding of how the host inflammatory response is being regulated which will pave the way for the development of immunoregulatory therapeutics that should have relevance well beyond the oral cavity.

project_terms:
Affect;Atherosclerosis;Back;Binding (Molecular Function);Boxing;CCAAT-Enhancer-Binding Protein-beta;CCAAT-Enhancer-Binding Proteins;Cells;Chronic;Computer software;Cre-LoxP;Cyclic AMP-Dependent Protein Kinases;Data;Development;Diabetes Mellitus;Disease;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;Family;Figs - dietary;Genes;Glucocorticoids;Gram-Negative Anaerobic Bacteria;Immune;Immune response;Immune system;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Low Birth Weight Infant;Mediating;Microbe;Modification;Molecular;Nature;Nuclear;Oral cavity;Outcome;Pathway interactions;Pattern;Periodontitis;Periodontium;Phosphatidylinositols;Phosphorylation;Phosphorylation Site;Phosphotransferases;Play;Porphyromonas gingivalis;Predisposition;Process;Production;Promotor (Genetics);Protein-Serine-Threonine Kinases;Proteins;Publications;Receptor Signaling;Regulation;Role;Septic Shock;Serine;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;System;Systemic disease;TLR2 gene;TLR4 gene;Therapeutic;Time;Toll-Like Receptor 2;Toll-like receptors;Tretinoin;Work;base;cytokine;high reward;in vivo;inhibitor/antagonist;innovation;microbial;novel;nucleotide receptor;public health relevance;receptor;research study;response;success;therapeutic target

public_health_relevance:
Periodontitis is a chronic inflammatory disease and Porphyromonas gingivalis (P. gingivalis) is considered as a major causative agent. The host's immune response to P. gingivalis has been shown to play a fundamental role in the disease process by controlling the inflammatory response. Thus identifying the intracellular molecule that controls the host inflammatory response and elucidating the related mechanisms are critical for developing potential therapeutic targets to control periodontitis.


application_id: 8666588
project_number: 5R01HL112788-02
project_title: BIOACTIVE LIPIDS IN STEM CELL HOMING AND MOBILIZATION
administering_ic: NHLBI
award_notice_date: 2014-03-21
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 112788
program_official: THOMAS, JOHN
project_start_date: 2013-06-01
project_end_date: 2017-03-31
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 Factor;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;public health relevance;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: 8666401
project_number: 1U01FD004892-01
project_title: Evaluation of Dissolution Methods for Complex Parenteral Liposomal Formulations
administering_ic: FDA
award_notice_date: 2013-09-10
opportunity_number: RFA-FD-13-019
application_type: 1
activity_code: U01
ic: FD
serial_number: 004892
program_official: JIANG, WENLEI
project_start_date: 2013-09-15
project_end_date: 2014-10-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 7875468
contact_pi: ANDERSON, BRADLEY D
other_pis: BUMMER, PAUL M
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:
PROJECT SUMMARY/ABSTRACTDespite extensive study of liposomal drug formulations reliable in vitro methods to monitor liposomal drugrelease and predict in vivo performance are still lacking. Currently competing methods employed to assessliposomal release often produce disparate method-specific release profiles. Progress in the development ofrobust predictive release methods has been hindered by lack of systematic quantitative characterization ofthese complex drug delivery systems with respect to the myriad of factors that may contribute to drug releaseprofiles the wide range of dissolution media employed and a lack of mechanistic models that can reliablyaccount for these critical factors on drug release. The proposed study combines evaluation of judiciouslyselected methods to monitor in vitro drug release from liposomal dosage forms with comprehensivemechanism-based computational models that incorporate the intra-liposomal microenvironment dissolutionmedia and drug speciation (e.g. ionization state membrane binding complex formation self-associationetc.). Method robustness will be assessed by statistical analyses of key mechanistic parameters that governdrug release (e.g. rate constants) as established by the mathematical models developed by the project team.The proposed mechanism-based models will enable analysts to extract those underlying parameters drivingdrug release thereby unifying seemingly conflicting method-specific results while providing scientificallyfounded in vitro-in vivo correlations (IVIVC). Though focused on liposomal formulations containing doxorubicinthe underlying project concepts will be applicable to release testing and IVIVC for other complex parenteraldosage forms such as polymeric micelles nanosuspensions and other nanotechnology-based drug deliverysystems. Specific aims are as follows: 1) Construct mechanism-based mathematical models for liposomaldoxorubicin release simulate release profiles and analyze the sensitivity of current in vitro release methods toalterations in key model parameters due to formulation differences; 2) Prepare and characterize liposomeformulations similar in composition to marketed doxorubicin HCl liposome injections but varying in key selectedproperties (e.g. ammonium sulfate concentration pegylation particle size etc.); 3) Conductdissolution/release studies of liposome formulations from aim 2 using in vitro release methods identified in aim1 varying dissolution conditions to probe method performance and to validate/refine the mechanistic models topredict condition-specific release profiles; 4) Adapt the release methods and validated mechanism-basedmathematical models developed in previous aims to establish in vitro-in vivo correlations and thereby predict invivo release profiles from in vitro experimental data. The expected outcome of these studies is to transformcurrent empirically based testing approaches to one founded on a mechanistic understanding of the deliverysystem and its release characteristics in any given environment.

public_health_relevance:
The proposed study combines a rigorous evaluation of experimental methods for monitoring in vitro drugrelease from complex liposomal dosage forms with comprehensive mechanism-based computational modelsthat incorporate the intra-liposomal microenvironment dissolution media and drug speciation (e.g. ionizationstate membrane binding complex formation self-association etc.). The expected outcome of these studies isto transform current empirically based testing approaches to one founded on a mechanistic understanding ofthe delivery system and its release characteristics in any given environment.


application_id: 8665875
project_number: 5R21AI107978-02
project_title: Farnesylated effectors of Legionella
administering_ic: NIAID
award_notice_date: 2014-04-17
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 107978
program_official: ERNST, NANCY L
project_start_date: 2013-05-24
project_end_date: 2015-04-30
study_section: Special Emphasis Panel[ZRG1-IDM-A(80)S]
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_abstract:
DESCRIPTION (provided by applicant) Bacterial pathogens utilize type III-VII translocation systems to inject a large cadre of protein effectors into the host cell leading to modulation of cellular processes and manifestation of disease. Although many injected bacterial effectors are targeted into host cellular membranes to attain biological function the mechanisms of membrane targeting of injected bacterial effectors are not well understood. We have recently described a novel mechanism for anchoring an injected bacterial effector into host membranes through host-mediated farnesylation which covalently links a protein to a 15-carbon "farnesyl" lipid moiety. Farnesylation of proteins is a conserved eukaryotic post-translational lipidation of  conserved cysteine residue within the C-terminal teterapeptide "CaaX" motif of a protein. Farnesylation of hydrophilic proteins such as Ras enable the lipidated protein to be anchored into the lipid bi-layer of membranes to exhibit biological function.   
       Within amoeba and human cells the Legionnaires' disease bacterium Legionella pneumophila (Lp) resides and proliferate within an ER-remodeled Legionella-containing vacuole (LCV) which evades lysosomal fusion. Remodeling the LCV within amoeba and human cells is dependent on the Dot/Icm type IV secretion system which injects ~300 effectors into the host cell. We have shown that the Ankyrin B (AnkB) Dot/Icm-injected effector of Lp is anchored to the LCV membrane through host-mediated farnesylation of its "CaaX" motif which is indispensable for Lp intracellular proliferation.    
       Our preliminary data show that the host farnesylation enzymes are recruited to the cytosolic side of the LCV membrane which is novel among intra-vacuolar pathogens. The cytosolic side of the LCV membrane is highly enriched with other farnesylated proteins in addition to AnkB. In silico genomic analyses of Lp genomes have identified 6 Lp genes encoding novel proteins that harbor a C-terminal CaaX motif. The 6 encoded novel proteins are translocated into the host cell by the Dot/Icm system and have been designated as prenylated effectors of Legionella (Pel). When the Pels are ectopically expressed in human cells evidence suggests that the effectors associate with cellular membranes but this membrane localization is perturbed upon: 1) inhibition of host farnesylation; or 2) substitution of the conserved cysteine residue (pel C-A) within the CaaX motif of the Pels. Importantly a pelB null mutant and a pelB 502C-A substitution mutant exhibit similar severe defects in intracellular proliferation in macrophages. Therefore our hypothesis is: The injected novel Pel effectors are farnesylated by the host cell farnesylation machinery that targets them to specific cellular membranes to exhibit their functions required for intracellular proliferation of Lp. To test the hypothesis our
specific aims are to determine: I) Host mediated farnesylation and membrane-anchoring of the Pel effectors; and 2) Role of the pel effectors and their farnesylation in the intracellular infection by Lp.    
       The Significance of our studies: 1) Lp is a major cause of pneumonia; 2) The proposed studies will enhance our knowledge of Lp-host interaction through deciphering the role of novel translocated effectors in the intracellular infection; 3) Since our in silico genomic analyses show
prevalence of the C-terminal CaaX motif in effectors of other pathogens with type III-VII translocated systems our studies will stimulate investigations into a new paradigm in other pathogens; and 4) Our findings will contribute to our understanding the role of farnesylation in various human diseases such as Ras-mediated malignancies.   
       Innovation of the proposed studies come from: 1) the hypothesis; 2) hijacking the host farnesylation machinery by the pathogen-containing vacuole which is highly enriched with farnesylated proteins; 3) Novelty of the 6 Pels Dot/Icm-translocated effectors indicating novel functions in cellular modulations; 4) Our multidisciplinary approach of deciphering role of host-mediated lipidation of the Pel effectors combined with their biological functions in the intracellular infection by Lp; and 5) The major role for PelB and its C-terminal CaaX motif in the intracellular infection of human macrophages.

project_terms:
Abbreviations;Amoeba genus;Ankyrins;Bacteria;Biological Process;C-terminal;Carbon;Cell physiology;Cells;Cellular Membrane;Co-Immunoprecipitations;Computer Simulation;Cysteine;Data;Defect;Disease;Enzymes;Exhibits;Genes;Genome;Genomics;Human;Infection;Investigation;Knowledge;Legionella;Legionella pneumophila;Legionnaires' Disease;Link;Lipids;Malignant Neoplasms;Mediating;Membrane;Pneumonia;Prevalence;Proliferating;Protein Farnesylation;Proteins;Recruitment Activity;Role;Side;System;Testing;Transferase;Type IV Secretion System Pathway;Vacuole;farnesylation;human disease;innovation;interdisciplinary approach;macrophage;mutant;novel;pathogen;protein farnesyltransferase;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  To proliferate within cells intracellular bacterial pathogens inject protein effectors into the host cell that interact with specific host targets to remodel the
host cell into a niche permissive for bacterial proliferation. Some of the injected bacterial effectors are anchored into host membranes but the mechanisms involved in this membrane anchoring are not known. Host-mediated lipidation of the injected effector is a potential mechanism of membrane anchoring. Our proposed studies on Legionella pneumophila explore 6 injected bacterial effectors that have the potential to be lapidated by the host. We will deciphe the role of the 6 effectors and their lipidation and membrane anchoring in their biological function in intracellular bacterial proliferation.


application_id: 8665363
project_number: 5R01AG042475-02
project_title: CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD
administering_ic: NIA
award_notice_date: 2014-05-20
opportunity_number: PA-11-260
application_type: 5
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: 1884283
contact_pi: SCHEFF, STEPHEN W
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:
Actin-Binding Protein;Actins;Adult;Affect;Alzheimer's Disease;Amyloid;Antioxidants;Area;Binding (Molecular Function);Biochemical;Biological Markers;Brain region;Clinical;Cognition;Cognitive;Cytoskeletal Proteins;Data;Dementia;Development;Disease;Disease Progression;Early Diagnosis;Enzymes;Etiology;Event;Free Radicals;Functional disorder;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 Protein;Subcellular Fractions;Symptoms;Synapses;Synaptic plasticity;System;Temporal Lobe;Testing;cofilin;cognitive function;cohort;dentate gyrus;design;entorhinal cortex;frontal lobe;human tissue;hyperphosphorylated tau;insight;mental state;mild cognitive impairment;neurofibrillary tangle formation;novel;oxidative damage;pre-clinical;prevent;programs;public health relevance;research study;synaptic failure;tau Proteins;tau aggregation

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: 8663954
project_number: 5R01MH092226-04
project_title: A Clinic-Based Safer Sex Program for Young Black Men Who Have Sex with Men
administering_ic: NIMH
award_notice_date: 2014-05-12
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: MH
serial_number: 092226
program_official: KAMATH, SUSANNAH M A
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention (CDC) has termed AIDS a "health crisis" for African Americans and has called for a heightened national response. The crisis is especially dramatic in the South and it is now apparent that young African American men who have sex with men (MSM) are exceedingly likely to be infected. Unfortunately the ever-expanding HIV epidemic experienced by this population has not been matched by equal attention to the development of efficacious prevention programs. The proposed project expands upon an NIMH-funded study (R21 MH066682-01A1) conducted by Dr. Crosby. His study of young African American males found that a brief clinic-based intervention reduced incidence of subsequent STDs by about 50%. This brief one-on-one intervention program known as Focus on the Future (FOF) is a practical alternative to group-based safer sex programs that can be difficult to translate from science into practice. The program is now classified as a "Best Practice" intervention by CDC. This project will begin with an extensive formative phase designed to adapt FOF to MSM. The adapted program will seek to "sexualize" condoms to promote their consistent and correct use to better prevent STD/HIV. The program is uniquely flexible in that it can be applied to MSM regardless of their HIV serostatus. The adapted program will be tested by a two-arm efficacy trail. We will recruit 750 MSM (15-29 years of age) from a publicly-funded STD clinic in Jackson MS. Men in the treatment condition will be compared to men receiving the control condition comprised of standard of care counseling from the clinic plus a free ditty bag of supplies from the "condom and lube buffet" (condom/lube distribution). The trial will test five hypotheses. Men randomized to receive the intervention will: 1) have a lower incidence rate of laboratory-confirmed STDs (by urine assay and rectal swab) at each of three follow-up assessments (3 6 and 12 months) compared to controls; 2) report significantly fewer acts of unprotected penetrative sex (penile-vaginal or penile-anal) between follow-up assessments compared to controls; 3) report having significantly fewer unprotected penetrative (penile-vaginal or penile-anal) sex partners between follow-up assessments compared to controls; 4) report having significantly fewer negative experiences with condom use between follow-up assessments compared to controls; and 5) demonstrate significantly greater improvement in condom application skills throughout the 12-month study compared to those receiving the control condition. Given the dearth of evidence-based options for intervening with this vulnerable population in clinical settings demonstrated efficacy of the adapted program has important implications for public health efforts to prevent STD/HIV. The adapted FOF is also directly responsive to the President's National HIV/AIDS strategy particularly with regards to the target population of this proposal.

project_terms:
Acquired Immunodeficiency Syndrome;African American;Age-Years;Anal Sex;Anus;Attention;Behavior;Biological Assay;Biological Markers;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Clinical;Counseling;Development;Enrollment;Epidemic;Evidence based intervention;Funding;Future;Gays;Glare;Gonorrhea;HIV;Health;Heart;Hispanics;Incidence;Intervention;Laboratories;Methods;Modeling;National Institute of Mental Health (U.S.);Outcome;Patient Self-Report;Phase;Population;Prevention program;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Risk;Sampling;Science;Sexual Partners;Swab;Syphilis;Target Populations;Testing;Translating;Trichomonas Infections;Urine;Vagina;Vulnerable Populations;arm;base;clinical practice;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;evidence base;experience;flexibility;follow-up;high risk men;inclusion criteria;intervention effect;intervention program;male;men;men who have sex with men;novel;post intervention;prevent;programs;public health medicine (field);randomized trial;rectal;response;safer sex;sex;skills;standard of care;theories;therapy design;transmission process;two-arm study

public_health_relevance:
The proposed efficacy trial will occur in Jackson MS and it tests a brief clinic-based HIV/STD prevention program adapted specifically for young African American MSM. This program is based on a CDC-classified Evidenced-Based Intervention known as Focus on the Future. The randomized trial is designed with 3 follow-up assessments and it uses biomarker outcomes as well as a novel method of collecting self-reported outcomes.


application_id: 8663873
project_number: 5R01DC011285-04
project_title: Response of aging intrinsic laryngeal muscles to chronic electrical stimulation
administering_ic: NIDCD
award_notice_date: 2014-05-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DC
serial_number: 011285
program_official: SHEKIM, LANA O
project_start_date: 2011-06-22
project_end_date: 2016-05-31
study_section: Motor Function, Speech and Rehabilitation Study Section[MFSR]
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN A
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): This application is in response to the NIH Research Project Grant (Parent R01) (PA-10-067). As individuals age muscle weakness and the development of neuromuscular disorders have the potential to severely diminish the quality of one's life. The larynx is part of a complex sensorimotor system that serves as both a vibratory source for phonation and as a regulatory valving mechanism that protects the airway from the incursion of foreign bodies and food. In the elderly age-related changes in the laryngeal muscles may compromise voice quality impairing the ability of individuals to communicate and diminishing their ability to remain socially active and engaged. More significantly laryngeal muscle dysfunction may contribute to the emergence of dysphagia and subsequent increases in the risk of aspiration factors that contribute to higher rates of mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically therapies for certain voice disorders contend to use common principles of skeletal muscle rehabilitation in the hope of increasing muscle mass strength and endurance. However the rationale and applicability of limb muscle rehabilitation concepts to the laryngeal muscles has not been empirically tested. Therefore this proposal has three principle objectives:(1) to use chronic electrical stimulation as a fictive endurance "exercise" program in aging rat laryngeal muscle; (2) to characterize the morphological changes consequent to the fictive exercise model; and (3) to provide the background data to eventually extend these findings to clinical treatments with humans using vocal exercises. We will test the central hypothesis that the physiology of aged laryngeal muscle can be modified as a function of chronically-induced activity using the Fisher 344-Brown Norway F1 hybrid rat model of aging. We will examine to what extent chronic electrical stimulation remodels the aging posterior cricoarytenoid (PCA vocal fold abductor) and thyoarytenoid (TA vocal fold adductor) laryngeal muscles. Specific Aim I will examine the effects of chronic electrical stimulation on muscle morphology in aging PCA and TA. Specific Aim 2 will test whether chronic stimulation modifies the metabolic capacity in the aging PCA and TA muscles. Specific Aim 3 will determine to what extent chronic nerve stimulation will reverse functional denervation in aging laryngeal muscles. These studies will be a first test of the applicability of limb muscle rehabilitation interventions intended to effectively alleviate reverse and/or compensate for age-related dysfunction in the laryngeal muscles. This project will generate novel data to assist in the development of interventions aimed at preventing reversing and/or compensating for age-related dysfunction in the human larynx providing a first step toward testing the efficacy and legitimacy of current voice disorder interventions.

project_terms:
Aerobic;Affect;Age;Aging;Animal Model;Biochemistry;Chronic;Clinical Treatment;Complex;Data;Deglutition Disorders;Denervation;Development;Elderly;Electric Stimulation;Exercise;Exercise Physiology;Food;Foreign Bodies;Functional disorder;Human;Hybrids;Individual;Intervention;Laryngeal muscle structure;Larynx;Legitimacy;Life;Limb structure;Measures;Metabolic;Mitochondria;Modality;Modeling;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Motor;Muscle;Muscle Fibers;Muscle Weakness;Muscle denervation procedure;Muscle rehabilitation;Nerve;Neuromuscular Diseases;Neuromuscular Junction;Norway;Parents;Phenotype;Phonation;Physiological;Physiology;Population;Protocols documentation;Rattus;Rehabilitation therapy;Research Project Grants;Risk;Skeletal muscle structure;Source;Speech;Testing;Thyroarytenoid muscle structure;Training;United States National Institutes of Health;Voice;Voice Disorders;Voice Quality;Work;age related;aged;base;cricoarytenoideus;density;design;efficacy testing;indexing;muscle form;neurophysiology;novel;prevent;programs;research study;response;sensorimotor system;therapy development;vocal cord;voice therapy

public_health_relevance:
In older individuals changes in the laryngeal muscles may compromise voice quality impairing the ability to communicate and diminishing the ability to remain socially active and engaged. This project examines the muscle biophysiological changes that occur as a function of exercise and training using a well-accepted animal model for aging. Understanding the consequences of these changes is deemed important for eventually developing preventative and rehabilitative strategies for laryngeal muscle-related dysfunction in the older human population.


