# projects

application_id: 8360100
project_number: 5P20RR016481-11
project_title: EKU - LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8414
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The goal of this project is to provide INBRE support at Eastern Kentucky University. The PI provides research opportunities to undergraduate students and appropriate seminar speakers.

project_terms:
Biomedical Research;Funding;Goals;Grant;Kentucky;Lead;National Center for Research Resources;Principal Investigator;Research;Research Infrastructure;Resources;Source;Students;United States National Institutes of Health;Universities;cost


application_id: 8360099
project_number: 5P20RR016481-11
project_title: MSU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8413
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The major objective of the proposed project is to facilitate the development of faculty and student biomedical research activities with the overall goal of creating a self-sustaining biomedical research program and infrastructure at MSU independent of INBRE funding. This goal will be accomplished through two complimentary mechanisms. First faculty and student biomedical research capacity will be enhanced through participation in the state-wide INBRE program of investigator-initiated research projects student summer workshops seminars bioinformatics programs etc. Second faculty and student research will be encouraged and supported through the continuation of an MSU INBRE program that supports biomedical research and travel faculty NIH research grant proposal development and an INBRE seminar series.

project_terms:
Applications Grants;Bioinformatics;Biomedical Research;Development;Educational workshop;Faculty;Funding;Goals;Grant;Investigator-Initiated Research;Lead;National Center for Research Resources;Principal Investigator;Research;Research Activity;Research Infrastructure;Research Project Grants;Resources;Series;Source;Students;Travel;United States National Institutes of Health;cost;programs


application_id: 8360098
project_number: 5P20RR016481-11
project_title: INBRE: UOFL: GENOMICS CORE
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8412
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The shared centralized research core facility is designed to provide sequencing and gene-micro-array services to the University of Louisville and its KBRIN/INBRE affiliated institutions. 

In September 2009 the UofL Microarray Facility moved to the new Clinical Translational Research Building (CTRB) opened in August 2009 on the same Health Science Center Campus. This building provides state-of-the-art new and expanded lab space for the Facility. The new facility is approx. 1500 square feet which includes four large lab areas with benches a separate room for processing ozone sensitive Agilent arrays and a pre-PCR room. The facility houses an Agilent Microarray Scanner G2505B Workstation and Hybridization Oven G2545A an Affymetrix Microarray System including an Affymetrix GCS 3000 Scanner 7G two Fluidics Stations 450 and a Hybridization Oven 640 a Beckman CEQ 8000 Sequencer an Agilent Bioanalyzer 2000 a Nanodrop ND-1000 and three Applied Biosystems PCR Thermocyclers 9700. This core hosts specialized training on an on going basis.  

Most importantly the move allowed to physically merge the Affymetrix and Agilent components of the Facility and their respective personnel into one centralized Facility location with ample bench space for all hardware and instrumentation work and storage space and desk areas for all personnel.

The Facility is in the process of obtaining CLIA certification for the processing of standardized CGH genetic tests on clinical patient samples using the Agilent platform.

As expansion of the services offered microRNA expression profiling on human and rodent samples using either the Agilent or Affymetrix array platforms was introduced and is now routinely performed.

Also Yinlu Chen M.S. Sr. Research Analyst was hired in Dec 2009 as addition to the Facility personnel to support client data analyses onsite.

project_terms:
Area;Biomedical Research;Certification;Client;Clinical;Core Facility;Data Analyses;Funding;Genes;Genetic screening method;Grant;Health Sciences;Housing;Human;Human Resources;Institution;Location;MicroRNAs;Molecular Profiling;National Center for Research Resources;Ozone;Patients;Principal Investigator;Process;Research;Research Infrastructure;Resources;Rodent;Sampling;Services;Source;System;Training;Translational Research;United States National Institutes of Health;Universities;Work;base;cost;design;instrumentation;square foot


application_id: 8360097
project_number: 5P20RR016481-11
project_title: UOFL BIOINFORMATICS CORE
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8411
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.This is a network-distributed core with assets contributed by and shared among the KBRIN-affiliated institutions. The resources include hardware software and human resources.

Dr. Eric Rouchka a faculty member in CECS. His background and training is in computer sciences and genomics (sequencing). Dr. Rouchka serves as the KBRIN Bioinformatics Lead at the University of Louisville.

A University of Louisville Bioinformatics Research Group (CECS SOM and SPH faculty and students meet every other week; anyone interested in bioinformatics should attend). The group has developed a Web site which lists Bioinformatics Research Group personnel and projects. The BRG are developing new tools for the development of data banks for genomics data mining image analysis and for gene-array analysis. 