application_id: 8663184
project_number: 5R01AI101373-03
project_title: Role of Rapid IFNg Secretion by CD*+ T cells in Clearance of Food Borne Listeria
administering_ic: NIAID
award_notice_date: 2014-06-02
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 101373
program_official: MILLS, MELODY
project_start_date: 2012-06-20
project_end_date: 2016-05-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Listeria monocytogenes (Lm) is important an important pathogen to study because: 1) it causes life threatening food borne infections of significant public health concern 2) it is a genetically tractable organism with a unique intracellular lifestyle used as a tool for understanding the cell biology of mammalian cells and 3 systemic (i.v.) listeriosis is a highly reproducible infection frequently used by immunologists to study cell- mediated immune responses. Due to the lack of a small animal model that closely mimics human disease we still know very little about oral transmission of Lm or why the innate susceptibility to developing severe gastroenteritis sepsis and meningoencephalitis varies among individuals. To address this knowledge gap we recently developed a new model of oral listeriosis using mice fed Lm-contaminated food. This natural feeding model revealed clear differences in the ability of Lm to colonize the gut and spread systemically in susceptible (BALB) vs. resistant (B6) mice. Thus for the first time we can now study how gut-adapted Lm that survive digestive processes in the stomach are able to colonize the intestinal mucosa and serve as a nidus for continual seeding of peripheral tissues in susceptible mice unable to quickly clear the gut infection. Since the vast majority of patients hospitalized with listeriosis can be considered immune compromised in some way it has long been thought that protective immune responses were critical for limiting the infection to a mild gastroenteritis in resistant individuas. Our central hypothesis predicts that one such innate immune mechanism is the rapid secretion of IFN by a subset of memory phenotype CD8+ T cells. We postulate that T cell-derived IFN can rapidly initiate clearance mechanisms in B6 mice and that the delay in activation of CD8+ T cells in BALB mice allows Lm to replicate exponentially and spread to systemic tissues. This application has three specific aims: (1) to identify the cell types in the colon that support Lm growth and thus serve as the targets of protective innate immune responses; (2) to identify the specific subsets of CD8+ T cells that rapidly secrete IFN after ingestion of Lm and show that this T cell-derived IFN can rapidly limit the intracellular growth of Lm in the colon; (3) to idenify IFN-dependent innate immune mechanisms that promote rapid clearance of Lm in peripheral tissues after dissemination from the gut. A key strategy in this application will be the use of a unique adoptive transfer system wherein T cells from a responsive mouse are injected into a MHC-matched non-responsive mouse. This powerful approach will allow us to specifically isolate the function of IFN rapidly produced by CD8+ T cells while leaving all other innate immune mechanisms intact. The expected outcomes of the proposed studies are: [1] significant new insights into the pathogenic life style of food borne Lm and [2] a better understanding of the innate immune mechanisms that determine host resistance/susceptibility to intracellular bacterial pathogens.

project_terms:
Address;Adoptive Transfer;Animal Model;Antigens;Bacteria;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Cellular biology;Cheese;Colon;Dendritic Cells;Disease;Dose;Eating;Enterocytes;Feces;Food;Gastroenteritis;Gastrointestinal tract structure;Genes;Growth;Hepatocyte;Host resistance;Human;Immune;Immune response;Immunologist;In Vitro;Individual;Infection;Inflammatory;Ingestion;Interferons;Interleukin-12;Interleukin-18;Intestinal Mucosa;Intestines;Intravenous;Killings;Kinetics;Knowledge;Lamina Propria;Left;Life;Life Style;Listeria;Listeria monocytogenes;Listeriosis;Liver;Lymphocyte;M cell;Mammalian Cell;Meat;Memory;Meningoencephalitis;Modeling;Mortality Vital Statistics;Mus;Natural Immunity;Oral;Organism;Outcome;Pathway interactions;Patients;Peripheral;Phenotype;Population;Predisposition;Process;Proteins;Research Personnel;Resistance;Role;Seeds;Sepsis;Septicemia;Severities;Signal Transduction;Small Intestines;Source;Spleen;Stomach;Symptoms;System;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Time;Tissues;adaptive immunity;cell mediated immune response;cell type;cytokine;feeding;foodborne;foodborne infection;human disease;in vivo;insight;macrophage;oral infection;pathogen;public health medicine (field);receptor;response;tool;transmission process

public_health_relevance:
Listeria monocytogenes (Lm) is transmitted by ingestion of contaminated "ready-to-eat" food products such as unpasteurized cheeses deli meats and produce. Human infections vary greatly in severity from a mild self- limiting gastroenteritis to life-threatening septicemia and meningoencephalitis and the host susceptibility factors that contribute to this range of disease are not defined. In this study we test the idea that resistantindividuals respond to infection by rapidly producing a protective protein that activates multiple killing mechanisms that quickly clear the bacteria while susceptible individuals lack the ability t orchestrate this rapid immune response.


application_id: 8663176
project_number: 5R01AI087849-04
project_title: Biosynthesis of nucleoside antibiotics targeting bacterial translocase
administering_ic: NIAID
award_notice_date: 2014-05-12
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AI
serial_number: 087849
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2016-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The emergence of multiple drug resistant pathogens is becoming problematic worldwide and the discovery of new antibiotics continues to decline. The broad long-term objective of this proposal is to discover characterize and develop a new structural class of antibiotics-nucleoside antibiotics-that target bacterial translocase I involved in peptidoglycan cell wall biosynthesis. The specific aims of this proposal are (I) to characterize the assembly and incorporation of the aminoribosyl moiety found within the family of lipopeptidyl-nucleoside antibiotics and (II) to functionally and mechanistically characterize enzymes catalyzing novel or unusual biochemical reactions represented herein by a new family of serine hydroxymethyltransferase-like enzymes that are hypothesized to catalyze an aldol-type condensation to form unusual nonproteinogenic amino acids. Specific Aim I and II will be achieved by using the robust genetic system developed for the lipopeptidyl nucleoside A-90289-producing strain for in vivo studies employing gene inactivation and cross-complementation and recombinant proteins will be exploited for functional and mechanistic studies in vitro. The results will establish a new mechanism for incorporating ribosyl units into natural product scaffolds and will establish a paradigm for the entry into high-carbon nucleoside antibiotics. The results will be essential for our long-term goals of searching for new nucleoside antibiotics using genetic information (a genotype-to-chemotype approach) will allow for the structural diversification of the parent scaffolds using combinatorial biosynthesis and total synthesis and will provide the basis for the design of second generation antibiotics with improved biocompatibility and pharmacological properties.

project_terms:
3-hydroxybutanal;Acquired Immunodeficiency Syndrome;Amino Acids;Anabolism;Animals;Anti-Bacterial Agents;Antibiotics;Bacteria;Biochemical;Biochemical Reaction;Biological Assay;Biological Factors;Carbon;Case Study;Cell Wall;Cessation of life;Clinic;DNA Fingerprinting;Development;Disease;Drug resistance;Drug resistance in tuberculosis;Enzymes;Family;Fluorescence;Gene Silencing;Generations;Genes;Genetic;Genotype;Glycine Hydroxymethyltransferase;Goals;Health;Hexoses;Hospitals;Human;In Vitro;Infection;Killings;Libraries;Modeling;Modification;Multi-Drug Resistance;Natural Product Drug;Nucleosides;Parents;Peptidoglycan;Pharmaceutical Preparations;Physical condensation;Property;Reaction;Recombinant Proteins;Research;Streptomyces;Structure-Activity Relationship;System;Testing;Tuberculosis;United States;base;biomaterial compatibility;combinatorial;community setting;design;drug discovery;expectation;improved;in vivo;inhibitor/antagonist;methicillin resistant Staphylococcus aureus (organism);novel;pathogen;public health medicine (field);scaffold;sugar;tool;translocase

public_health_relevance:
Diseases caused by multidrug resistant bacteria are becoming a significant threat to human health worldwide. The goal of this proposal is to study nucleoside antibiotics that represent a new structural class of antibiotics have a different mode of action than clinically used antibacterial drugs and are in general not toxic to animals.


application_id: 8662734
project_number: 5R01DA033932-02
project_title: Evaluation of Novel Pharmacotherapies for the Treatment of Opioid Dependence
administering_ic: NIDA
award_notice_date: 2014-06-03
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DA
serial_number: 033932
program_official: ANDERSON, ANN
project_start_date: 2013-06-01
project_end_date: 2017-05-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prescription opioid abuse and dependence are increasing public health problems in the U.S. with nearly 2 million people meeting DSM-IV criteria for a prescription opioid use disorder. While treatment demand continues to grow only three medications are FDA-approved and a broader spectrum of treatment options is needed. A large body of evidence supports the hypothesis that cannabinoid (CB) agonists may be useful pharmacotherapies for the treatment of opioid dependence. CB agonists are already approved available for human testing and used for indications relevant to opioid withdrawal symptomatology. Two proof-of-concept placebo-controlled inpatient laboratory-based studies are proposed to evaluate the efficacy of the CB agonists dronabinol and nabilone. Experiments 1 and 2 will employ within-subject crossover designs with the classic morphine substitution procedure whereby opioid dependent volunteers (n=10/study) are stabilized on a fixed dose of morphine (15 mg/qid). On a scheduled basis subjects receive double-blind substitution of placebo for morphine to induce a period of spontaneous opioid withdrawal. Double-blind test doses are then administered to determine their ability to suppress opioid withdrawal signs and symptoms as the initial target for potential efficacy in treatment. Exp. 1 will examine dronabinol (5 10 20 and 30 mg) and Exp. 2 will examine nabilone (1 2 4 and 6 mg) for efficacy and safety; each of these studies includes positive (morphine 15 and 30 mg) and negative (placebo) control conditions. A broad array of physiological subjective observer-rated and psychomotor performance measures will be collected to assess safety tolerability and efficacy at withdrawal suppression. These studies are innovative and significant as they are the first to our knowledge to examine the efficacy of CB1 agonists as potential pharmacotherapies for the treatment of opioid dependence in humans and will yield new data on the interaction of CB1 and opioid systems. Moreover they will provide critical data to guide drug and dose selection for future studies aimed at examining their potential efficacy for use in the treatment of opioid dependence for maintenance relapse prevention ambulatory detoxification and/or as transitional agents for initiating opioid antagonist therapy.

project_terms:
Acquired Immunodeficiency Syndrome;Adverse effects;Adverse event;Agonist;Analgesics;Appetite Stimulants;Area;Body Weight decreased;Brain region;Cannabinoids;Caring;Cessation of life;Chronic;Clinical;Crossover Design;DSM-IV;Data;Data Collection;Dependence;Disease;Dose;Double-Blind Method;Drug Metabolic Detoxication;Drug usage;Employment;Evaluation;Future;Gold;Health;Human;Individual;Inpatients;Label;Laboratories;Lead;Life Style;Mainstreaming (Education);Maintenance;Maintenance Therapy;Marketing;Measures;Medical;Methodology;Morphine;Nabilone;Narcotic Antagonists;Nature;Nausea and Vomiting;Nociception;Opiate Addiction;Opioid;Outcome;Pain;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Physiological;Placebo Control;Placebos;Population;Procedures;Psychomotor Performance;Receptor Cannabinoid CB1;Receptors Opioid mu;Relapse;Reporting;Research;Research Design;Rewards;Safety;Schedule;Seminal;Signs and Symptoms;Surveys;System;Testing;Tetrahydrocannabinol;United States Food and Drug Administration;Urine;Wasting Syndrome;Withdrawal;Withdrawal Symptom;Work;addiction;base;chemotherapy;design;disorder later incidence prevention;drug testing;efficacy testing;human data;innovation;meetings;novel;opioid misuse;opioid withdrawal;parole;pre-clinical;prescription opioid;prescription opioid abuse;public health medicine (field);public health relevance;research study;social stigma;volunteer

public_health_relevance:
This research will provide important information regarding the potential benefits and safety of using marketed cannabinoid pharmaceuticals for the treatment of prescription opioid dependence a public health problem that has grown dramatically over recent years. Moreover this work will provide new information on the safety of cannabinoids in individuals dependent on opioids.


application_id: 8662211
project_number: 5R03CA156561-02
project_title: Clinical characteristics and patterns of care for rare brain tumor sub-types
administering_ic: NCI
award_notice_date: 2014-04-14
opportunity_number: PAR-12-039
application_type: 5
activity_code: R03
ic: CA
serial_number: 156561
program_official: SHELBURNE, NONNIEKAYE F
project_start_date: 2013-05-15
project_end_date: 2016-04-30
study_section: ZCA1-SRLB-4(J2)
contact_pi_person_id: 8541678
contact_pi: VILLANO, JOHN LEE
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): With over 100 different histological subtypes many rare brain and CNS tumor histologies cannot be adequately assessed for factors that may influence treatment or survival patterns. An estimated 1000 ependymomas 1200 primary CNS lymphomas 100 choroid plexus tumors and 100 pineal parenchymal tumors are reported in the United States per year. Because of the small number of individuals who develop these tumors studies are often restricted and may not provide information representative of the general population. The National Cancer Data Base (NCDB) is the largest clinical database in the world and collects information on all cancers including all primary brain and CNS tumors from Commission on Cancer accredited institutions representing about 70% of all cancer cases diagnosed in the U.S. The NCDB collects a wealth of demographic tumor characteristic treatment and follow-up (survival) data. The goal of this proposal is to describe presenting clinical characteristics and treatment and survival patterns for patients diagnosed with a subset of the rarest brain and CNS tumor subtypes mainly ependymomas primary CNS lymphomas choroid plexus tumors and pineal parenchymal tumors using data from the NCDB. A second goal of this proposal is to conduct a comprehensive evaluation of clinical or treatment factors that may influence survival time. We anticipate that approximately 7000 ependymomas 8500 primary CNS lymphomas 600 choroid plexus tumors and 250 pineal parenchymal tumors will be available for analyses for the years 1998 - 2010 providing a large and diverse data set for analyses of these important tumors.

project_terms:
Achievement;American College of Surgeons;Benchmarking;Biological;Brain;Brain Neoplasms;Caring;Central Nervous System Lymphoma;Central Nervous System Neoplasms;Characteristics;Choroid Plexus Neoplasms;Clinical;Data;Data Set;Databases;Diagnosis;Ependymoma;Evaluation;General Population;Glioma;Goals;Grouping;Histology;Hospitals;Individual;Institution;Malignant Neoplasms;Masks;Medical;Neuraxis;Outcome;Patients;Pattern;Patterns of Care;Persons;Pineal Gland Neoplasm;Population;Population Heterogeneity;Primary Brain Neoplasms;Reporting;Research;Sample Size;Source;Subgroup;Time;Treatment Factor;Tumor Subtype;United States;base;follow-up;improved;public health relevance;research clinical testing;treatment site;tumor

public_health_relevance:
The proposed descriptive study will provide baseline information on clinical characteristics and patterns of care and outcomes for a large and diverse population of patients with rare brain tumor subtypes. This study has the potential to make valuable contributions to better understand and inform future research by accurately describing these rare tumors independent of other tumor histologies and guide the achievement of optimal medical management.


application_id: 8658871
project_number: 5R01NS083405-02
project_title: Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
administering_ic: NINDS
award_notice_date: 2014-06-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 083405
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;3-nitrotyrosine;4 hydroxynonenal;Aldehydes;Antioxidants;Attenuated;Brain;Brain Injuries;Buffers;Calcium;Calpain;Clinical Trials;Complex;Cyclosporine;Dose;Effectiveness;Elements;Extravasation;Failure (biologic function);Free Radicals;Functional disorder;Future;Generations;Goals;Human;Impairment;Injury;Intervention;Lesion;Lipid Peroxidation;Lipids;Logic;Mediating;Membrane Lipids;Mitochondria;Modeling;Molecular;Mortality Vital Statistics;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurologic;Neurons;Patients;Permeability;Peroxonitrite;Pharmaceutical Preparations;Phase III Clinical Trials;Phenelzine;Post-Translational Protein Processing;Production;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery of Function;Regimen;Reporting;Subarachnoid Hemorrhage;Testing;Therapeutic;Tissues;Translating;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;Treatment Protocols;Tyrosine;attenuation;base;cognitive function;controlled cortical impact;design;improved;inhibitor/antagonist;injured;lipid peroxidation inhibitor;mitochondrial dysfunction;neuroprotection;neurotoxic;nitration;oxidative damage;protective effect;public health relevance;relating to nervous system;research study;respiratory;response;success;treatment strategy

public_health_relevance:
This project will examine the potentially greater benefits that might be obtained in the rat controlled cortical impact traumatic brain injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a combination multi-mechanistic antioxidant treatment strategy combining two or three of the following mechanistically complimentary antioxidant compounds: 1) the lipid peroxidation-inhibiting drug U-83836E 2) the commercially available compound phenelzine that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4- hydroxynonenal (4-HNE) and 3) the extensively demonstrated mitochondrial protective compound cyclosporine A(CsA) which reduces post-TBI mitochondrial permeability transition and free radical leakage. After determining the best neuroprotective dose optimal treatment regimen and therapeutic efficacy window of each compound pharmacologically-optimized dosing regimens of each of the compounds will be compared in a single experiment. This will be followed by the testing of the combination effectiveness of two (U-83836E + phenelzine U-83836E + CsA phenelzine + CsA) or all three (U-83836E + phenelzine + CsA).


application_id: 8658392
project_number: 5R01CA133171-05
project_title: The role of the Ras effector Nore1a in tumor suppression
administering_ic: NCI
award_notice_date: 2014-04-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133171
program_official: WATSON, JOANNA M
project_start_date: 2010-07-01
project_end_date: 2017-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nore1a is a member of the RASSF family of tumor suppressors. It is frequently down- regulated in primary human tumors and is genetically linked to a familial human cancer syndrome. Over-expression of Nore1a can promote apoptosis cell cycle arrest and senescence. Restoration of Nore1a expression to physiological levels blocks the tumorigenic phenotype and shRNA mediated inactivation of Nore1a enhances the transformed phenotype. Thus the evidence that Nore1a is an important human tumor suppressor is strong. Nore1a also directly binds the Ras oncoprotein and appears to serve as a novel effector mediating some of the pro-apoptotic and pro-senescent effects of oncogenic Ras. Thus loss of function of Nore1a may be particularly important to Ras dependent tumors allowing oncogenic Ras to circumvent its apoptotic and senescent functions. However the signaling pathways controlled by Nore1a have not been defined and no animal model for Nore1a function has been investigated. Furthermore the effects of loss of Nore1a function on the transforming effects of oncogenic Ras have not been characterized.  Nore1a lacks obvious enzymatic activity and little is known about its mechanism of action. However it has been hypothesized that it may serve as a scaffolding protein to modulate the formation of tumor suppressor complexes. We have now identified two tumor suppressors in endogenous complex with Nore1a: the Homeodomain Interacting Protein Kinase 2 (HIPK2) protein and the Von Hippel-Lindau protein (VHL) a notorious tumor suppressor which plays a critical role in the development of the majority of Renal Cell Carcinomas (RCC). Both HIPK2 and VHL act in part by directly modulating the master tumor suppressor p53. Defects in p53 have been detected in approximately 50% of human tumors and it may be argued that p53 is the most critical tumor suppressor yet identified. Thus Nore1a may function by modulating p53 by dual pathways and could serve as part of the well known but poorly characterized link between Ras and p53.  We propose a series of experimental aims designed to determine the precise role of Nore1a loss of function in the development of the tumorigenic phenotype and in Ras mediated transformation. This includes a proposal to determine the role of the Nore1a/Ras interaction in vivo using a novel Nore1a knockout mouse model. We will then determine if the mechanism of action of Nore1a involves the modulation of the HIPK2 or VHL tumor suppressors and whether Nore1a acts to integrate their effects upon p53. We anticipate that these experiments will identify Nore1a as an important novel diagnostic and therapeutic target for cancer.