The Eighth Annual UT-ORNL-KBRIN Bioinformatics Summit was held at Fall Creek Falls State Park in Pikeville Tennessee from March 20-22 2009.  A total of 202 participants registered for the summit with 94 from various Tennessee institutions and 68 from various Kentucky institutions.  A number of additional participants came from universities and research institutions from other states and countries e.g. the National Institutes of Health Virginia Commonwealth University University of Cincinnati Emory University and the University of British Columbia.  Seventy-seven registrants were faculty with an additional 62 student 43 staff and 20 postdoctoral level participants.
 The conference program included three days of presentations.  The first day was devoted to workshops including two Geospiza/Digital World Biology workshops along with a bioinformatics education and a microarray analysis workshop.  The last day and a half were dedicated to scientific sessions in bioinformatics divided into three plenary sessions: Medical and Translational Informatics (plenary speakers Bruce Aronow University of Cincinnati; Ian Brooks University of Tennessee Health Science Center) Systems Biology (plenary speakers Mike Miles VCU; Greg Buck VCU; Zhongming Zhao VCU; Ping Xu VCU; Damail Bonchev VCU) and Next-Generation Sequencing and Epigenetics (plenary speakers Jarret Glasscock Cofactor Genomics; Robert Hanson NIH-NIDDK). 


The Ninth  Annual UT-ORNL-KBRIN Bioinformatics Summit that will be held March 19-21 2010 at Lake Barkley State Park Western Kentucky University was tasked with some of the responsibility to arrange and facilitate the meeting. To assist in preparing and executing the summit Donna Schulte was hired to help Dr. Claire Rinehart in this task.

project_terms:
Bioinformatics;Biology;Biomedical Research;British Columbia;Computer software;Country;Databases;Educational aspects;Educational workshop;Epigenetic Process;Faculty;Funding;Genes;Genomics;Grant;Health Sciences;Human Resources;Image Analysis;Informatics;Institution;Kentucky;Lead;Medical;Microarray Analysis;National Center for Research Resources;National Institute of Diabetes and Digestive and Kidney Diseases;Participant;Principal Investigator;Research;Research Infrastructure;Resources;Source;Students;Systems Biology;Tennessee;Training;United States National Institutes of Health;Universities;Virginia;cofactor;computer science;cost;data mining;digital;falls;interest;meetings;member;next generation;programs;symposium;tool development;web site


application_id: 8360096
project_number: 5P20RR016481-11
project_title: INBRE: UOFL KENTUCKY INBRE ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8410
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Administrative Core:
The administrative core provides a leadership role in the development of the statewide network. The core is located in approximately 600 sq ft of office space on the Health Sciences campus at the University of Louisville. The office provides budget management services for the network and logistical support for KBRIN committees and their activities. The KBRIN administrative office works with the Grants Management Office at the University of Louisville for the development of subcontracts to KBRIN affiliates and the subsequent invoicing. Dr. Nigel Cooper is Director of the Administrative Core.  He is aided by Dr. Bruce Mattingly the Program Coordinator who is located at Morehead State University. In addition the Administrative Core is managed on a daily basis by 3 staff including: Ms Stephanie Dearing (budget) Ms Michelle Padgett (reconciliation) and Ms Jane Thornton (logistics). A Steering Committee comprising individuals from each affiliated institution the PD and the PC meets on a regular basis to provide guidance on programmatic activities and budget distributions.

project_terms:
Biomedical Research;Budgets;Development;Funding;Grant;Health Sciences;Individual;Institution;Kentucky;Leadership;Logistics;National Center for Research Resources;Office Management;Principal Investigator;Research;Research Infrastructure;Resources;Role;Services;Source;United States National Institutes of Health;Universities;Work;base;cost;meetings;programs;square foot


application_id: 8357018
project_number: 1R21DE022867-01
project_title: Pathogenic mechanisms of F. alocis
administering_ic: NIDCR
award_notice_date: 2012-07-19
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: DE
serial_number: 022867
program_official: LUNSFORD, DWAYNE
project_start_date: 2012-07-19
project_end_date: 2014-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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):  Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. Recent developments in molecular based bacterial detection technologies have identified a number of previously unrecognized or under-appreciated organisms as associated with periodontal lesions. One such emerging pathogen is the gram-positive anaerobe Filifactor alocis. This organism is a constituent of subgingival biofilms and is present in elevated numbers at site of periodontal disease as compared to health. F. alocis produces proteases and can invade gingival epithelial cells; however little else is known regarding the potential pathogeniciy of the organism. In order to capitalize on the human microbiome studies it is necessary to functionally characterize the newly identified organisms. Hence in this study we shall contribute to the process of assessing the pathogenic potential of F. alocis in vitro and in vivo. Our preliminary data indicate that F. alocis can induce apoptosis in gingival epithelial cells an event
with relevance to disruption of periodontal tissue homeostasis. The first goal of the current proposal therefore is to begin to characterize the mechanistic basis of F. alocis-induced apoptosis. We will focus on the MEK-FOXO pathway as preliminary data show that F. alocis can inhibit MEK and potentially activate the pro-apoptotic transcriptional factor FOXO. The role of MEK will be assessed by gene knockin experiments with constitutively mutants and the relevance of FOXO determined by reporter assays and siRNA knockdowns. Secondly we will establish the in vivo characteristics of F. alocis in the mouse chamber model. The ability of F. alocis to survive and replicate in vivo will be established and in addition host cytokine responses neutrophil recruitment and apoptosis will be assayed. These studies will generate both in vitro and in vivo data that will begin to establish the pathogenic credentials of F. alocis and provide a platform for future studies directed toward a more comprehensive understanding of molecular and cellular pathogenic mechanisms. Ultimately the knowledge gained could be translated into novel diagnostic therapeutic or preventive strategies for periodontal diseases.   
   
PUBLIC HEALTH RELEVANCE: Periodontal diseases afflict millions of Americans and recent molecular techniques have identified a variety of bacteria associated with the disease that have yet to be studied in depth. In this project we will examine the interactions between F. alocis and the human cells that are colonized by the organism and we will determine the ability of the organism to survive in mouse models of infection. The information to be gathered could result in a re-evaluation of the causes of periodontal disease and ultimately be used to identify targets for novel therapeutic agents or diagnostic tests.

project_terms:
American;Anaerobic Bacteria;Apoptosis;Apoptotic;Applications Grants;Area;Bacteria;Bacterial Infections;Biological Assay;Cell Death;Cells;Characteristics;Communities;Complex;Consensus;Data;Data Set;Detection;Development;Diagnosis;Diagnostic tests;Disease;Disease Progression;Disorder by Site;Epithelial Cells;Etiology;Evaluation;Event;Future;Genes;Gingiva;Goals;Health;Healthcare Systems;Homeostasis;Human;Human Microbiome;In Vitro;Individual;Induction of Apoptosis;Infection;Invaded;Knowledge;Lead;Lesion;MEK inhibition;MEKs;Measurement;Microbiology;Modeling;Molecular;Mouth Diseases;Mus;Neutrophil Infiltration;Oral health;Organism;Outcome Study;Pathogenicity;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Phenotype;Plasmids;Porphyromonas gingivalis;Prevention strategy;Prevention therapy;Process;Property;Reporter;Reporting;Rods (Retina);Role;Signal Transduction;Site;Small Interfering RNA;Techniques;Technology;Testing;Therapeutic;Therapeutic Agents;Tissues;Translating;Virulence;Work;base;caspase;cytokine;in vivo;microbial;mouse model;mutant;novel;novel diagnostics;oral microbiome;pathogen;research study;response;subcutaneous;subgingival biofilm

public_health_relevance:
Periodontal diseases afflict millions of Americans and recent molecular techniques have identified a variety of bacteria associated with the disease that have yet to be studied in depth. In this project we will examine the interactions between F. alocis and the human cells that are colonized by the organism and we will determine the ability of the organism to survive in mouse models of infection. The information to be gathered could result in a re-evaluation of the causes of periodontal disease and ultimately be used to identify targets for novel therapeutic agents or diagnostic tests.


application_id: 8356521
project_number: 2P50DA005312-22
project_title: Administrative Core
administering_ic: NIDA
award_notice_date: 2012-07-09
opportunity_number: PAR-10-189
application_type: 2
activity_code: P50
ic: DA
serial_number: 005312
study_section: Special Emphasis Panel[ZDA1 EXL-T (02)]
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: 2012-07-15
budget_end_date: 2013-06-30
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;prevent;psychologic;psychosocial;relating to nervous system;social;substance use prevention;symposium