project_terms:
Animal Model;Apoptosis;Apoptotic;Binding (Molecular Function);Cell Cycle Arrest;Complex;Defect;Development;Diagnostic;Epigenetic Process;Family;Human;Knockout Mice;Link;Malignant Neoplasms;Mediating;Oncogene Proteins;Oncogenic;Pathway interactions;Phenotype;Physiological;Play;Prognostic Marker;Protein Kinase;Protein p53;Proteins;Renal Cell Carcinoma;Role;Scaffolding Protein;Series;Signal Pathway;Signal Transduction;Syndrome;Tumor Suppression;Tumor Suppressor Proteins;VHL protein;Von Hippel-Lindau Tumor Suppressor Protein;design;homeodomain;in vivo;loss of function;member;mouse model;neoplastic cell;new therapeutic target;novel;novel diagnostics;public health relevance;research study;restoration;senescence;small hairpin RNA;tumor;tumorigenic

public_health_relevance:
These studies will serve to define the role of a novel potential tumor suppressor Nore1a in human cancer. They will determine if Nore1a is an important diagnostic/prognostic marker for cancer. They will also determine if Nore1a may be a suitable candidate for the development of epigenetic therapy to restore its normal function in tumor cells.


application_id: 8657965
project_number: 5R01AG027297-08
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2014-03-21
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 027297
program_official: WISE, BRADLEY C
project_start_date: 2006-09-01
project_end_date: 2017-03-31
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 A?40 and A?42 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;Promotor (Genetics);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;improved;in vivo;inhibitor/antagonist;innovation;interest;mouse model;neuroinflammation;neuropathology;neuroprotection;novel strategies;prevent;protein expression;relating to nervous system;research study;response;signal processing;synaptic function;transcription factor;treatment strategy;vector


application_id: 8657963
project_number: 5R37AG004542-25
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2014-03-21
opportunity_number: PA-10-067
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: WISE, BRADLEY C
project_start_date: 1998-01-01
project_end_date: 2016-02-29
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
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):  This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP) that follows a burst of action potentials in hippocampal pyramidal neurons is larger in aged than in young-adult animals. Importantly larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely smaller sAHPs are found in animals that learn a task. Since then we and others have determined that Ca2+ action potentials Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a) leads to a cascade of RyR destabilization greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging immunohistochemistry and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.

project_terms:
Action Potentials;Affect;Age-Years;Aging;Alzheimer's Disease;Animals;Base of the Brain;Behavior;Behavioral;Binding (Molecular Function);Binding Proteins;Biological Markers;Brain;Brain-Derived Neurotrophic Factor;Calcium;Chronic;Control Animal;Data;Disinhibition;Down-Regulation;Elderly;Electrophysiology (science);Exposure to;Fostering;Genes;Genomics;Goals;Healthcare Systems;Heart failure;Hippocampus (Brain);Image;Immunohistochemistry;Immunophilins;Impaired cognition;Intervention;Intervention Studies;Lead;Learning;Maze Learning;Mediating;Memory;Methods;Microarray Analysis;Microinjections;Modeling;Molecular;Muscle Cells;Neurons;Open Reading Frames;Outcome;Outcome Measure;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Population;Process;Progress Reports;Protein Isoforms;Proteins;Protocols documentation;Quality of life;RNA;Rattus;Regulation;Regulatory Pathway;Role;RyR2;Ryanodine Receptors;Severities;Sirolimus;Slice;Small Interfering RNA;Structure;Synapses;Tacrolimus Binding Proteins;Techniques;Testing;Therapeutic;United States;Up-Regulation (Physiology);Viral Vector;Work;adeno-associated viral vector;age related;aged;aging brain;aging hippocampus;aging population;base;behavior test;cognitive function;gene therapy;hippocampal pyramidal neuron;human FRAP1 protein;in vivo;innovation;interdisciplinary approach;knock-down;mTOR protein;mature animal;neuronal excitability;novel;overexpression;prevent;protein expression;public health relevance;response;vector;voltage;young adult

public_health_relevance:
The aging population of the United States is projected to increase at a dramatic rate with numbers that will undoubtedly impact our healthcare system (20% of the population will be >65 years of age by the year 2030). Cognitive decline frequently accompanies aging and depending on the severity can significantly affect quality of life. Our results indicate that a specific pathway (FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain aging and cognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial therapeutic implications.


application_id: 8657873
project_number: 5R01CA149274-05
project_title: Diffuse Optical Monitoring of Head and Neck Tumor Therapy
administering_ic: NCI
award_notice_date: 2014-05-01
opportunity_number: PA-07-279
application_type: 5
activity_code: R01
ic: CA
serial_number: 149274
program_official: BAKER, HOUSTON
project_start_date: 2010-07-01
project_end_date: 2016-04-30
study_section: Biomedical Imaging Technology Study Section[BMIT]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Treatment with radiation or chemo-radiotherapy is the standard therapy for head and neck cancers but thistreatment is well known to be less efficacious in patients with hypoxic tumors. Furthermore cancer therapymay alter tumor physiological status thus impacting treatment efficacy. Factors that modulate tumoroxygenation include blood flow blood oxygenation oxygen metabolism and nicotine levels (i.e. tobacco use).Tumor hemodynamics and metabolism however are not routinely measured during cancer therapy due to thelack of appropriate technologies. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are thebest currently available and reproducible methods to measure target lesions selected for objective responseassessment but these modalities require large and costly instrumentation that severely limits their routine usein clinics. The capabilities of diffuse optics for continuously monitoring tumor hemodynamics and metabolismduring therapy at the clinical bedside have recently been demonstrated in our preliminary studies. Theobjective of this project is to develop and optimize a noninvasive versatile multi-modality clinical opticalinstrument to aid in evaluating and predicting tumor responses at the most early stage possible. Morespecifically this optical instrument will monitor and predict hemodynamic and metabolic responses to chemo-radiotherapy in head and neck tumors. We hypothesize that functional assessment of tumor physiologicalstatus and dynamic changes during therapy will provide information for early prediction of long-term treatmentoutcomes thus enabling clinicians to optimize therapy for each patient in a time sensitive fashion. To achievethis goal we will assemble a hybrid flow and oxygen system that combines a newly developed diffusecorrelation spectroscopy (DCS) flowmeter with a commercial tissue-oximeter for simultaneous measurement oftumor blood flow oxygenation and oxygen metabolism (derived from the flow and oxygenation data). Theinstrument including optical probes and a software platform will be tested and optimized for continuous andlongitudinal monitoring of tumor physiological status and hemodynamic/metabolic changes before during andafter therapy in patients including smokers and nonsmokers (n=125). It is anticipated that significantcorrelations will be observed between therapy outcomes (e.g. tumor volume change tumor toxicity time todisease recurrence survival) and tumor physiological status and changes as well as nicotine levels. Differenttypes of physiological parameters may show different sensitivities to cancer therapy in each patient whichcould reveal the primary factor(s) affecting individual therapy outcomes. Our novel hybrid optical system willprovide hemodynamic and metabolic imaging contrasts complementary to those of CT and MRI and holdsunique potential for early evaluating and predicting cancer therapy responses. Our long-term goal is to developrobust scientific collaborations to optimize and individualize cancer therapy at early stages with noninvasiveoptical technologies.

project_terms:
Accounting;Acute;Affect;Aftercare;Blood;Blood Volume;Blood flow;Cessation of life;Clinic;Clinical;Collaborations;Computer software;Cotinine;Data;Data Analyses;Data Collection;Devices;Diffuse;Disease;Drug Delivery Systems;Evaluation;Exhibits;Fiber Optics;Flowmeters;Forearm;Goals;Head and Neck Cancer;Head and Neck Neoplasms;Hybrids;Hypoxia;Image;Individual;Lesion;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolism;Methods;Modality;Monitor;Muscle;Nicotine;Non-smoker;Optical Instrument;Optical Methods;Optics;Outcome;Oxygen;Patient Care;Patients;Physiological;Progressive Disease;Property;Radiation;Recurrence;Reporting;Research;Roentgen Rays;Scanning;Serum;Smoker;Smoking;Spectrum Analysis;Stable Disease;Staging;System;Technology;Testing;Time;Tissues;Tobacco use;Toxic effect;Treatment Efficacy;Treatment outcome;Tumor Oxygenation;Tumor Volume;Ultrasonography;Withdrawal;X-Ray Computed Tomography;base;blood flow measurement;cancer therapy;chemoradiation;chemotherapy;cost;design;follow-up;hemodynamics;improved;insight;instrument;instrumentation;novel;prognostic;prototype;response;simulation;therapy outcome;tissue phantom;tool;treatment duration;treatment planning;tumor

public_health_relevance:
Project Narrative:Treatment with radiation alone or in combination with chemotherapy is standard therapy for the head and neckcancers but this treatment is well known to be less efficacious in patients with poorly-vascularized/hypoxictumors. The objective of this project is to develop and test a low-cost clinical-level optical instrument that canquickly assess tumor hemodynamic and metabolic status and responses to cancer therapy in the early stages.This in depth assessment of tumor hemodynamic and metabolic properties will provide essential informationfor the early prediction and evaluation of treatment outcomes thus enabling clinicians to optimize individualtreatment.


application_id: 8657840
project_number: 5R01CA131075-05
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2014-04-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 131075
program_official: OKANO, PAUL
project_start_date: 2010-07-01
project_end_date: 2016-04-14
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
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): We seek to understand the molecular responses that occur when skin is exposed to UV radiation in order to devise novel strategies to protect against damage and carcinogenesis. In this proposal we will examine two major risk factors for skin cancer: UV radiation and pigment (melanin) phenotype. Our studies focus on the melanocyte and its cell surface receptor the melanocortin-1 receptor (Mc1r) which regulates melanin synthesis. We hypothesize that Mc1r protects melanocytes against UV-mediated mutagenesis and transformation by modulating melanization and recovery from UV-mediated cellular injury. Loss-of-function polymorphisms in Mc1r correlate with fair skin and a high incidence of melanoma while robust Mc1r function correlates with darker skin and UV resistance. We have developed a novel genetically-matched murine model of human skin as well as a protocol for growing primary melanocytes from these mice. These isogenic melanocytes span eumelanotic pheomelanotic and amelanotic melanin composition will serve a unique and potent tool to delineate the role of Mc1r function in response to UV. Using our unique animal model and primary melanocytes derived thereof we propose the following aims: Aim 1. Characterize the mechanism of Mc1r-mediated enhancement of nucleotide excision repair (NER); Aim 2. Determine whether Mc1r signaling protects against UV-mediated oxidative damage; and Aim 3. Determine the ability of pharmacologic Mc1r rescue to protect against UV damage. With respect to Aim 1 we will examine the role of Mc1r in the repair of UV-induced photolesions by southwestern and flow cytometric analysis and determine the influence of Mc1r on cellular levels of nucleotide excision repair enzymes by qRT-PCR and Western analysis. We will investigate a molecular link between Mc1r signaling and enhanced repair enzyme levels by examining expression of the NER enzymes basally and in the setting of UV irradiation and by investigating the ability of cAMP-responsive transcription factors downstream of Mc1r signaling (namely Mitf and CREB) to bind to and induce transcription of NER enzyme promoters. In Aim 2 we will study whether pheomelanin which is produced as a result of low Mc1r function promotes oxidative damage in melanocytes by complementary measures of oxidative load (DCF-mediated fluorescence flow cytometry Southwestern blotting hOGG1-adapted Comet assay TBARS assay and direct quantification of oxidative DNA adducts by GC/MS). Importantly we will directly test whether  pheomelanin functions as a pro-carcinogen by an HPRT-based forward mutagenesis approach in primary melanocytes. Finally we will directly test the ability of forskolin an activator of adenylyl cyclase to bypass defective Mc1r function to enhance recovery from UV-mediated DNA damage and to rescue UV protection in melanocytes and in whole skin. Together these studies will lay the foundation for future translational studies designed to develop novel small molecule-based approaches for UV and cancer protection to prevent many cases of melanoma.

project_terms:
Address;Adenylate Cyclase;Animal Model;Automobile Driving;Binding (Molecular Function);Biological Assay;Bypass;CREB1 gene;Carcinogens;Cell Line;Cell Surface Receptors;Cells;Comet Assay;Cyclic AMP;DNA;DNA Adducts;DNA Damage;DNA Repair;Defect;Exposure to;Flow Cytometry;Fluorescence;Forskolin;Foundations;Future;Genes;Genetic Polymorphism;Genetic Transcription;Goals;Human;In Vitro;Incidence;Individual;Injury;Link;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Methods;Modeling;Molecular;Monophenol Monooxygenase;Mus;Mutagenesis;Nucleotide Excision Repair;Phenotype;Pigmentation physiologic function;Pigments;Primary Cell Cultures;Promotor (Genetics);Protocols documentation;Receptor Signaling;Receptor Melanocortin Type 1;Recovery;Research Design;Resistance;Risk Factors;Role;Skin;Skin Cancer;Skin Pigmentation;Southwestern Blotting;Sun Exposure;Surface;System;Testing;The Sun;UV induced;UV induced DNA damage;UV protection;UV response;Ultraviolet B Radiation;Ultraviolet Rays;Variant;alpha-Melanocyte stimulating hormone;base;carcinogenesis;cell injury;congenic;defined contribution;eumelanin;high risk;loss of function;melanocyte;melanoma;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;public health relevance;receptor;receptor binding;receptor function;repair enzyme;repaired;research study;response;small molecule;synthetic enzyme;tool;transcription factor;translational study;ultraviolet damage;ultraviolet irradiation

public_health_relevance:
Though it has long been known that people with functional defects of the melanocortin 1 receptor (Mc1r) protein are at high risk of developing melanoma the way(s) in which Mc1r protects against melanoma are not understood. Using pigment cells known as melanocytes we will study how the Mc1r protein influences UV- mediated DNA and cellular damage in melanocytes and contributes to melanoma resistance. Our goal is to develop the strategy of pharmacologic Mc1r rescue toward translational applicability so that many cases of melanoma can be prevented.


application_id: 8657838
project_number: 5R01CA128903-05
project_title: Chemical Probes of Immunoproteasome Function in Cancer
administering_ic: NCI
award_notice_date: 2014-04-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 128903
program_official: FU, YALI
project_start_date: 2010-06-07
project_end_date: 2016-04-30
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 essential roles of the ubiquitin-proteasome system (UPS) in many cellular processes are now well recognized. However many questions still remain unanswered. Intriguing yet not fully understood are the functions of the immunoproteasome an alternative form of the constitutive proteasome. It has been shown that the roles of the immunoproteasome in cells are not just limited to the generation of antigenic peptides but far more multifaceted. In this regard recent studies have shown that catalytic subunits of the immunoproteasome are implicated in various types of diseases including cancer. Despite these therapeutic implications the immunoproteasome remains largely untapped for cancer drug discovery. A better understanding of immunoproteasome functions would be crucial in developing the optimum LMP2 inhibitor(s). In our continuing efforts to better understand the role of the immunoproteasome in cells we have recently developed a small molecule probe ('UK-101') that specifically targets LMP2 a major catalytic subunit of the immunoproteasome. Further we found that LMP2 is highly expressed in several types of primary tumor tissues and cancer cell lines. Interestingly cancer cells that highly express LMP2 are markedly more sensitive to UK-101 than those expressing low level of LMP2. Consistent with these in vitro results UK-101 inhibits tumor growth in a mouse xenograft model of human prostate tumor that highly expresses LMP2 but not that of tumor that expresses low level of LMP2. These observations further support a potential role of LMP2 in cancer cell growth and survival. The goals of this application are to determine the roles of the immunoproteasome in prostate cancer and to investigate therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy. Towards this goal we propose to use innovative chemical probes that selectively target and visualize individual catalytic subunits of the immunoproteasome. In order to accomplish this goal four specific aims are proposed: 1) To validate the immunoproteasome as the major pharmacological target of UK-101 2) To determine dynamic cellular distribution of the catalytically active immunoproteasome and 3) To determine the unique functions of the immunoproteasome compared to the constitutive proteasome and 4) To develop an optimum LMP2 inhibitor(s) by generating a structurally diversified small molecule library. The proposed work integrates both chemical and biological approaches. Successful completion of the project will significantly expand our knowledge on the role of the immunoproteasome. In addition the study will yield critical information in developing immunoproteasome-specific inhibitors as a potential therapeutic agent. Finally small molecule probes that will be used in this application will provide valuable research tools for the ubiquitin-proteasome biology community.

project_terms:
Affinity;Antineoplastic Agents;Attention;Binding Proteins;Biological;Biology;Bortezomib;Cancer Cell Growth;Cancer cell line;Catalytic Domain;Cell Death;Cell Line;Cell Survival;Cell physiology;Cells;Chemicals;Clinical;Communities;Complex;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Generations;Goals;Human;In Vitro;Individual;Inflammatory;Inflammatory Bowel Diseases;Interferon Type II;Investigation;Knowledge;Libraries;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Multiple Myeloma;Mus;Normal Cell;Organ;PC3 cell line;Peptide Library;Peptides;Pharmaceutical Preparations;Play;Primary Neoplasm;Prostatic Neoplasms;Proteasome Inhibitor;Proteomics;Publications;Refractory;Research;Role;Signal Pathway;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Toxic effect;Tumor Tissue;Ubiquitin;Up-Regulation (Physiology);Work;Xenograft Model;cancer cell;cancer therapy;drug discovery;imaging probe;in vivo;inhibitor/antagonist;innovation;multicatalytic endopeptidase complex;neoplastic cell;novel;overexpression;prostate cancer cell;protein function;public health relevance;screening;small molecule;small molecule libraries;tool;tumor;tumor growth

public_health_relevance:
Small molecule probes are valuable tools in deciphering protein functions. We have developed a novel cell permeable small molecule that selectively targets the immunoproteasome. Using this small molecule and other molecular tools we will investigate the roles of the immunoproteasome in cancer cells and therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy.


application_id: 8657816
project_number: 7R01CA100656-11
project_title: Integrating innate and adaptive immunity in cancer therapy
administering_ic: NCI
award_notice_date: 2014-07-30
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 100656
program_official: SOMMERS, CONNIE L
project_start_date: 2004-05-21
project_end_date: 2017-04-30
study_section: Cancer Immunopathology and Immunotherapy Study Section[CII]
contact_pi_person_id: 2793463
contact_pi: EGILMEZ, NEJAT K
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:
Sustained delivery of Interleukin-12 and GM-CSF to the tumor microenvironment induces rapid activation ofpre-existing CD8+ Teffector/memory cells promotes elimination of CD4+ CD25+ Foxp3+ T-suppressor cellsand results in the priming of a secondary CD8+ T-effector response in the tumor-draining lymph nodes (TDLN).However reversal of tumor immune suppression is transient and effector activation is followed by a dramaticrebound of T-suppressor cells and return of T-effector quiescence. Re-stimulation results in the intensificationof the regulatory rebound and ultimately in the loss of therapeutic efficacy. Recent work demonstrated thatboth CD8+ T-effector cell priming and T-suppressor cell rebound were mediated by the same myeloid Dendriticcell (DC) population that was recruited to the TDLN following treatment. More importantly IFN was requiredfor the development of both the initial immunogenic and the subsequent tolerogenic DC (tDC) phenotype. Thebroad hypothesis that will be tested in this application is that IFN-driven immunogenic and tolerogenicpathways in DC can be uncoupled and that selective inhibition of the tolerogenic pathway will neutralize thehomeostatic T-suppressor cell rebound resulting in durable tumor regression. To this end Aim 1 studies aredesigned to delineate the little-known mechanisms controlling the IFN-driven differentiation of immunogenicDC (iDC) to tDC. More specifically the specific roles of selected interferon regulatory factors (IRFs) in thedifferentiation of iDC and tDC phenotypes are elucidated to identify potential checkpoints that can be targetedfor selective blocking of tDC development and persistence. In Aim 2 two different strategies aimed atabrogating counter-regulation via the use of unique in vivo macromolecule delivery technologies are tested.First potential regulators of post-therapy tDC differentiation and activity including IRF-8 SOCS-1 IDO-1/2GCN-2 and MyD88 as well as additional candidates that are identified in Aim 1 are targeted via siRNA/goldnanorod complexes and sustained-release cytokine/small molecule drug formulations to block tDC function.Second based on recent findings demonstrating considerable plasticity in T-suppressor cell phenotype theabove technologies are utilized to re-program rebounding T-suppressor cells via Foxp3 silencing and deliveryof TH1/TH17-promoting cytokines. In Aim 3 the long-term curative potential of the above approach isinvestigated in two clinically-relevant tumor models. First a surgical metastasis model is utilized to determinewhether local abrogation of the T-suppressor cell rebound will result in enhanced eradication of disseminateddisease. In the second model the utility of chronic immune therapy in long-term management of non-resectable disease is evaluated in an advanced primary tumor model. Elucidation of the molecular basis oftreatment-induced homeostatic counter-regulation and identification of potential regulatory checkpoints thatcan be targeted for neutralization of the T-suppressor rebound represents a new paradigm which if successfulcan significantly improve clinical efficacy of immune-based therapies.

project_terms:
Back;CD8B1 gene;Cell physiology;Cells;Chronic;Complex;Dendritic Cells;Development;Disease;Drug Formulations;Effector Cell;Event;Funding;Goals;Gold;Granulocyte-Macrophage Colony-Stimulating Factor;IFN consensus sequence binding protein;IL2RA gene;Immune;Immunotherapy;Interferons;Interleukin-12;Local Therapy;Mediating;Memory;Modeling;Molecular;Molecular Analysis;Monitor;Mus;Myelogenous;Natural Immunity;Natural Killer Cells;Natural immunosuppression;Neoplasm Metastasis;Operative Surgical Procedures;Pathway interactions;Pharmaceutical Preparations;Phenotype;Population;Primary Neoplasm;Recombinant Cytokines;Recombinant Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Research;Research Design;Resectable;Role;Small Interfering RNA;Suppressor-Effector T-Lymphocytes;T-Lymphocyte;Technology;Testing;Treatment Efficacy;Work;adaptive immunity;base;cancer therapy;clinical efficacy;clinically relevant;controlled release;cytokine;immunogenic;improved;in vivo;inhibitor/antagonist;lymph nodes;macromolecule;nanorod;novel;paracrine;programs;response;small molecule;tumor;tumor eradication;tumor microenvironment;tumor progression

public_health_relevance:
PROJECT NARRATIVEThis proposal will define the molecular mechanisms underlying the homeostatic regulatory rebound that short-circuits therapy-induced antitumor cytotoxic cell activity. Delineation of how treatment itself leads to themobilization of a regulatory counter-response is expected to reveal checkpoints that can be targeted forabrogation of the regulatory rebound. To this end novel controlled-release formulations of siRNArecombinant proteins and small molecule drugs are utilized in conjunction with therapy to target anticipatedcheckpoints and reprogram regulatory cells to achieve durable tumor regression.


application_id: 8657793
project_number: 5R01CA049797-23
project_title: Mechanisms of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2014-04-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2017-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to identify novel redox base mechanisms that lead to the development of cancer. Our studies have identified the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) as an important regulator that can both modulate the development of cancer and be modulated during the progression of cancer. Our studies in the previous funding period demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that the level of p53 regulates the expression of MnSOD. We also found that the level of the mitochondrial uncoupling protein 1 (UCP1) is significantly increased in skin tissues of MnSOD-deficient mice. We hypothesize that the activities of p53 MnSOD and UCP1 are regulated to minimize reactive oxygen species (ROS) production in mitochondria.  We propose that: 1) as a critical transcription factor p53 cooperates with transcriptional activators and suppressors to regulate MnSOD transcription (Aim 1) and 2) the reduction of MnSOD levels in mitochondria leads to UCP1 induction as a result of compromised mitochondrial function which induces transcriptional responses to reduce superoxide production from mitochondrial respiration (Aim 2). The positive and negative feedback loops between nuclei and mitochondria help to ensure that superoxide levels are minimized to prevent mitochondrial dysfunction and subsequent neoplastic transformation. We will use state-of-the-art molecular biology biochemistry and free radical biology approaches to address these specific aims.  Because mitochondria are major sites of cellular energy production and cellular ROS homeostasis and are integrators of apoptosis signaling that are altered in cancer cells understanding the regulation of mitochondrial ROS levels is important and will provide a unique opportunity to design novel interventions that maximize the benefits to normal tissues and prevent cancer development. Given that cellular redox status contributes to almost all aspects of biological function and that MnSOD and p53 are critical for normal cellular function and for cancer prevention the results from this study of cancer will have a broad impact on human health and the prevention of other diseases including obesity and metabolic disorders.

project_terms:
Address;Antioxidants;Apoptosis;Binding (Molecular Function);Binding Sites;Biochemistry;Biogenesis;Biological Process;Biology;Cell Nucleus;Cell physiology;Cells;Chemicals;DNA Structure;Data;Development;Disease;Ensure;Enzymes;Exhibits;Family;Feedback;Free Radicals;Funding;Gene Expression;Genes;Genetic Transcription;Goals;Health;Homeostasis;Human;In Vitro;Intervention;Knowledge;Lead;Learning;Link;Luciferases;Malignant - descriptor;Malignant Neoplasms;Manganese;Mediating;Messenger RNA;Metabolic;Metabolic Diseases;Mitochondria;Mitochondrial Proteins;Molecular Biology;Monitor;Mus;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Obesity;Oxidation-Reduction;Oxidative Phosphorylation;Physiological;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;RNA-Binding Proteins;Reactive Oxygen Species;Regulation;Regulatory Element;Reporter Genes;Reporting;Respiration;Ribonucleoproteins;Role;SOD2 gene;Signal Transduction;Site;Skin Cancer;Skin Carcinogenesis;Skin Tissue;Structure;Superoxide Dismutase;Superoxides;Testing;Transcription Coactivator;Transgenic Mice;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;base;cancer cell;cancer prevention;design;disorder prevention;fascinate;in vivo;insight;link protein;liposarcoma;member;mitochondrial dysfunction;mitochondrial uncoupling protein;mouse model;neoplastic cell;novel;nucleophosmin;prevent;public health relevance;research study;response;skin cancer prevention;transcription factor;tumor progression;uncoupling protein 1

public_health_relevance:
Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is an important regulator that can modulate the development of cancer as well as be modulated during the progression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that expression of MnSOD is regulated by p53. We also found that the levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficient mice. In this application we will extend from this novel finding to determine how UCPs acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and/or alteration of mitochondrial function.


application_id: 8657492
project_number: 5R21NS080576-02
project_title: Probes to differentiate AD brain beta-amyloid from model beta-amyloid systems
administering_ic: NINDS
award_notice_date: 2014-06-27
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: NS
serial_number: 080576
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2017-06-30
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 2421413
contact_pi: LEVINE, HARRY
other_pis: SPIELMANN, H PETER
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): Animal models of Alzheimer's disease (AD) recapitulate early phases of the human condition but not the later stages of neuronal death and dementia. These models develop histologically similar but distinguishable A beta amyloid pathology. The imaging ligand Pittsburgh Compound B (PIB) binds insoluble A beta from human animal and synthetic systems with nM affinity. However the stoichiometry of PIB binding to human AD brain is approximately 500- to 10000-fold greater than that in animal models or synthetic A beta fibrils. Other A beta ligands such as Thioflavin S and Congo Red do not discriminate between human animal and synthetic A beta fibrils. We hypothesize that the difference in PIB binding between human brain and animal A beta fibrils is integral to the mechanism of neuronal death and dementia in human AD and contributes to the lack of complete recapitulation of the disease in animal models.  Preliminary data indicate that uncharacterized biochemical components in addition to A beta are required for the high binding stoichiometry of PIB in AD brain which resides in a denaturation-resistant assembly. The proposed work will generate photoaffinity probes for the human A beta PIB binding site that also contain a tag to enable affinity purification and we will utilize these probes to affinity isolate nd identify protein and lipid components contacting the PIB ligand in the AD brain by mass spectral analysis. Specific Aim 1. Synthesize and optimize a series of photoaffinity ligands with handles for affinity tags that are selective for the PIB binding site of human AD brain. Specific Aim 2. Identify the protein and lipid components that form the PIB ligand binding site of AD brain using MR-PIB and mass spectrometry.  The long term goal of this project is to use the identified components and structure of the human AD A beta fibril and its PIB ligand binding pocket to provide insight into unique properties of human AD A beta assemblies that contribute to AD. Ultimately we will determine the differences between human and AD animal models A beta assemblies to elucidate AD-related cellular and environmental mechanisms that will inform the improvement of animal models and identify potential novel drug targets.

project_terms:
Acetylene;Affect;Affinity;Affinity Chromatography;Alkynes;Alzheimer's Disease;Amyloid beta-Protein;Animal Model;Animals;Azides;Binding (Molecular Function);Binding Sites;Biochemical;Biological Models;Biotin;Brain;Brain Mass;Carbohydrates;Cessation of life;Characteristics;Chemistry;Complex;Congo Red;Copper;Couples;Data;Dementia;Disease;Drug Design;Drug Targeting;Etiology;Goals;Histologic;Human;Image;In Vitro;Libraries;Ligand Binding;Ligands;Lipids;Mass Spectrum Analysis;Modeling;Neurons;Parents;Phase;Phospholipids;Photoaffinity Labels;Pittsburgh Compound-B;Property;Proteins;Proteomics;Radioisotopes;Reaction;Research;Research Personnel;Resistance;Series;Staging;Streptavidin;Structure;Synaptosomes;System;Techniques;Temperature;Thioflavin S;Work;adduct;amyloid pathology;analog;beta amyloid pathology;cycloaddition;design;human disease;in vivo;innovation;insight;interest;new therapeutic target;novel;particle;public health relevance;reconstitution;scaffold;stoichiometry;thioflavine

public_health_relevance:
Current animal models of Alzheimer's disease (AD) do not replicate the later stages of this uniquely human disease. The proposed photoaffinity probes will allow us to characterize the differences between human A beta fibrils and that of animal models and may provide additional clues as to the causes of "full-blown AD" not recapitulated in animal models.


application_id: 8657377
project_number: 5R01DE019826-05
project_title: Tobacco-induced alterations to P. gingivalis-host interactions
administering_ic: NIDCR
award_notice_date: 2014-05-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 019826
program_official: LUNSFORD, DWAYNE
project_start_date: 2010-05-15
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a destructive infectious disease that has been associated with multiple fatal and debilitating chronic systemic diseases and consumes billions of dollars in health costs annually in the US. Tobacco smokers exhibit increased susceptibility to periodontitis; are more likely to be infected with the key periodontal pathogen Porphyromonas gingivalis; and to harbor higher numbers of this bacterial species relative to non-smokers. Despite this smokers consistently exhibit reduced clinical inflammation. We show that the pro-inflammatory response of purified human monocytes is significantly suppressed when P. gingivalis is exposed to cigarette smoke extracts (CSE) and that the inflammation inducing potential of P. gingivalis is restored when cells are sub-cultured back into fresh medium without CSE. However the influence of tobacco on the regulation of genes encoding P. gingivalis virulence determinants is essentially unknown.  We hypothesize that CSE represents an environmental stress and that P. gingivalis responds by altering gene expression to adapt to this stress. We believe that this adaptive response may involve the induction of stress-related genes virulence determinants and alterations of bacterial surface components. We also hypothesize that such cigarette smoke-induced physiological changes in P. gingivalis will include altered activities of genes encoding key pathogen recognition determinants which will explain the reduced inflammatory response of smoke-exposed P. gingivalis. It is our aim to identify isolate and test CSE-altered gene products in a primary human monocyte model of inflammation.  Preliminary data generated through transcriptome analyses and the structural characterization of several microbial determinants are strongly supportive of our hypotheses. We have identified several genes gene products and bacterial structures that are dysregulated on CSE exposure that may play pivotal roles in the engagement of the innate immune system by P. gingivalis. These include fimbrial proteins LPS major outer membrane antigens and other P. gingivalis components of known inflammatory potential such as dnaJ grpE and ragA.  These studies represent a novel area of investigation and will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers. Thus these studies will break new ground and provide the foundation for future studies that will elucidate mechanisms explaining how tobacco influences pathogen-host response interactions.

project_terms:
Anabolism;Antibodies;Antigens;Area;Back;Bacteria;Bacterial Proteins;Cells;Cellular Structures;Characteristics;Chronic;Chronic Obstructive Airway Disease;Clinical;Communicable Diseases;Conditioned Culture Media;Coronary Arteriosclerosis;Cytokine Suppression;Data;Dental;Diabetes Mellitus;Disease;Economic Burden;Exhibits;Exposure to;Foundations;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Genome;Genomics;Goals;Gram-Negative Anaerobic Bacteria;Health Care Costs;Human;IS Elements;Immune;Immune response;Immune system;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Investigation;Lipid A;Lung diseases;Membrane;Membrane Proteins;Microarray Analysis;Microbial Biofilms;Modeling;Molecular;Non-smoker;Operon;Organism;Pathogenesis;Patients;Periodontitis;Persons;Phenotype;Physiological;Play;Pneumonia;Polysaccharides;Population;Porphyromonas gingivalis;Predisposition;Proteins;Refractory;Relative (related person);Reporter Genes;Risk;Rodent Model;Role;Severities;Smoke;Smoker;Smoking;Specificity;Stress;Structure;Surface;Systemic disease;TNF gene;Testing;Tissues;Tobacco;Tobacco smoke;Tooth structure;Transcript;Transposase;United States;Vascular Diseases;Virulence;capsule (pharmacologic);cigarette smoke;cigarette smoke-induced;fimbria;in vivo;insight;microbial;monocyte;neutrophil;novel;pathogen;public health relevance;response;stroke;tobacco exposure;trait

public_health_relevance:
The Gram negative anaerobic bacterium Porphyromonas gingivalis is a causative agent of chronic periodontitis a destructive tobacco-induced and/or exacerbated disease. Smokers are more likely to be infected by P. gingivalis and to harbor higher numbers of these bacterial cells than non-smokers. However smokers also exhibit reduced clinical inflammation and in keeping with this smoke-exposed P. gingivalis exhibits a reduced capacity to illicit an inflammatory response from immune cells. The mechanisms underlying this reduced inflammatory potential are entirely unknown. Therefore we will identify P. gingivalis genes that are dysregulated by tobacco exposure by microarray analysis of P. gingivalis cultured in cigarette smoke extract (CSE)-conditioned medium. We will also examine the effects of CSE on the characteristics of cellular structures known to play critical roles in the activation of innate immune cells such as LPS and fimbriae. The inflammatory potential of tobacco-altered bacterial structures and the products of CSE-dysregulated genes will be tested in freshly isolated human monocytes. This study will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers.


application_id: 8656084
project_number: 5R01DA023476-06
project_title: Web-Based Contingency Management for Smoking Abstinence with Adolescents
administering_ic: NIDA
award_notice_date: 2014-03-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 023476
program_official: AKLIN, WILL
project_start_date: 2010-03-01
project_end_date: 2016-03-31
study_section: ZDA1-GXM-A(06)M
contact_pi_person_id: 7740063
contact_pi: REYNOLDS, BRADY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Adolescence may represent a uniquely challenging life period for smoking-cessation efforts. Many current cigarette smokers began smoking during adolescence and there is substantial evidence that the vast majority of adolescents who ever smoked daily continue smoking into adulthood. However as many as 65% of adolescent daily smokers report wanting to quit or reduce smoking. The disparity between adolescent smokers reporting an interest in abstinence and the percentage of these adolescents who ultimately continue smoking into adulthood illustrates the need for feasible and powerful behavioral treatments to support this population. In response to the need for treatments appropriate for adolescent smokers this research (utilizing a two-group randomized-control design n = 63 per group) will evaluate the effectiveness and efficacy of a new and innovative Internet-based contingency-management (CM) program for smoking abstinence with adolescent smokers. Because this CM program is Internet based it can be completed from home which stands to be more viable as a treatment option for adolescent smokers than other treatments requiring frequent trips to a clinical facility. From preliminary work with adult and adolescent smokers it is expected this treatment program will be highly effective in creating favorable changes in adolescent smoking behavior. This research will also involve eight monthly post-treatment follow-up sessions to determine long-term consistencies or changes in smoking behavior. A secondary goal of this research is to explore pre-treatment assessments of different dimensions of impulsive behavior as predictors of treatment outcome. These behavioral assessments will provide highly detailed information about the specific behavioral styles of adolescent smokers who are unable to effectively change their smoking behavior during treatment. This information should provide new points of emphasis for treatment- program modifications to improve these programs to be more effective for adolescents most challenged in their efforts to quit or reduce smoking.

project_terms:
Abstinence;Adolescence;Adolescent;Adult;Aftercare;Behavior;Behavior Therapy;Behavior assessment;Behavioral;Carbon Monoxide;Cause of Death;Characteristics;Cigarette Smoker;Clinical;Computers;Data;Decision Making;Dimensions;Disinhibition;Drug usage;Effectiveness;Evaluation;Goals;Home environment;Image;Impulsive Behavior;Individual;Internet;Life;Measures;Modification;Online Systems;Outcome;Participant;Persons;Population;Process;Psychological reinforcement;Randomized;Reporting;Research;Sampling;Schedule;Services;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Status;Substance Use Disorder;Time;Transportation;Treatment outcome;United States;Video Recording;Visit;Work;adolescent smoking;base;cigarette smoking;contingency management;design;discounting;follow-up;improved;inattention;innovation;interest;laptop;novel;programs;public health relevance;reinforcer;response;smoking cessation;stem;treatment planning;treatment program

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cigarette smoking is the top preventable cause of death in the United States. This study will evaluate a novel behavioral treatment for cigarette smoking cessation with adolescent smokers. Further this study will advance our understanding of the different behavioral styles associated with an adolescent's ability to quit or reduce smoking during a treatment program for smoking cessation. This latter aim is expected to guide smoking treatment modifications to make these treatments more effective for adolescents who are trying to quit or reduce smoking.


application_id: 8655864
project_number: 5R01EY014701-09
project_title: Ganglion Cell Function in Retinal Disease
administering_ic: NEI
award_notice_date: 2014-03-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 014701
program_official: GREENWELL, THOMAS
project_start_date: 2004-02-01
project_end_date: 2016-03-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Program Director/Principal Investigator (Last First Middle):PROJECT SUMMARY/ABSTRACTThe goals of this research are focused on understanding signaling mechanisms that regulate the developmentof visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease.Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways ofinformation flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizingbipolar cells which detect luminance increases and decreases and/or vision under dark- and light-adaptedconditions. As a result the pathways extend the dynamic range of information processing in the intensitydomain and increase specialization of information processing for salient environmental features e.g. motiondirection and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina andthese interactions culminate in and define the receptive field organization of the retinal ganglion cells. Thereceptive field is a basic property shared across all sensory neurons in all species. It defines the types andrange of environmental stimuli that each cell encodes. Thus understanding how receptive field propertiesdevelop is key to understanding visual function in the retina and the ganglion cells are a vital part because theyrepresent both the culmination of all retinal processing and the scaffold for the rest of visual processing.Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells theprocesses underlying their development have been relatively intractable to investigation. That normal visionrequires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visualdefects that occur in patients with and mouse models of congenital stationary night blindness (CSNB) wheredepolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we willcontinue to use to probe the synaptic circuitry underlying CSNB in which normal photoreceptor function isretained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the threemutants provides a unique opening to study the development of receptive field organization and ganglion cellsignaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mousewill be relevant to primate peripheral retinal processing. We suggest that the characterization of these mousemodels represents a significant opportunity not afforded by other mouse or vertebrate models and representsa critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal developmentand function.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

project_terms:
Address;Affect;Afferent Neurons;Age;Amacrine Cells;Cations;Cell physiology;Cells;Data;Defect;Detection;Development;Developmental Delay Disorders;Diagnosis;Disease;Electroretinography;Eye;Functional disorder;Funding;Genes;Glutamate Receptor;Glutamates;Goals;Human;Individual;Investigation;Lead;Light;Masks;Mediating;Modeling;Motion;Mus;Mutant Strains Mice;Mutation;Nature;Nervous system structure;Night Blindness;Pathway interactions;Patients;Pattern;Peripheral;Phenotype;Photoreceptors;Phylogenetic Analysis;Play;Primates;Principal Investigator;Process;Property;Research;Rest;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Sensory;Signal Transduction;Stimulus;Synapses;Testing;Therapeutic;Vision;Visual;Visuospatial;Work;disease phenotype;ganglion cell;information processing;luminance;mouse model;mutant;neural circuit;programs;receptive field;receptor;research study;response;scaffold;vision development;visual process;visual processing

public_health_relevance:
Program Director/Principal Investigator (Last First Middle):Project NarrativeThis proposal seeks to understand the mechanisms that govern the development of vision in the retina and toinvestigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of theparallel pathways of information processing in the retina. One focus is to understand the exact changes thatoccur in complete congenital stationary night blindness a retinal disease that does not involve photoreceptordysfunction or morphological defects. A second focus is to understand the fundamental processes thatregulate the development of normal retinal function particularly in the ganglion cells. We believe that ourresults will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant toother blinding diseases in people of all ages.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8655736
project_number: 3R01CA131075-04S1
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2013-05-09
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 131075
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
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
project_abstract:
DESCRIPTION (provided by applicant): We seek to understand the molecular responses that occur when skin is exposed to UV radiation in order to devise novel strategies to protect against damage and carcinogenesis. In this proposal we will examine two major risk factors for skin cancer: UV radiation and pigment (melanin) phenotype. Our studies focus on the melanocyte and its cell surface receptor the melanocortin-1 receptor (Mc1r) which regulates melanin synthesis. We hypothesize that Mc1r protects melanocytes against UV-mediated mutagenesis and transformation by modulating melanization and recovery from UV-mediated cellular injury. Loss-of-function polymorphisms in Mc1r correlate with fair skin and a high incidence of melanoma while robust Mc1r function correlates with darker skin and UV resistance. We have developed a novel genetically-matched murine model of human skin as well as a protocol for growing primary melanocytes from these mice. These isogenic melanocytes span eumelanotic pheomelanotic and amelanotic melanin composition will serve a unique and potent tool to delineate the role of Mc1r function in response to UV. Using our unique animal model and primary melanocytes derived thereof we propose the following aims: Aim 1. Characterize the mechanism of Mc1r-mediated enhancement of nucleotide excision repair (NER); Aim 2. Determine whether Mc1r signaling protects against UV-mediated oxidative damage; and Aim 3. Determine the ability of pharmacologic Mc1r rescue to protect against UV damage. With respect to Aim 1 we will examine the role of Mc1r in the repair of UV-induced photolesions by southwestern and flow cytometric analysis and determine the influence of Mc1r on cellular levels of nucleotide excision repair enzymes by qRT-PCR and Western analysis. We will investigate a molecular link between Mc1r signaling and enhanced repair enzyme levels by examining expression of the NER enzymes basally and in the setting of UV irradiation and by investigating the ability of cAMP-responsive transcription factors downstream of Mc1r signaling (namely Mitf and CREB) to bind to and induce transcription of NER enzyme promoters. In Aim 2 we will study whether pheomelanin which is produced as a result of low Mc1r function promotes oxidative damage in melanocytes by complementary measures of oxidative load (DCF-mediated fluorescence flow cytometry Southwestern blotting hOGG1-adapted Comet assay TBARS assay and direct quantification of oxidative DNA adducts by GC/MS). Importantly we will directly test whether  pheomelanin functions as a pro-carcinogen by an HPRT-based forward mutagenesis approach in primary melanocytes. Finally we will directly test the ability of forskolin an activator of adenylyl cyclase to bypass defective Mc1r function to enhance recovery from UV-mediated DNA damage and to rescue UV protection in melanocytes and in whole skin. Together these studies will lay the foundation for future translational studies designed to develop novel small molecule-based approaches for UV and cancer protection to prevent many cases of melanoma.

project_terms:
Address;Adenylate Cyclase;Animal Model;Automobile Driving;Binding (Molecular Function);Biological Assay;Bypass;CREB1 gene;Carcinogens;Cell Line;Cell Surface Receptors;Cells;Comet Assay;Cyclic AMP;DNA;DNA Adducts;DNA Damage;DNA Repair;Defect;Exposure to;Flow Cytometry;Fluorescence;Forskolin;Foundations;Future;Genes;Genetic Polymorphism;Genetic Transcription;Goals;Human;In Vitro;Incidence;Individual;Injury;Link;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Methods;Modeling;Molecular;Monophenol Monooxygenase;Mus;Mutagenesis;Nucleotide Excision Repair;Phenotype;Pigmentation physiologic function;Pigments;Primary Cell Cultures;Promotor (Genetics);Protocols documentation;Receptor Signaling;Receptor Melanocortin Type 1;Recovery;Research Design;Resistance;Risk Factors;Role;Skin;Skin Cancer;Skin Pigmentation;Southwestern Blotting;Sun Exposure;Surface;System;Testing;The Sun;UV induced;UV induced DNA damage;UV protection;UV response;Ultraviolet B Radiation;Ultraviolet Rays;Variant;alpha-Melanocyte stimulating hormone;base;carcinogenesis;cell injury;congenic;defined contribution;eumelanin;high risk;loss of function;melanocyte;melanoma;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;receptor;receptor binding;receptor function;repair enzyme;repaired;research study;response;small molecule;synthetic enzyme;tool;transcription factor;translational study;ultraviolet damage;ultraviolet irradiation

public_health_relevance:
Though it has long been known that people with functional defects of the melanocortin 1 receptor (Mc1r) protein are at high risk of developing melanoma the way(s) in which Mc1r protects against melanoma are not understood. Using pigment cells known as melanocytes we will study how the Mc1r protein influences UV- mediated DNA and cellular damage in melanocytes and contributes to melanoma resistance. Our goal is to develop the strategy of pharmacologic Mc1r rescue toward translational applicability so that many cases of melanoma can be prevented.


application_id: 8655073
project_number: 275201200010C-1-0-1
project_title: Novel Pharmacotherapies for Alcoholism
administering_ic: NICHD
project_start_date: 2012-09-24
project_end_date: 2015-03-23
contact_pi_person_id: 12067063
contact_pi: LITTLETON, JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Alcoholism is a complex condition in which there are many potential molecular and therapeutic targets for pharmacotherapy. This "fast track" SBIR contract aims to investigate compounds targeted on the glutamate/NMDA receptor (NMDAR) and the nicotinic receptor for acetylcholine (nicAChR). These targets have direct relevance to several of the major therapeutic targets including detoxification of acute withdrawal neurotoxicity relapse organ damage co-morbid neuropathic pain and co-morbid drug abuse (including smoking). Naprogenix first identifies synthetic drugs or plant metabolites by high throughput pharmacological screening prioritizing lead compounds which have valuable multifunctionality. Leads are then tested in whole animal screens and models reflecting different specific aspects of alcoholism and the most promising are optimized by synthetic modification or by a novel plant genomic approach. Phase 1 of this "fast track" proposal is to complete preliminary studies at the molecular level on the 4 current best therapeutic candidates (2 synthetics and 2 natural products) and to prepare sufficient quantities of these for cellular studies and whole animal evaluation in phase 2. Also during phase 2 the company with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) will contact major pharmaceutical and nutritional companies to explore the further development of these compounds as medications or nutraceuticals.

project_terms:
Acute;Address;Alcoholism;Animal Model;Animals;Biological Factors;Complex;Contracts;Development;Drug Metabolic Detoxication;Drug abuse;Evaluation;Genomics;Glutamates;Investigation;Lead;Modeling;Modification;Molecular;Molecular Target;N-Methyl-D-Aspartate Receptors;National Institute on Alcohol Abuse and Alcoholism;Nicotinic Receptors;Nutraceutical;Nutritional;Organ;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Plants;Relapse;Small Business Innovation Research Grant;Smoking;Staging;Testing;Therapeutic;Withdrawal;alcoholism pharmacotherapy;neurotoxicity;novel;painful neuropathy;preclinical evaluation;programs;screening;synthetic drug;therapeutic target


application_id: 8654322
project_number: 5R42DA030001-05
project_title: Naloxone Nasal Spray Development
administering_ic: NIDA
award_notice_date: 2014-04-29
opportunity_number: PA-12-089
application_type: 5
activity_code: R42
ic: DA
serial_number: 030001
program_official: HAMPSON, AIDAN
project_start_date: 2010-07-15
project_end_date: 2015-04-30
study_section: Special Emphasis Panel[ZRG1-IMST-M(13)B]
contact_pi_person_id: 10086391
contact_pi: WERMELING, DANIEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_uei: DC9CX5GXZSU4
duns_number: 831025338
uei: DC9CX5GXZSU4
fips: US
organization_id: 10023078
organization_name: ANTIOP, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405151273
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-05-01
project_abstract:
DESCRIPTION:  The following proposal is a follow-on Phase 2 b application from our initial proposal (1-R42 DA 030001). U.S. drug overdose deaths mostly commonly from opioids now exceed deaths from automobile accidents. There is a significant unmet medical need to provide additional pharmacologic options for treatment of opioid overdose. Emergency medical service personnel would prefer a non- injection based antidote to avoid accidental needle-sticks and associated risks of hepatitis or HIV in the revival of opioid overdose victims. Some communities prescribe/provide naloxone (NLX) injection for injection or nasal administration to high-risk pai patients or drug abusers. A proven needle-free delivery system would be an advance in all settings. The specific objective is to create a NLX nasal spray (NS) that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g. Oxycontin(R)) and illicit (e.g. heroin) opioids. The hypothesis of th ongoing Fast Track STTR project was that a NLX NS could be created and will have biopharmaceutics comparable to NLX subcutaneous (SC) and intramuscular (IM) injection without the use of a needle. Previous published research has demonstrated nasal delivery of NLX is feasible and produces pharmacologically appropriate responses. A NLX nasal spray product has been created and is undergoing commercial-scale manufacturing development ahead of typical drug development schedule. An IND is now active (#106431) and a pilot bioavailability study to compare NLX nasal spray pharmacokinetics to approved injection routes and doses is being conducted in parallel with this grant review. Data from the pilot study will allow us to make adjustments (based upon pharmacokinetic modeling) in nasal spray drug concentration and manufacturing of the final drug product for further clinical testing. Our firm ha had extensive negotiations with the Food and Drug Administration (FDA) regarding the development path for NLX NS (see Appendix). The new aims of this Phase 2 b proposal follow the STTR aims aligned with the scientific and regulatory agreements made with the FDA and will result in the rapid commercialization of NLX nasal spray. The project hypothesis will be tested by the following Specific Aims:  1. Validate all analytical methods according to FDA/ICH GMP and GLP guidance's 2. Manufacture another clinical study batch of NLX NS under commercial scale conditions and continue long-term stability studies of all batches compliant with FDA/ICH GMP guidance's 3. Conduct a confirmatory pharmacokinetic study of the formulation as compared to approved IM doses in order to further inform the pivotal comparative bioavailability study statistical model 4. Conduct a human nasal tolerability study of the final formulation

project_terms:
Agreement;Antidotes;Biological Availability;Biopharmaceutics;Cessation of life;Chemicals;Clinical;Clinical Research;Communities;Data;Development;Dose;Drug Formulations;Drug Kinetics;Drug abuser;Emergency medical service;Goals;Grant;Grant Review;HIV;Health;Hepatitis;Heroin;Human;Human Resources;Injection of therapeutic agent;Insurance;Intramuscular;Intramuscular Injections;Licensing;Marketing;Mediation;Medical;Methods;Modeling;Morphine;Naloxone;Needles;Needlestick Injuries;Nose;Opioid;Overdose;Oxycodone;Pain;Patients;Pattern;Pharmaceutical Preparations;Phase;Pilot Projects;Policies;Prevention;Publishing;Qualifying;Research;Risk;Route;Saline;Schedule;Small Business Technology Transfer Research;Statistical Models;System;Testing;United States Food and Drug Administration;analytical method;automobile accident;base;commercialization;comparative;cost;design;dosage;drug development;good laboratory practice;high risk;meetings;novel therapeutics;overdose death;pharmacokinetic model;programs;research and development;research clinical testing;response;risk perception;safety study;stability testing;subcutaneous

public_health_relevance:
There is a significant unmet medical need to provide additional pharmacologic treatments for treatment and prevention of opioid (morphine like medications) overdose. The specific objective is to create a nasal spray that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g. heroin).


application_id: 8654316
project_number: 5R01DA016718-10
project_title: Licit & Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2014-04-16
opportunity_number: PA-08-127
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: ANDERSON, ANN
project_start_date: 2004-07-10
project_end_date: 2017-09-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): While rates of heroin dependence have been fairly stable over the last several years rates of prescription opioid abuse dependence and diversion have risen significantly. The initial 5-year award focused on the emerging prescription opioid abuse epidemic by conducting a series of studies on the clinical pharmacology of the most widely abused opioids (hydrocodone oxycodone and Oxycontin(R)). These studies investigated relative abuse potential estimates relative potency effects of pain on abuse liability and pharmacokinetics and pharmacodynamics of these drugs when misused by the oral intranasal and intravenous routes. The present application extends these findings by conducting a series of studies to collect new data on opioids purported to have low abuse liability but based upon surveillance studies are emerging as new drugs of abuse including tramadol buprenorphine (Subutex(R)) and buprenorphine/naloxone (Suboxone(R)). Three studies will be conducted enrolling both sporadic opioid abusers and opioid dependent individuals to examine the relative abuse potential and reinforcing efficacy of tramadol buprenorphine and buprenorphine/naloxone when misused by various routes of administration. These studies include careful double-blind randomized placebo- controlled crossover designs and incorporate innovative methodological additions to the standard abuse liability approach including 1) concurrent evaluation of the direct reinforcing efficacy of these compounds using human self-administration procedures to assess the concordance of findings between the "gold standard" approach to a model that examines drug-taking behavior directly 2) multiple relevant comparator agents and 3) multi-dimensional outcomes of safety subjective reports observer-rating and psychomotor performance along. The three proposed inpatient studies will examine the comparative abuse liability and reinforcing efficacy of 1) oral tramadol over a range of doses in comparison to oxycodone (a high efficacy agonist) codeine (an intermediate efficacy agonist) and placebo in non-dependent opioid abusers 2) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone codeine and placebo in non-dependent opioid abusers and 3) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone naloxone and placebo in opioid-dependent subjects maintained on a short-acting pharmaceutical opioid. These studies will provide important new information on two emerging drugs of abuse- tramadol and buprenorphine- both drugs at risk for being rescheduled to more restrictive status in the U.S. It is critical that availability of these drugs be preserved for their target patient groups (i.e. pain patients and opioid dependent individuals seeking office- based treatment for drug dependence respectively) while protecting the public safety. These studies will provide empirical data on the relative abuse liability of these drugs in a relevant population and can inform and support evidence-based regulatory decision-making.

project_terms:
Abuse Reporting;Adolescent and Young Adult;Agonist;Arkansas;Award;Behavior;Buprenorphine;Case Study;Clinical Pharmacology;Codeine;Comparative Study;Crossover Design;Data;Decision Making;Dependence;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Enrollment;Epidemic;Epidemiology;Evaluation;Gold;Health;Heroin;Heroin Dependence;Human;Hydrocodone;Individual;Inpatients;Intravenous;Kentucky;Learning;Marketing;Methadone;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Naloxone;Opiate Addiction;Opioid;Oral;Outcome;Oxycodone;Pain;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Placebo Control;Placebos;Population;Procedures;Psychomotor Performance;Randomized;Relative (related person);Reporting;Research Design;Risk;Route;Rural;Safety;Schedule;Self Administration;Series;Solid;Subutex;System;Tramadol;United States;base;comparative;drug of abuse;evidence base;indexing;innovation;opioid abuse;overdose death;prescription opioid abuse;public health medicine (field);public health relevance;surveillance study;tramadol abuse

public_health_relevance:
Prescription opioid abuse has increased dramatically in the United States and is a significant public health problem. It is important to understand the pharmacological effects of prescribed opioids in order to predict and control their abuse and other negative health consequences. These studies will provide new information on the abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination with naloxone (used for treatment of opioid dependence).


application_id: 8653955
project_number: 5K08DA032296-04
project_title: African American Offenders: Drug Use Mental Health and HIV Risk
administering_ic: NIDA
award_notice_date: 2014-05-06
opportunity_number: PA-11-193
application_type: 5
activity_code: K08
ic: DA
serial_number: 032296
program_official: JONES, DIONNE
project_start_date: 2012-05-01
project_end_date: 2017-04-30
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;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;Symptoms;Techniques;Testing;Training;Universities;Unsafe Sex;Writing;career;career development;community reentry;correctional system;depressive symptoms;drug testing;experience;follow-up;health care service utilization;health disparity;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 medicine (field);public health research;racism;sex risk


application_id: 8652837
project_number: 5F32NS083182-02
project_title: Role of beta catenin mediated neural stem cell and astrocyte proliferation in TBI
administering_ic: NINDS
award_notice_date: 2014-03-13
opportunity_number: PA-11-113
application_type: 5
activity_code: F32
ic: NS
serial_number: 083182
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-04-15
project_end_date: 2016-04-14
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 9632738
contact_pi: SAMA, DIANA M.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Approximately 1.5 million traumatic brain injuries (TBIs) occur in the United States annually. Although much research has focused on neuronal death following TBI TBI also initiates a proliferative response in some cell types including neural progenitor cells (NPCs) and astrocytes. Proliferating NPCs are thought to replace dying neurons through neurogenesis but the function of astrocyte proliferation is more controversial. Both normally rely on -catenin for proliferation but the importance of the -catenin pathway in posttraumatic proliferation has not yet been established. Because quiescent NPCs and astrocytes express glial fibrillary acidic protein (GFAP) this study utilizes a novel transgenic mouse in which -catenin signaling is conditionally knocked-out using the Cre-lox system under the GFAP promoter (GFAP-tta/Tet-O-Cre/-cateninflox/flox; cat-KO) allowing for the specific manipulation of NPCs and astrocytes after trauma. The central hypothesis is that -catenin- mediated NPC and astrocyte proliferation promotes recovery after contusion brain injury. The main goals of this proposal are to understand the extent to which -catenin signaling affects NPC and astrocyte proliferation after controlled cortical impact (CCI) brain injury (Aim 1) and to
assess the role of dividing NPCs and astrocytes in the injured brain (Aim 2). Aim 1 tests the hypothesis that -catenin signaling is critical for NPC and astrocyte proliferation following CCI. cat-KO and wild-type (WT) mice will receive moderate CCI injury and injection of 5-bromo-2-deoxyuridine (BrdU a thymidine analog) to label dividing cells. Immunostaining will be used to compare numbers of BrdU-positive NPCs and astrocytes in cat-KO and WT mice. Aim 2 tests the hypothesis that eliminating -catenin-dependent proliferation in GFAP-positive NPCs and astrocytes will impair spontaneous recovery after CCI. Astrocytes are normally key regulators of blood-brain barrier (BBB) integrity and dendritic/synaptic outgrowth. Because -catenin affects astrocyte proliferation it is expected that cat-KO mice will show greater deficits than WT mice in
BBB integrity (assessed by IgG or Evan's blue extravasation) and dendritic/synaptic recovery (assessed through immunostaining and Golgi staining). Because -catenin affects NPC proliferation recovery of immature neuronal populations in the hippocampus (evaluated with doublecortin immunolabeling) is expected to be impaired in cat-KO mice compared to WT mice. The combined loss of astrocyte and NPC proliferation are predicted to result in greater cognitive impairment which will be evaluated using a Morris Water Maze learning paradigm and Novel Object Recognition (memory) Task. These studies will provide novel insights on NPC and astrocyte proliferation in posttraumatic recovery thereby identifying new therapeutic targets for posttraumatic intervention. The proposed studies will greatly enhance my training in the pathobiology of TBI and my technical expertise for studying neurodegenerative conditions.

project_terms:
Address;Adult;Affect;Age;Animals;Astrocytes;Behavioral;Blood - brain barrier anatomy;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Communication;Cell Cycle;Cell Differentiation process;Cell Proliferation;Cell division;Cells;Cessation of life;Contusions;DLG4 gene;Data;Deoxyuridine;Evans blue stain;Exhibits;Extravasation;Felis catus;Glial Fibrillary Acidic Protein;Goals;Golgi Apparatus;Growth;Hippocampus (Brain);Immunoglobulin G;Impaired cognition;Injection of therapeutic agent;Injury;Intervention;Knock-out;Label;Life;Link;Maze Learning;Measures;Mediating;Memory;Modeling;Monitor;Mus;Nerve Degeneration;Neurons;Outcome;Pathway interactions;Perfusion;Permeability;Population;Production;Proliferating;Promotor (Genetics);Proteins;Recovery;Research;Role;Signal Transduction;Staining method;Stains;Stem cells;Synapses;Synaptophysin;System;Technical Expertise;Testing;Tetanus Helper Peptide;Thymidine;Time;Training;Transgenic Mice;Trauma;Traumatic Brain Injury;United States;Vertebral column;Vulnerable Populations;Wild Type Mouse;analog;behavioral impairment;beta catenin;cell type;cognitive recovery;cohort;controlled cortical impact;disability;functional loss;improved;injured;insight;morris water maze;nerve stem cell;neurogenesis;neuron loss;new therapeutic target;novel;object recognition;public health relevance;repaired;research study;response;therapeutic target

public_health_relevance:
Traumatic brain injury is the leading cause of death and disability under age 45. This research study will establish how proliferation of neural stem cells and astrocytes in the brain after trauma contributes to repair of the injured brain ultimately leading to improved behavioral outcome.


application_id: 8652123
project_number: 1R21HD079256-01
project_title: NMDA modulation of diabetes-induced glutamate synaptic plasticity
administering_ic: NICHD
award_notice_date: 2014-04-07
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: HD
serial_number: 079256
program_official: GRAVE, GILMAN D
project_start_date: 2014-04-10
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1 IFCN-Z (02)]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project summaryDiabetes mellitus is a major health concern affecting nearly 26 million people in the United States. Seriouscomplications resulting from diabetes including heart disease stroke hypertension blindness nervous systemdamage and autonomic dysfunction. A major impediment to developing successful diabetes treatments(versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systemsthat contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticityof central neural circuitry involved in autonomic control including control of blood glucose homeostasis.Experiments utilize a model of type 1 diabetes but findings will more broadly apply to other forms ofdiabetes since autonomic dysfunction increases the risk of developing type 2 diabetes. Preautonomic neuronsof the dorsal vagal complex which contains second-order viscerosensory neurons in the nucleus tractussolitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus(DMV) are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis.Vagal motor output is suppressed in diabetes leading to autonomic dysregulation including excess hepaticglucose production and gastric motility dysfunction. Preliminary results show that glutamate release in theDMV is persistently enhanced in a model of type 1 diabetes in a manner consistent with development of apossible compensatory response to prolonged hyperglycemia that suggests homeostatic plasticity thatmitigates against the decreased vagal output seen in diabetes. In addition NMDA receptor modulation has arelatively larger effect on glutamate release in diabetic mice versus controls. This exploratory proposalaims to determine the causes and underlying features of the recently-discovered diabetes-inducedenhancement of tonic excitatory drive to DMV neurons. Electrophysiological recordings from vagal complexneurons in slices from control and diabetic mice will be used to obtain functional cellular data related to NMDAreceptor sensitivity changes associated with diabetes development in the streptozotocin- treated mouse amodel of type 1 diabetes. Aim 1 will determine if recently-identified NMDA receptors located on presynapticterminals contacting DMV cells are upregulated in diabetes. Aim 2 will determine if postsynapticNMDA receptors on the somadendritic portion of identified glutamatergic NTS neurons that project to theDMV are upregulated in diabetes. The sensitivity of these changes to glucose and insulin will also beidentified. Results will guide future studies aimed at disease-modifying therapies from a systemic standpointbased on modulating specific neural functions in the brainstem to eventually address diabetes- relatedautonomic dysregulation in patients.

project_terms:
Abdomen;Accounting;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Diseases;Brain Stem;Cell Nucleus;Cells;Chronic;Complex;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Equilibrium;Functional disorder;Future;Gastrointestinal tract structure;Glucose;Glutamates;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Mediating;Metabolic Control;Modeling;Modification;Motor Neurons;Motor output;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Nucleus solitarius;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Play;Presynaptic Terminals;Receptor Activation;Regulation;Relative (related person);Risk;Role;Slice;Staging;Stomach;Streptozocin;Symptoms;Synapses;Synaptic plasticity;System;Testing;Tissues;United States;Vagus nerve structure;Viscera;Whole Blood;base;blood glucose regulation;cell body (neuron);cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;gastrointestinal;glucose metabolism;glucose production;neural circuit;postsynaptic;presynaptic;public health relevance;receptor;receptor function;receptor sensitivity;research study;response;stroke

public_health_relevance:
Preganglionic parasympathetic neurons in the vagal complex innervate the abdominal organs and criticallyregulate whole blood glucose metabolism. These neurons are sensitive to elevated glucose and undergo long-lasting changes in synaptic excitability in an animal model of diabetes. The proposed exploratory experimentswill examine mechanisms underlying diabetes-associated synaptic changes in the vagal complex that mayrepresent a compensatory response to chronic hyperglycemia with the eventual goal of informing futurestudies aimed at treating pathologies underlying diabetic hyperglycemia.


application_id: 8652016
project_number: 1R13GM109727-01
project_title: Increasing the Participation and Visibility of Women in Statistics and Biostatistics
administering_ic: NIGMS
award_notice_date: 2014-02-28
opportunity_number: PA-12-212
application_type: 1
activity_code: R13
ic: GM
serial_number: 109727
program_official: SESMA, MICHAEL A
project_start_date: 2014-03-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZGM1 TRN-3 (CO)]
contact_pi_person_id: 1859011
contact_pi: DATTA, SUSMITA
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In this application we seek the support for a two and a half day inaugural conference "Celebrating women in Statistics: Know Your Power" which will take place in May 15 to 17 2014 in the research Triangle Park NC. Some of the goals of this conference are to empower women statisticians and biostatisticians by showcasing the accomplishments of successful women professionals sharing information on how to elevate their status by successful negotiations balance work-life and increase visibility of women in the field. Specifically the ultimate intent of this conference is to increase the proportion of succesul women leaders who are ready to take the challenges of 'big-data' oriented research in twenty-first century especially in biomedical field. STEM fields such as astronomy computer science and mathematics have similar conferences and workshops designed for women that address issues women face in these fields and provide a venue for the exchange of research networking and mentoring for women. This is the first time women in statistics and biostatistics are undertaking such initiative. We will target to achieve the following objectives. 1. Through multiple professional development workshop we provide information regarding negotiation skill gender neutral communication skill conflict resolution skill balancing work-life and leadership training. 2. Through multiple invited technical sessions we highlight the research of female rising
stars mid-career and senior researchers and in turn present exciting and challenging biostatistical research topics. 3. Through multiple mentorship and networking sessions of academic government and industry participants prepare women junior participants to succeed in their career. 4. Through sessions dedicated to the journal editorial process and structure provide wisdom relating the authorship in a collaborative world. 5. Through panel discussions for funding opportunities at NSF/NIH and other federal and non-federal funding agencies make women researchers aware of the opportunities available to fund their research.

project_terms:
Address;American;Area;Astronomy;Authorship;Big Data;Biomedical Research;Biometry;Communication;Communities;Data;Development;Educational workshop;Equilibrium;Face;Female;Funding;Funding Agency;Funding Opportunities;Gender;Gender Role;Generations;Goals;Government;Grant;Industry;Institution;Joints;Journals;Knowledge;Leadership;Life;Marketing;Mathematics;Mediation;Mentors;Mentorship;National Heart Lung and Blood Institute;National Institute of General Medical Sciences;North Carolina;Occupations;Participant;Process;Publications;Research;Research Infrastructure;Research Personnel;Science Technology Engineering and Mathematics;Series;Societies;Solutions;Staging;Structure;Students;Time;Training;United States National Institutes of Health;Universities;Woman;Women Status;Work;Writing;career;computer science;conflict resolution;design;editorial;empowered;empowerment;interdisciplinary collaboration;interest;novel;public health relevance;role model;skills;statistics;success;symposium

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The conference "Celebrating Women in Statistics: Know Your Power" is designed to encourage women to join and remain in the statistics and biostatistics profession to elevate the status of women in the profession by showcasing their accomplishments and to empower women to increase their visibility and to rise professionally in statistics. This unique conference will have sessions and workshops on broad issues such as leadership training understanding the role of gender in communication effective negotiation and networking skills and managing work-life balance as well as specific topics such as interdisciplinary collaboration publication grant writing and novel scientific sessions through data and new paradigms of big data.


application_id: 8650926
project_number: 5R01NS070899-05
project_title: Regulation signaling and dynamics of glucan phosphatases.
administering_ic: NINDS
award_notice_date: 2014-03-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 070899
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The objective of this grant is to elucidate the regulation downstream signaling and structural dynamics of the glucan phosphatase laforin. Mammalian cells store readily mobilized energy in the form of glycogen a water-soluble carbohydrate. Recessive mutations in genes encoding the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin disrupt glycogen metabolism and result in a fatal neurodegenerative epilepsy called Lafora disease (LD). A hallmark of LD is poorly branched hyperphosphorylated insoluble carbohydrate accumulations called Lafora bodies (LBs) thought to be the causative agent of LD.  We established that malin is a single-subunit E3 ubiquitin ligase that ubiquitinates and triggers the degradation of multiple proteins involved in glycogen metabolism. In addition we discovered that laforin is the founding member of a unique class of phosphatases that dephosphorylate phospho-glucans. These results allowed us to propose molecular mechanisms that cause LD: 1) loss of malin results in LBs due to an imbalance in glycogen metabolism proteins i.e. protein levels are not properly maintained; 2) loss of laforin results in LBs due to glucan hyperphosphorylation that inhibits glucan branching; 3) laforin also acts as a targeting subunit for malin so that loss of laforin disrupts some malin-directed ubiquitination events. While we have made significant strides in determining the molecular mechanisms of LD we lack an understanding of how these enzymes are regulated. This proposal will elucidate the deficiencies in our current knowledge.  We recently identified novel phosphorylation and ubiquitination events on laforin. Phosphorylation and ubiquitination are post-translational modifications that direct changes in protein concentration enzymatic activity protein localization protein-protein interactions and structural dynamics. In Aim 1 we will define the in vivo conditions triggering laforin phosphorylation and characterize the functional consequences. We will utilize 1) overexpression and endogenous protein levels in tissue culture cells to monitor the status of laforin localization and modification 2) assay laforin function in vitro using purified proteins and 3) utilize a LD mouse model to verify our results. In Aim 2 we will utilize a similar strategy to determine the affects of ubiquitination on laforin function. In addition we will define the role of laforin in malin directed ubiquitination as we have recently discovered that laforin acts as a targeting protein for malin. In Aim 3 we will determine how perturbations of the structural components of glucan phosphatases contribute to LD. We will utilize Hydrogen- Deuterium exchange mass spectrometry to define the structural dynamics of laforin and x-ray crystallography to determine the structure of a glucan phosphatase. This proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intercalated events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better understanding of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.

project_terms:
5'-AMP-activated protein kinase;Affect;Binding (Molecular Function);Biological Assay;CNS degeneration;Carbohydrates;Cardiac;Cells;Cessation of life;Complex;Comprehension;Crystallography;Deterioration;Deuterium;Disease;Energy Metabolism;Enzymes;Epilepsy;Event;Family suidae;Genes;Glucans;Glycogen;Glycogen (Starch) Synthase;Glycogen Debranching Enzyme;Grant;Human;Human body;Hydrogen;In Vitro;Knowledge;Lafora Disease;Life;Link;Mammalian Cell;Mass Spectrum Analysis;Metabolism;Modification;Molecular;Monitor;Motor;Mutation;Myocardium;Myoclonic Epilepsies;Nerve Degeneration;Neurodegenerative Disorders;Neurologic;Parkinson Disease;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Post-Translational Protein Processing;Progressive Myoclonic Epilepsies;Proteins;Regulation;Review Literature;Role;Seizures;Series;Signal Transduction;Single Seizures;Skeletal muscle structure;Specificity;Structure;Symptoms;Therapeutic;Tonic - clonic seizures;Ubiquitin;Ubiquitination;Water;Wolff-Parkinson-White Syndrome;Wolves;Work;base;design;glycogen metabolism;in vivo;insight;loss of function;loss of function mutation;member;mouse model;novel;overexpression;protein protein interaction;public health relevance;research study;sensor;tissue/cell culture;ubiquitin-protein ligase

public_health_relevance:
The focus of our work is to determine how loss of function of either of two proteins leads to the fatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intertwined events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better comprehension of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.


application_id: 8650812
project_number: 5R21DA035481-02
project_title: Buspirone as a Candidate Medication for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2014-03-24
opportunity_number: PA-10-269
application_type: 5
activity_code: R21
ic: DA
serial_number: 035481
program_official: HAMPSON, AIDAN
project_start_date: 2013-04-15
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)S]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse is an unrelenting public health concern. While behavioral therapies are effective for reducing MA use many patients enrolled are unable to achieve significant periods of abstinence suggesting other strategies are needed. Despite being a high priority for the National Institute on Drug Abuse (NIDA) and extensive efforts by the scientific and treatment communities an effective medication for MA abuse has not been identified. MA acts as a substrate for monoamine transporters and is taken into the nerve terminal where it promotes the release of dopamine (DA) serotonin (5-HT) and norepinephrine (NE) into the synapse by preventing the accumulation of neurotransmitter in storage vesicles and by carrier-mediated exchange. MA abuse is largely attributed to its ability to increase synaptic DA levels. However targeting DA systems has not identified a broadly effective pharmacotherapy for managing MA abuse. MA also promotes 5- HT release which mediates the reinforcing effects of MA. MA abuse is also characterized by perturbations in DA and 5-HT systems. Thus an effective medication for MA abuse will likely need to target 5-HT systems in addition to DA which is an innovative strategy. Buspirone (BUSP) an anxiolytic medication with limited abuse potential is a partial agonist at serotonin 5-HT1A receptors an antagonist at DA auto receptors and a selective antagonist at DA D3 receptors. Partial agonists have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e. during abstinence) and block receptors when neurotransmitter tone is high (i.e. following a lapse). DA auto receptors stabilize dopaminergic tone and antagonists at these receptors can increase DA release. DA D3 receptors play a critical role in motivation to take drugs. Despite a favorable pharmacological profile and positive preclinical results we are unaware of any human laboratory research that tested the influence of BUSP on the abuse-related effects of MA. Human laboratory research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This proposed study will assess the reinforcin subject-rated performance and physiological effects of MA during maintenance on BUSP. Human drug reinforcement procedures have good predictive validity for the clinical efficacy of MA pharmacotherapies. By determining how BUSP impacts the behavioral effects of MA we will provide important evidence regarding the potential efficacy of this compound for managing MA use disorders. These results will help to broaden the current clinical neuroscience paradigm of MA medications development efforts beyond a focus on DA systems. In addition demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans.

project_terms:
Abstinence;Admission activity;Adverse effects;Agonist;American;Amphetamines;Anti-Anxiety Agents;Attenuated;Autoreceptors;Behavior Therapy;Behavioral;Benzodiazepines;Buspirone;Cardiovascular system;Cereals;Clinical;Clinical Research;Clinical Trials;Communicable Diseases;Communities;Crime;Data;Development;Disease;Dopamine;Dopamine Agonists;Dopamine D2 Receptor;Dose;Enrollment;Exploratory/Developmental Grant;Future;Human;Impaired cognition;Laboratories;Laboratory Procedures;Laboratory Research;Locomotion;Maintenance;Mediating;Medical;Methamphetamine;Methamphetamine dependence;Monkeys;Motivation;National Institute of Drug Abuse;Nausea;Nerve;Neurosciences;Neurotransmitters;Nicotine;Nicotine Use Disorder;Norepinephrine;Opioid;Participant;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Play;Premature Mortality;Probability;Procedures;Productivity;Receptor Serotonin 5-HT1A;Reporting;Research;Resources;Rodent;Role;Safety;Sedation procedure;Self Administration;Serotonin;Synapses;System;Testing;United States;Vesicle;clinical efficacy;clinical practice;cost;dopamine D3 receptor;dopamine system;double-blind placebo controlled trial;drug reinforcement;indexing;innovation;methamphetamine abuse;monoamine;novel;pre-clinical;presynaptic;prevent;public health medicine (field);public health relevance;receptor;reinforcer;research study;response;stereotypy;success;tool

public_health_relevance:
The research proposed in this application will determine the initial efficacy safety and tolerability of buspirone as a putative pharmacotherapy for methamphetamine dependence. This research is important because it will demonstrate the initial efficacy of a commercially available drug buspirone thereby impacting clinical research more quickly than waiting for novel molecules to be available for testing in humans. The proposed study is innovative because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of buspirone for managing methamphetamine dependence.


application_id: 8650771
project_number: 5R01AI065530-11
project_title: Type III exported effectors of Chlamydia trachomatis
administering_ic: NIAID
award_notice_date: 2014-03-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 065530
program_official: HILTKE, THOMAS J
project_start_date: 2005-06-01
project_end_date: 2016-11-14
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The human pathogen Chlamydia trachomatis is a significant concern in the United States due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens and possess the ability to modulate host-cell functions while sequestered within a membrane-bound vacuole. Expression of a virulence-associated type III secretion system (T3SS) represents one mechanism employed to modulate critical host cell pathways. During the past funding cycle we identified multiple chlamydial T3S substrates capable of influencing these host cellular processes. The C. trachomatis locus containing the identified effector protein CT694 contains multiple substrates that are deployed by infectious particles during or subsequent to the invasion process. We propose to elucidate molecular mechanisms regarding the anti-host activities of these proteins and delineate the consequences of effector activity on the ability of Chlamydiae to establish and maintain a specialized intracellular niche. A combination of methods designed to identify interactions of chlamydial proteins with host targets will be employed to establish relevant functions. The consequences of these interactions will be investigated in both a tissue culture infection model and a murine model of acute chlamydial infection. We furthermore propose to evaluate whether differences in these effectors among chlamydial species account for any of the distinct species-specific events related to early chlamydial development. The chlamydial type III secretion system represents an attractive yet relatively unexplored mechanism to achieve modulation of host cell activities. Given the comparative difficulty associated with study of obligate intracellular bacteria investigation of host pathways specifically targeted by the type III secretion mechanism continues to represent a productive approach to elucidate novel pathogenic mechanisms. These studies will lead to an enhanced understanding of Chlamydia-mediated disease and have the potential to yield novel preventative and treatment therapies.

project_terms:
Accounting;Acute;Acute Disease;Address;Affect;Area;Bacteria;Binding (Molecular Function);Cell membrane;Cell physiology;Cells;Cellular Morphology;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chlamydophila pneumoniae;Chronic Disease;Complement;Data;Development;Disease;Economic Burden;Ensure;Environment;Event;Funding;Goals;Health;Homologous Gene;Human;In Vitro;Infection;Investigation;Lead;Maintenance;Mediating;Membrane;Methods;Microbe;Modeling;Molecular;Mus;Pathogenesis;Pathway interactions;Phenotype;Play;Prevalence;Process;Proteins;Relative (related person);Role;Sexually Transmitted Diseases;Type III Secretion System Pathway;United States;Vacuole;Virulence;Work;comparative;design;health economics;in vivo;insight;novel;particle;pathogen;public health relevance;socioeconomics;tissue culture

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specialized secretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis. This application contains work designed to identify these anti-host proteins and determine their specific contributions to chlamydial disease.


application_id: 8650655
project_number: 5R01ES018883-05
project_title: HIF-alphia in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2014-03-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 018883
program_official: REINLIB, LESLIE J
project_start_date: 2010-08-09
project_end_date: 2017-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription translation and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro tumorigenesis tumor growth and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38 promoting Cr(VI)-induced cell transformation tumorigenesis tumor growth and metastasis. .

project_terms:
Anchorage-Independent Growth;Blood Vessels;Carcinogens;Cell Hypoxia;Cell Line;Cells;Development;Diffuse;Dominant-Negative Mutation;Environmental Carcinogens;Epithelial;Exposure to;Female;Generations;Genetic Transcription;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;Hypoxia;In Vitro;Incidence;Inhalation Exposure;International Agency for Research on Cancer;MAPK14 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;NADPH Oxidase;Neoplasm Metastasis;Nose;Nude Mice;Nutrient;Occupational;Occupational Groups;Oxidative Stress;Oxygen;Pathway interactions;Physiological Processes;Play;Post-Translational Protein Processing;Process;Reactive Oxygen Species;Regulation;Reporting;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Source;Superoxides;System;T-Lymphocyte;Testing;Thymus Gland;Translations;Vascular Endothelial Growth Factors;Writing;angiogenesis;cancer initiation;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genetic regulatory protein;hypoxia inducible factor 1;in vivo;insight;millimeter;mitogen-activated protein kinase p38;new growth;overexpression;public health relevance;tumor;tumor growth;tumor progression;tumorigenesis;wasting

public_health_relevance:
Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesize that Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathway leading to cell transformation tumorigenesis tumor growth and metastasis. The goal of this proposal is to test that hypothesis.


application_id: 8649942
project_number: 2P42ES007380-17A1
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2014-04-04
opportunity_number: RFA-ES-13-001
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
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: 2014-04-01
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;Reaction;Relative (related person);Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solutions;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;cost effective;dechlorination;demineralization;design;drinking;drinking water;global environment;hazard;innovation;iron oxide;metal oxide;microbial;nanoparticle;nanoscale;nanosized;nanostructured;novel;nutrition;oxidation;particle;pollutant;prevent;public health medicine (field);remediation;scaffold;sensor;superfund chemical;superfund site;treatment strategy


application_id: 8649941
project_number: 2P42ES007380-17A1
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2014-04-04
opportunity_number: RFA-ES-13-001
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
suffix: A1
study_section: Special Emphasis Panel[ZES1 LKB-K (S)]
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: 2014-04-01
project_terms:
Address;Affinity;Antibodies;Binding (Molecular Function);Binding Proteins;Biodistribution;Biological;Biomimetics;Chemistry;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Relative (related person);Reporting;Research;Resources;Risk;Route;Sampling;Sensitivity and Specificity;Soil;Solubility;Solutions;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;fundamental research;global environment;imprint;nanocomposite;nanomaterials;nanoparticle;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polymerization;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site;tool


application_id: 8649511
project_number: 7R01DA023087-06
project_title: Impulsive Behavior and Treatment Outcomes for Adolescent Smoking
administering_ic: NIDA
award_notice_date: 2013-04-11
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: DA
serial_number: 023087
program_official: GROSSMAN, DEBRA
project_start_date: 2008-07-01
project_end_date: 2014-06-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7740063
contact_pi: REYNOLDS, BRADY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this research is to assess the relationships between different dimensions of impulsive behavior and treatment response for adolescent smokers receiving treatment to quit or reduce their smoking. This study will collect data from and follow over time treatment-seeking adolescent smokers who are enrolled in a widely-prescribed adolescent smoking treatment program. Laboratory behavioral assessments of impulsivity including assessments of delay and probability discounting behavioral disinhibition and sustained attention will be examined as predictors of (a) adherence to the smoking-treatment program (b) the ability of these adolescent smokers to quit or reduce smoking during treatment and (c) the continuation of changed smoking behaviors (reductions in smoking) during the 24 weeks following treatment. It is expected that this research will establish a behavioral profile for teen smokers who want to quit or reduce smoking but who are ultimately unsuccessful in changing their smoking behavior during treatment. The inclusion of laboratory behavioral assessments will provide highly detailed information about the specific behavioral styles of adolescent smokers who are unable to effectively change their smoking behaviors during a treatment program. This information should provide new points of emphasis for treatment-program modifications to improve these programs to be more effective for those adolescents most challenged in their efforts to quit or reduce smoking. The potential of this research to guide treatment modifications oriented to reducing adolescent cigarette smoking makes it relevant to important public-health issues involving cigarette smoking and the mission of the National Institute on Drug Abuse. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the top preventable cause of death in the United States. This study will advance our understanding of the different behavioral styles associated with an adolescent's ability to quit or reduce smoking during treatment for smoking cessation. It is expected that the results of this study will guide smoking treatment modifications to make these treatments more effective for adolescents who are trying to quit or reduce smoking.


application_id: 8649000
project_number: 5R01AI093450-05
project_title: Development of New Bivalent Cross-Protective Arenaviral Vaccines
administering_ic: NIAID
award_notice_date: 2014-03-12
opportunity_number: RFA-AI-10-003
application_type: 5
activity_code: R01
ic: AI
serial_number: 093450
program_official: REPIK, PATRICIA M
project_start_date: 2011-04-01
project_end_date: 2016-03-31
study_section: ZAI1-NLE-M(J3)
contact_pi_person_id: 6955101
contact_pi: LUKASHEVICH, IGOR S.
other_pis: PUSHKO, PETER M.
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): Highly pathogenic arenaviruses Lassa Junun Machupo are dominant viral species among NIAID Category A Priority Pathogens. The development of safe and efficacious vaccines against these pathogens with particular emphasis on multivalent and cross protective strategy and advanced platform technology is one of the priorities of NIH/NIAID. The main goal of this project is an advanced development and optimization of alphavirus-based VLPV (virus-like-particle-vectors) technology (patent is pending) as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses. Using this technology and rational vaccine design we will develop: (i) a bivalent LASV vaccine with enhanced immunogenicity and cross-protective potential against distantly-related LASV genotypes and (ii) a bivalent JUNV&MACV vaccine. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for preclinical testing in nonhuman primates. SPECIFIC AIM I: Rational Design of Multivalent VLPV Expressing Arenaviral Glycoproteins with Enhanced Immunogenicity and Cross-Reactivity. The goal of this aim is to design: (i) VLPV expressing LASV GP able to induce strong CD8+ T cell responses to distantly-related LASV lineages I and IV through the conventional MHC I peptide presentation and through cross-priming; ii) VLPV expressing JUNV&MACV GP to induce neutralizing Abs against both pathogens; and iii) to optimize alphavirus bi-cistronic replicon structures for product development. SPECIFIC AIM II: Selection of Immunogenic and Cross-Reactive Recombinant VLPV Vaccines in Experimental Animals. In-process Safety Testing. SPECIFIC AIM III: Pre-Clinical Safety Immunogenicity and Efficacy in NHP. Tox Lot vaccine products will be tested for Safety Immunogenicity and Efficacy in the NHP challenge model we recently developed. The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses Lassa-Junin-Machupo. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for Safety Immunogenicity and Efficacy Studies in non-human primates

project_terms:
Advanced Development;Adverse event;Affect;Africa;Alphavirus;Am 80;Animals;Antigen-Presenting Cells;Antigens;Arenavirus;Attenuated Live Virus Vaccine;Bolivian Hemorrhagic Fever Virus;CD8B1 gene;Categories;Cavia;Cells;Cessation of life;Cross-Priming;DNA;Development;Ebola virus;Ensure;Environment;Equilibrium;Filovirus;Frequencies (time pattern);Generic Drugs;Genes;Genetic;Genotype;Geographic Distribution;Glycoproteins;Goals;Human;Immunization;Individual;Junin virus;Lassa Fever;Lassa virus;Lead;Legal patent;Modeling;Mus;National Institute of Allergy and Infectious Disease;Nucleoproteins;Old World Arenaviruses;Peptides;Preclinical Testing;Preventive;Process;Production;Promotor (Genetics);Recombinants;Replicon;Safety;South Africa;Structural Protein;Structure;T cell response;Tacaribe Complex Viruses;Technology;Technology Transfer;Testing;United States National Institutes of Health;Vaccination;Vaccine Design;Vaccines;Viral;Viral Hemorrhagic Fevers;Virus;Virus-like particle;base;biodefense;cross reactivity;design;environmental change;immunogenic;immunogenicity;neutralizing antibody;next generation;nonhuman primate;particle;pathogen;peptide I;pre-clinical;product development;public health medicine (field);recombinant virus;safety testing;scale up;vaccine safety;vector;vector vaccine

public_health_relevance:
The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefensevaccines against highly pathogenic arenaviruses Lassa-Junin-Machupo. The VLPVtechnology will be transferred to a manufacturing environment and scaled-up to produceGLP-grade vaccines for Safety Immunogenicity and Efficacy Studies in non-humanprimates


application_id: 8646572
project_number: 2R44AI098179-02
project_title: Biological vector control reducing arboviruses including Dengue and Chikungunya
administering_ic: NIAID
award_notice_date: 2014-05-15
opportunity_number: PA-13-088
application_type: 2
activity_code: R44
ic: AI
serial_number: 098179
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2012-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-V (12)]
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the absence of effective approved drugs or vaccines vector control remains the only means of intervention for many against mosquito-borne diseases. This problem grows more complex with the recent establishment of multiple exotic mosquito species and mosquito-borne pathogens. Furthermore changing climate conditions are predicted to alter the traditional range for native mosquitoes. A notable example is Aedes albopictus the Asian Tiger mosquito introduced into the USA in the mid-1980s this invasive species has spread throughout the southeast and with warmer winters its range is now moving into New York and other northern states where it has become the primary biting mosquito. A stable infestation was discovered in California in 2011 which persists despite an ongoing elimination campaign. The cryptic biology of this mosquito makes it difficult to find and treat using traditional insecticidal approaches. In addition to its importance as a biting nuisance A. albopictus is a competent vector of over twenty pathogens. Epidemiological models show risk of returning travelers infected with chikungunya virus infecting A. albopictus and starting local
transmission. This hypothesized event would be similar to recent epidemics that have occurred in Europe India Sri Lanka and La Reunion. Our discussions with major mosquito control districts around the country (California Florida New York) demonstrate the need and commercial opportunity for new approaches against A. albopictus and an interest in the our product. Our Phase I results demonstrate feasibility of a Wolbachia biopesticide approach. Repeated releases of Wolbachia- infected males cause a form of conditional sterility capable of eliminating an A. albopictus population within eight weeks. In the proposed Phase II work we will continue the research and development of the Wolbachia biopesticide approach with the major goals of (1) demonstrating a prototype mass production unit (2) providing field performance data for Wolbachia-infected A. albopictus males and (3) measuring the pesticidal effect of Wolbachia- infected A. albopictus males against an indigenous field population.

project_terms:
Adult;Aedes (genus);American Samoa;Arboviruses;Asians;Bacteria;Biological;Biological Assay;Biology;Bite;California;Chikungunya virus;Collaborations;Complex;Country;Culicidae;Data;Dengue;Disease;Disease Vectors;Environment;Epidemic;Epidemiologist;Europe;Event;Female;Florida;Goals;Grant;India;Indigenous;Insecticides;Intervention;Kentucky;Legal patent;Licensing;Longevity;Los Angeles;Marketing;Measures;Medical;Methods;Modeling;Monitor;Mosquito Control;Mosquito-borne infectious disease;Native-Born;New York;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Population;Positioning Attribute;Practice Management;Preparation;Production;Recommendation;Regulatory Pathway;Risk;Simulate;Site;Sri Lanka;Sterility;System;Technology;Tigers;Time;Vaccines;Vision;Wolbachia;Work;chikungunya;climate change;commercialization;cost;density;design;effective therapy;epidemiological model;fitness;improved;interest;male;manufacturing process;novel strategies;pathogen;prototype;public health relevance;research and development;sex;tool;transmission process;vector;vector control;vector mosquito

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective control tools are needed against the invasive disease vector mosquito Aedes albopictus (Asian Tiger mosquito). Contained trials in Phase I have shown that the repeated release of males infected with Wolbachia bacteria can cause sterility and eliminate A. albopictus populations. The proposed Phase II work will (1) demonstrate efficacy of the control approach in the field against an established population and (2) improve product production to improve the overall production levels and reduce downstream cost.


application_id: 8645914
project_number: 1R43DE024015-01
project_title: Rapid Point-of-Care Salivary Diagnostic for Periodontal Health
administering_ic: NIDCR
award_notice_date: 2014-07-25
opportunity_number: PA-13-088
application_type: 1
activity_code: R43
ic: DE
serial_number: 024015
program_official: ATKINSON, JANE C
project_start_date: 2014-08-01
project_end_date: 2016-07-15
study_section: Special Emphasis Panel[ZRG1 MOSS-K (11)]
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078739664
duns_number: 078739664
fips: US
organization_id: 10033642
organization_name: INNOVATIVE DIAGNOSTICS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-08-01
budget_end_date: 2016-07-15
project_abstract:
DESCRIPTION (provided by applicant): The dental profession has searched for many years for additional "real time" chair-side measures to provide objective measures to aid in the monitoring of periodontal health and early diagnosis of disease. Research efforts have produced solid evidence that constituents present in saliva can provide important complimentary diagnostic information and have the potential for point-of-care (POC) device use by dental/healthcare professionals and the general public. Of the many biomarkers demonstrated in saliva accumulated evidence shows that matrix metalloproteinase (MMP)-8 has high sensitivity and specificity for discriminating periodontal disease from health and is present at a high concentration in saliva. Yet rapid chairside biochemical tests that utilize this informatio for risk assessment of periodontal disease are not yet available in the U.S. We are developing a hand held (1.5 x 3 inch) POC device that detects MMP-8 in saliva. This device designated "Quik-'PD" measures MMP-8 by lateral flow chromatography. Our recent findings involving the sensitivity specificity and accuracy of this device suggest that this product is commercially viable and potentially effective for assessing the risk for periodontitis. The goals of this Phase  SBIR proposal are to confirm the accuracy of the device for detecting a broad range of MMP-8 concentrations in saliva to develop a smartphone app to evaluate results and to establish a pathway for FDA approval. Phase I of the SBIR funded research involves testing the accuracy of the device using saliva from 174 participants. The Phase II SBIR will be a large validation study involving thousands of participants which is required to meet FDA guidelines. The Phase I study has three Specific Aims: Aim 1: Determine the accuracy of Quik-'PD for detecting MMP-8 levels in saliva Aim 2: Develop prototype software for detection of results Aim 3: Establish regulatory feasibility

project_terms:
Adoption;Affect;Agreement;Biochemical;Biological;Biological Assay;Biological Markers;Chromatography;Clinical;Collaborations;Color;Computer software;Dental;Dentistry;Dentists;Detection;Development;Devices;Diagnostic;Diagnostic tests;Discriminant Analysis;Disease;Doctor of Philosophy;Early Diagnosis;Engineering;Ensure;Funding;General Population;Gingivitis;Goals;Gold;Guidelines;Hand;Health;Health Professional;Health Transition;Human;Image;Immune response;Immunoassay;Immunology;Inflammatory;Institutional Review Boards;Kentucky;Laboratories;Lateral;Lead;Life;Measurable;Measures;Methods;Microbiology;Monitor;Neutrophil Collagenase;Numerical value;Oral Medicine;Participant;Pathogenesis;Pathway interactions;Performance;Periodontal Diseases;Periodontitis;Phase;Procedures;Reading;Reporting;Research;Research Personnel;Risk;Risk Assessment;Saliva;Salivary;Sample Size;Sampling;Scanning;Sensitivity and Specificity;Severities;Side;Small Business Innovation Research Grant;Software Engineering;Solid;Speed (motion);Technology;Testing;Time;Tissues;Translating;Universities;base;biomedical scientist;clinical practice;commercialization;cost;disorder risk;improved;innovation;meetings;novel;phase 1 study;point of care;prototype;research clinical testing;saliva diagnostic;validation studies;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontal disease is an inflammatory and destructive disease that silently affects millions of people. The purpose of this study is to develop a novel point-of-care device that evaluates human saliva in order to provide a simple rapid non-invasive highly sensitive and accurate diagnostic risk assessment for periodontitis.


application_id: 8645880
project_number: 1R43HL121970-01
project_title: Wireless Vagal Nerve Stimulation System for Treating Atrial Fibrillation
administering_ic: NHLBI
award_notice_date: 2014-07-18
opportunity_number: PA-13-088
application_type: 1
activity_code: R43
ic: HL
serial_number: 121970
program_official: LATHROP, DAVID A
project_start_date: 2014-07-21
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 10313138
contact_pi: DUKE, AUSTIN ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 968130778
duns_number: 968130778
fips: US
organization_id: 10032915
organization_name: ROSELLINI SCIENTIFIC, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-21
budget_end_date: 2015-12-31
project_abstract:
DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial risk of morbidity and mortality. AF currently affects more than 2.5 million Americans and the affected population is steadily growing with our aging society. AF independently increases the risk of stroke by 4- to 5-fold is an independent risk factor for stroke recurrence and is responsible for at least 15-20% of all ischemic strokes. In addition to its associated health risks and diminished quality of life AF is a financial burden
on the US Healthcare system with annual Medicare costs currently estimated at $16 billion. Over the past decade neuromodulator emerged as an alternative to antiarrhythmic medications and ablative procedures for the treatment of some forms of AF. Applying low levels of electrical stimulation to the vagus nerves inhibits AF inducibility. This innovative form of neural cardiac control is a non-pharmacological non- ablative modality for the treatment of AF that maintains healthy myocardium. The ultimate goal of this project is to enhance the quality of life for individuals with AF by translating this recent cutting edge research into a clinically viable technology. To date the majority of studies investigating neuromodulation as a treatment for AF were acute procedures. To progress this approach towards clinical application will require the development of suitable devices capable of chronic stimulation. Rosellini Scientific has partnered with Stimwave Technologies Inc. to apply their wireless spinal cord stimulation technology to a form factor and therapeutic treatment protocol suitable for low-level vagus nerve stimulation (LL-VNS) to treat AF. The goal of the proposed study is to evaluate the therapeutic value of LL- VNS for treating AF in a long-term study. To accomplish this goal we will implant our system in a high-yield canine model of AF and evaluate changes in AF frequency as a result of LL-VNS for a period of 4 weeks. During the experimental period an implantable pulse generator (IPG) will deliver rapid atrial pacing (RAP) to the left atrial appendage for 6 hours/day
to induce AF. Concurrent with RAP the experimental group will receive LL-VNS from the Rosellini Scientific VNS system while the control group will receive sham stimulation. The weekly AF burden defined as the sum of the duration of all spontaneous AF episodes during the period without RAP will be calculated and compared between groups. For our treatment to be indicated as feasible we must see e 50% reduction in AF burden for the treatment group versus control. If feasibility is achieved we will apply to the NIH for Phase 2 funding to determine the appropriate treatment protocol in a chronic study and will submit a U44 to further develop the device.

project_terms:
Accounting;Acute;Affect;Aging;American;Animals;Arrhythmia;Atrial Fibrillation;Autonomic nervous system;Biomedical Engineering;Canis familiaris;Cardiac;Cessation of life;Chronic;Computational Biology;Control Groups;Development;Device or Instrument Development;Devices;Doctor of Philosophy;Electric Stimulation;Electrodes;Electronics;Frequencies (time pattern);Funding;Goals;Health;Healthcare Systems;Heart Atrium;Heart Rate;Hour;Human Resources;Implant;Individual;Intervention;Ischemic Stroke;Left;Legal patent;Longitudinal Studies;Medical Device;Medicare;Methods;Metric;Modality;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Multi-Institutional Clinical Trial;Myocardium;Nerve;Neuromodulator;Neurosciences;Neurostimulation procedures of spinal cord tissue;Pathology;Pharmaceutical Preparations;Phase;Physiologic pulse;Population;Procedures;Publishing;Quality of life;Recurrence;Research;Risk;Risk Factors;Societies;Sum;System;Techniques;Technology;Testing;Therapeutic;Tinnitus;Translating;Treatment Protocols;United States National Institutes of Health;Vagus nerve structure;Wireless Technology;auricular appendage;austin;clinical application;cost;implantable device;innovation;nervous system disorder;neuroregulation;neurotechnology;novel;pre-clinical;public health relevance;relating to nervous system;stroke;vagus nerve stimulation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Atrial Fibrillation (AF) is the most common cardiac arrhythmia affecting more than 2.5 million Americans. AF independently increases the risk of stroke and stroke recurrence and is associated with an increase in the risk of death. This is a proposal to develop a device to provide treatment for AF.


application_id: 8645565
project_number: 5R01AG037868-04
project_title: Psychosocial stress interactions with electrophysiology and brain aging
administering_ic: NIA
award_notice_date: 2014-02-21
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: WISE, BRADLEY C
project_start_date: 2011-03-01
project_end_date: 2016-02-29
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
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): This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices immunohistochemistry with a battery of stains separate microarray analysis of individual rat brains EEG monitoring of sleep patterns and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral electrophysiological sleep monitoring microarray and immunohistochemical analyses to test the proposition that conversion these interventions may reduce/reverse UBA symptoms and if so to determine through which brain pathways this occurred. Overall these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers and should importantly determine the role of age in modulating stress impact. Further the proposed intervention studies should have direct translational relevance.

project_terms:
21 year old;Accounting;Acute;Address;Adrenal Glands;Affect;Age;Age-Months;Aging;Animals;Area;Behavioral;Blood;Brain;Chronic;Chronic stress;Cognition;Cognitive aging;Development;Electroencephalography;Electrophysiology (science);Ensure;Exhibits;Exposure to;Gene Expression;Genomics;Glial Fibrillary Acidic Protein;Hippocampus (Brain);Hormones;Human;Immunohistochemistry;Inbred F344 Rats;Individual;Inflammatory;Intervention;Intervention Studies;Killings;Link;Literature;Longitudinal Studies;Mediating;Microarray Analysis;Mifepristone;Modeling;Monitor;NIH Program Announcements;Nature;Neurobiology;Outcome;Outcome Measure;Pathway interactions;Pattern;Polysomnography;Predisposition;Process;Psychosocial Stress;RU-486;Rattus;Research;Resistance;Role;Sleep;Sleep disturbances;Slice;Staining method;Stains;Steroids;Stress;Symptoms;Techniques;Testing;Therapeutic;Time;Trazodone;Wireless Technology;Work;age group;age related;aged;aging brain;behavior test;biological adaptation to stress;brain pathway;combat;environmental enrichment for laboratory animals;functional outcomes;genome-wide;interdisciplinary approach;interest;intervention effect;middle age;morris water maze;multidisciplinary;novel;prevent;public health relevance;research study;response;restraint;restraint stress;serotonergic regulation;steroid hormone;stressor;transmission process;voltage clamp;young adult

public_health_relevance:
This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function in an established rat model of aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy brain aging focusing on changes beginning around midlife and will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects of psychosocial stress. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human brain aging.


application_id: 8645141
project_number: 1R41DK097862-01A1
project_title: Mitochondrial Uncoupling as a Therapeutic Target in Obesity
administering_ic: NIDDK
award_notice_date: 2014-09-15
opportunity_number: PA-13-089
application_type: 1
activity_code: R41
ic: DK
serial_number: 097862
suffix: A1
program_official: DENSMORE, CHRISTINE L
project_start_date: 2014-09-16
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1 EMNR-E (10)]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 171691988
duns_number: 171691988
fips: US
organization_id: 10030824
organization_name: NANO-MITE TECHNOLOGIES, LLC
organization_city: GEORGETOWN
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403248040
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-09-16
project_abstract:
DESCRIPTION (provided by applicant): Obesity is recognized as a national and global epidemic as approximately 65% of adults in the United States are classified as overweight or obese as defined by body mass index (BMI). In fact in the year 2000 the human race reached a historical landmark when for the first time in history the number of adults with excess weight surpassed the number of those who were underweight. Obesity is linked with several cardiovascular risk factors cumulatively recognized as the metabolic syndrome. While obesity is associated with increased risk for metabolic syndrome and cardiovascular disease; consequently weight loss in obese subjects has been demonstrated to reduce or reverse health risk factors. Fundamentally irrespective of the method by which weight loss occurs even a modest reduction in body weight has been shown to consistently reduce or reverse risk factors. In the 1930s it was recognized that increasing the body's basal metabolism using mitochondrial uncouplers directly resulted in steady and rapid weight loss. During this period the mitochondrial uncoupler 24-dinitophenol (24-DNP) was sold over the counter as a weight-loss supplement. It is the only compound to date that has been shown to be 100% effective for weight-loss; however it was eventually pulled from the shelves by the FDA as people were routinely overdosing on the compound in an effort to increase their rate of weight loss. To overcome this challenge we have developed and patented non-carbon-based "self-rectifying" nano-scale devices in which we can specifically and step-wise set the uncoupling capacity that when reached shuts the device off to further proton conductance. The goal of the current application is to further establish proof of concept and to explore the potential use of these devices to promote weight loss.

project_terms:
24-Dinitrophenol;Address;Adult;Animals;Basal metabolic rate;Biodistribution;Bioenergetics;Body Composition;Body Weight;Body Weight decreased;Body mass index;Brain;Calories;Cardiovascular Diseases;Cessation of life;Custom;Data;Devices;Diet;Dose;Epidemic;Food;Generations;Genus Hippocampus;Glucose;Goals;Health;Heart;Heating;Human;Hyperthermia;In Vitro;Indirect Calorimetry;Laboratories;Legal patent;Link;Liver;Membrane Potentials;Metabolic syndrome;Methods;Mites;Mitochondria;Modeling;Mus;Muscle;Nanomanufacturing;Obesity;Overdose;Overweight;Pathology;Phase;Pilot Projects;Production;Property;Protons;Race;Recording of previous events;Respiration;Risk;Risk Factors;Rodent Model;Series;Serum;System;Techniques;Technology;Testing;Time;Toxic effect;Uncoupling Agents;Underweight;United States;United States Food and Drug Administration;Weight;base;cardiovascular risk factor;dosage;efficacy testing;in vivo;insulin tolerance;mitochondrial membrane;nanoscale;public health relevance;sound;success;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is recognized as a national and global epidemic as approximately 65% of adults in the United States are classified as overweight or obese as defined by body mass index (BMI). The goal of this project is to uncouple mitochondria in a controlled manner to induce weight loss.


application_id: 8644866
project_number: 5R01HL107319-03
project_title: Mechanisms of thoracic aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2014-03-28
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 107319
program_official: TOLUNAY, ESER
project_start_date: 2012-04-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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): Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases; one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics.  We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis the following specific aims will be addressed: Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression?

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Address;Affect;Angiotensin II;Anterior;Aorta;Area;Attenuated;Blood;CC chemokine receptor 2;CCL2 gene;Cardiac;Cells;Cessation of life;Complex;Defect;Development;Diagnosis;Disease;Embryo;Endothelial Cells;Fibroblasts;Growth;Health;Heart;Human;Individual;Infiltration;Infusion procedures;Leukocytes;Life;Ligands;Literature;Medial;Mediating;Mediator of activation protein;Medical;Monocyte Chemoattractant Protein-1;Mus;Neural Crest;Operative Surgical Procedures;Pathology;Patients;Pericytes;Population;Research;Role;Rupture;Smooth Muscle Myocytes;Source;Specificity;Structure;Surface;Testing;Therapeutic;Thoracic Aortic Aneurysm;Thoracic aorta;Tissues;Tunica Adventitia;Ulcer;ascending aorta;attenuation;base;cell type;chemokine;disease characteristic;insight;macrophage;neutralizing antibody;paracrine;public health medicine (field);receptor

public_health_relevance:
Aortic aneurysmal diseases have devastating health consequences and are increasingly more common. Despite the large impact on public health there is a relatively paucity of investigative efforts on these diseases. Consequently there are no defined medical options developed to provide an alternative to surgical intervention. Further research in aortic aneurysmal diseases is a public health imperative.


application_id: 8644776
project_number: 5K02AG033629-03
project_title: Self-Regulation and Aging: Substrates and Health Consequences
administering_ic: NIA
award_notice_date: 2014-02-18
opportunity_number: PA-10-057
application_type: 5
activity_code: K02
ic: AG
serial_number: 033629
program_official: NIELSEN, LISBETH
project_start_date: 2012-03-15
project_end_date: 2017-02-28
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
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): Suzanne C. Segerstrom is an independent investigator (PhD 1997) who has established a productive research program in personality self-regulation and physiology. The application proposes to protect a high level of research effort (80%) by releasing her from teaching service and administrative responsibilities. This support will facilitate an expansion of her research program in the interactions among self-regulation physiology well-being and health in older adults. The application has three foci: (i) executive cognitive function and heart rate variability are predicted to covary with self-regulatory success (ii) self-regulatory success across domains (e.g. control of repetitive thought acquisition of social or status resources) is predicted to correlate with mental and physical health and (iii) social resources will have disproportionate effects on health with increasing age as predicted by socioemotional selectivity theory. Career development activities under the award will include didactic and experiential training in aging longitudinal design and analysis and the responsible conduct of research; collaborations with dedicated aging researchers in cognition neuropsychology immunology neurology and methodology; and spearheading special projects and meetings. Research activities will include analysis of the relationship between executive function and self- regulation in her existing R01-funded longitudinal research with community-dwelling older adults (N = 150) and studies of self-regulation and health in the R01 sample a cross-sectional study of younger and older women focusing on immunosenescence (N=76) a longitudinal follow-up in a study of middle-aged adults (N = 96) that began in 1994 and a longitudinal study of amyotrophic lateral sclerosis patients and caregivers (N = 266). Proposed studies illustrating future directions examine the role of goal selection and optimization in promoting psychological and physiological well-being in older women with pain and the role of self-regulation in socioemotional selectivity and the contributions of executive cognitive function and heart rate variability to this relationship in older adults. The University of Kentucky and the Department of Psychology provide a rich environment for the development of this work. It is expected that K02 support would allow Dr. Segerstrom to acquire additional expertise in cognition physiology and aging; produce and disseminate cutting-edge research in self-regulation aging and health; expand her grant portfolio to continue this line of research; and train PhD students in the conduct of this research.

project_terms:
Adult;Age;Aging;Amyotrophic Lateral Sclerosis;Attention;Award;Behavior;Caregivers;Cognition;Collaborations;Communities;Cross-Sectional Studies;Data Collection;Databases;Development;Disease Progression;Doctor of Philosophy;Educational process of instructing;Elderly;Emotional;Emotions;Environment;Failure (biologic function);Funding;Future;Goals;Grant;Health;Health Resources;Hydrocortisone;Immune response;Immunology;Individual;Individual Differences;Inflammation;Informal Social Control;Interleukin-6;Kentucky;Lead;Longevity;Longitudinal Studies;Medical;Memory;Mental Depression;Mental Health;Methodology;Neurology;Neuropsychology;Pain;Patients;Peripheral;Personal Satisfaction;Personality;Physiological;Physiology;Process;Psychology;Regimen;Regulation;Research;Research Activity;Research Personnel;Resources;Rest;Risk;Role;Sampling;Science;Self-control as a personality trait;Series;Services;Social Interaction;Social status;Students;Testing;Thinking function;Time;Training;United States National Institutes of Health;Universities;Vaccination;Work;behavior change;beta-2 Microglobulin;career development;cognitive function;executive function;falls;follow-up;heart rate variability;immune activation;immunosenescence;longitudinal analysis;longitudinal design;meetings;middle age;older women;physical conditioning;programs;psychologic;psychosocial;public health medicine (field);research study;response;responsible research conduct;satisfaction;social;success;theories;thought control;young woman

public_health_relevance:
NARRATIVE Older adults' ability to control thoughts emotions and behaviors - that is to self-regulate - is important for acquiring and maintaining resources such as social relationships as well as meeting other demands such as compliance with medical regimens. Understanding the underlying resources for self-regulation such as cognitive function as well as the psychological social and physical consequences of self-regulatory ability and success is important for optimizing older adults' health and well-being.


application_id: 8644758
project_number: 5K23AA018399-05
project_title: Zinc supplementation in alcoholic cirrhosis
administering_ic: NIAAA
award_notice_date: 2014-04-01
opportunity_number: PA-09-043
application_type: 5
activity_code: K23
ic: AA
serial_number: 018399
program_official: WANG, JOE
project_start_date: 2010-04-01
project_end_date: 2016-03-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology clinical trial design and biostatistics and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01) and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis we will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status (ii) increased intestinal tight junctions with decreased permeability (iii) improved serum pro-inflammatory cytokine profile (iv) reduced oxidative stress and improved serum antioxidant status (v) reduced hepatocyte death (vi) decreased fibrosis and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.

project_terms:
Accounting;Advisory Committees;Alcohol consumption;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcoholism;American;Animal Model;Antioxidants;Attenuated;Biometry;Blood Circulation;Board Certification;Cell Death;Cell Wall;Cessation of life;Child;Chronic;Cirrhosis;Clinical;Clinical Research;Clinical Trials Design;Data;Development;Development Plans;Disease;Doctor of Medicine;Double-Blind Method;Drops;Endotoxemia;Endotoxins;Epithelial;FDA approved;Fibrosis;Funding;Generations;Goals;Gram-Negative Bacteria;Health Benefit;Hepatocyte;Human;Immune system;Inflammatory;Interdisciplinary Study;Intestines;Kupffer Cells;Liver;Master of Science;Mediator of activation protein;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oral;Oxidative Stress;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Placebo Control;Play;Primary carcinoma of the liver cells;Principal Investigator;Production;Publishing;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Research Proposals;Role;Safety;Serum;Staging;Structure;Supplementation;TNF gene;Techniques;Testing;Tight Junctions;Toxicology;Translational Research;United States;Universities;Venous;Work;Zinc;Zinc Sulfate;Zinc deficiency;alcohol research;animal data;base;career development;clinical practice;cytokine;human subject;improved;liver injury;nutrition;prevent;problem drinker;programs;public health relevance;translational approach

public_health_relevance:
This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.


application_id: 8644591
project_number: 1R25AA022823-01
project_title: Basic and Applied Summer Training in Alcohol Research
administering_ic: NIAAA
award_notice_date: 2014-01-28
opportunity_number: PAR-13-104
application_type: 1
activity_code: R25
ic: AA
serial_number: 022823
program_official: GRANDISON, LINDSEY
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advertising;Alcohol consumption;Alcohols;Arts;Behavioral Sciences;Biomedical Research;Brain Injuries;Career Choice;Cellular biology;Development;Domestic Violence;Engineering;Evaluation;Faculty;Goals;Hand;Institution;Kentucky;Laboratories;Laboratory Personnel;Mathematics;Nerve Degeneration;Pharmacologic Substance;Play;Qualifying;Research;Research Infrastructure;Role;STEM field;Schools;Science;Students;Supervision;Surveys;Technology;Training;Underrepresented Minority;Universities;Work;addiction;alcohol research;bench to bedside;career;college;experience;peer;programs;public health relevance;responsible research conduct;scientific organization;success;symposium;undergraduate research;undergraduate student;web site


application_id: 8644453
project_number: 7R01DA023476-04
project_title: Web-Based Contingency Management for Smoking Abstinence with Adolescents
administering_ic: NIDA
award_notice_date: 2013-04-08
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: DA
serial_number: 023476
program_official: GROSSMAN, DEBRA
project_start_date: 2010-03-01
project_end_date: 2015-03-31
study_section: ZDA1-GXM-A(06)M
contact_pi_person_id: 7740063
contact_pi: REYNOLDS, BRADY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Adolescence may represent a uniquely challenging life period for smoking-cessation efforts. Many current cigarette smokers began smoking during adolescence and there is substantial evidence that the vast majority of adolescents who ever smoked daily continue smoking into adulthood. However as many as 65% of adolescent daily smokers report wanting to quit or reduce smoking. The disparity between adolescent smokers reporting an interest in abstinence and the percentage of these adolescents who ultimately continue smoking into adulthood illustrates the need for feasible and powerful behavioral treatments to support this population. In response to the need for treatments appropriate for adolescent smokers this research (utilizing a two-group randomized-control design n = 63 per group) will evaluate the effectiveness and efficacy of a new and innovative Internet-based contingency-management (CM) program for smoking abstinence with adolescent smokers. Because this CM program is Internet based it can be completed from home which stands to be more viable as a treatment option for adolescent smokers than other treatments requiring frequent trips to a clinical facility. From preliminary work with adult and adolescent smokers it is expected this treatment program will be highly effective in creating favorable changes in adolescent smoking behavior. This research will also involve eight monthly post-treatment follow-up sessions to determine long-term consistencies or changes in smoking behavior. A secondary goal of this research is to explore pre-treatment assessments of different dimensions of impulsive behavior as predictors of treatment outcome. These behavioral assessments will provide highly detailed information about the specific behavioral styles of adolescent smokers who are unable to effectively change their smoking behavior during treatment. This information should provide new points of emphasis for treatment- program modifications to improve these programs to be more effective for adolescents most challenged in their efforts to quit or reduce smoking.    PUBLIC HEALTH RELEVANCE: Cigarette smoking is the top preventable cause of death in the United States. This study will evaluate a novel behavioral treatment for cigarette smoking cessation with adolescent smokers. Further this study will advance our understanding of the different behavioral styles associated with an adolescent's ability to quit or reduce smoking during a treatment program for smoking cessation. This latter aim is expected to guide smoking treatment modifications to make these treatments more effective for adolescents who are trying to quit or reduce smoking.

public_health_relevance:
Cigarette smoking is the top preventable cause of death in the United States. This study will evaluate a novelbehavioral treatment for cigarette smoking cessation with adolescent smokers. Further this study will advanceour understanding of the different behavioral styles associated with an adolescent's ability to quit or reducesmoking during a treatment program for smoking cessation. This latter aim is expected to guide smokingtreatment modifications to make these treatments more effective for adolescents who are trying to quit orreduce smoking.