application_id: 8355348
project_number: 1R03NS079818-01
project_title: Cavities in Choline Acetyltransferase and Neuromuscular Disorders
administering_ic: NINDS
award_notice_date: 2012-06-18
opportunity_number: PA-11-262
application_type: 1
activity_code: R03
ic: NS
serial_number: 079818
program_official: STEWART, RANDALL R
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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): Our goal is to understand the effects of congenital mutations in choline acetyltransferase (ChAT) which synthesizes the prototypical neurotransmitter acetylcholine. Decreases in ChAT activity are associated with a number of neurological disease states and mutations in the enzyme cause a severe neuromuscular disorder known as congenital myasthenic syndrome with episodic apnea (CMS-EA). Our crystal structure of ChAT showed that the known congenital mutations are distributed widely over the enzyme despite their common effects on function and recent structures show that two of the mutations affect the conformation of the catalytic histidine residue. Further the core residue packing in ChAT is poor leaving an unusually large number of cavities (voids). Based on these observations we hypothesize that the large number of cavities in ChAT makes it conformationally unstable so that point mutations cause structural changes that propagate to disrupt function. We will use a combination of structural biophysical and cell biological approaches to test this hypothesis focusing on a cavity near the two congenital mutations that have been characterized structurally. Two specific aims are proposed: 1) characterize the role of an internal cavity in mediating the functional effects of two congenital mutations 2) assess how filling the cavity effects structural changes associated with the congenital mutations This work will serve as an initial test of our hypothesis regarding the role of packing defects in ChAT
directly addressing the molecular mechanism underlying a human disease and guiding future studies of ChAT and the motor disorders associated with decreases in its function.   
   
PUBLIC HEALTH RELEVANCE: The proposed research will provide an understanding of a molecular disease that disrupts communication between the nervous system and muscles. Knowledge of the basis for the disorder will provide an approach for developing effective therapies for this and similar diseases of the nervous system.

project_terms:
Acetylcholine;Active Sites;Address;Affect;Animal Model;Apnea;Biological;Cells;Choline O-Acetyltransferase;Communication;Congenital Myasthenic Syndromes;Cultured Cells;Data;Defect;Disease;Enzymes;Future;Goals;Hereditary Disease;Histidine;Investigation;Kinetics;Lead;Left;Location;Maps;Measures;Mediating;Molecular;Molecular Conformation;Muscle;Mutate;Mutation;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Neuromuscular Diseases;Neurotransmitters;Play;Point Mutation;Research;Role;Structure;System;Testing;Therapeutic;Work;base;drug candidate;effective therapy;human disease;knowledge base;motor disorder;nervous system disorder;novel therapeutics;restoration;small molecule

public_health_relevance:
The proposed research will provide an understanding of a molecular disease that disrupts communication between the nervous system and muscles. Knowledge of the basis for the disorder will provide an approach for developing effective therapies for this and similar diseases of the nervous system.


application_id: 8354265
project_number: 271201100017C-0-0-1
project_title: TAS::75 0893::TAS DEVELOPMENT AND MANUFACTURE OF PHARMACEUTICAL PRODUCTS/ADDICT
administering_ic: NIDA
project_start_date: 2011-09-18
project_end_date: 2015-09-17
contact_pi_person_id: 8538852
contact_pi: MURTY, RAM B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
This contract involves the development and manufacture of dosage forms suitable for administration in preclinical and clinical evaluations. The work includes performulation studies formulation studies analytical methods development and validation stability studies packaging storage and distribution of the drug products.  The work to be conducted in accordance with Current Good Manufacturing Practices regulations (cGMPs). Data and documentation are to be prepared in a form acceptable to the FDA for inclusion in Drug Master Files (DMFs) Investigational New Drug (INDs) or New Drug Application (NDAs).

project_terms:
Clinical Trials;Contractor;Contracts;Data;Data Reporting;Development;Documentation;Dosage Forms;Drug Formulations;Evaluation;Generations;Investigational Drugs;Maintenance;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Preparation;Regulation;Resources;Site;Validation;Work;analytical method;drug distribution;method development;pre-clinical;preclinical evaluation;research clinical testing


application_id: 8353455
project_number: 2P50DA005312-22
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2012-07-09
opportunity_number: PAR-10-189
application_type: 2
activity_code: P50
ic: DA
serial_number: 005312
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZDA1 EXL-T (02)]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Drug abuse is a significant health-related problem and novel preventive intervention strategies are needed to address this problem. The Center for Drug Abuse Translation (CDART) is a prevention center responding to the NIDA "Center of Excellence" (PA-10-189). CDART proposes to determine the biologically-based facets of personality that increase risk for drug abuse and to test different preventive interventions that target these multiple risk-related facets. The central theme of CDART is that: (1) sensation seeking involves the reward relevant dopamine system and is most closely related to initiation of use; (2) disinhibition involves the inhibition-relevant prefrontal cortex and is most closely relatd to escalation of use; and (3) urgency or mood-based rash action involves the stress-relevant amygdala and is most closely related to problem use. CDART hypothesizes that prevention interventions may be maximally effective if they are tailored specifically to these risk-related facets. Three integrated research projects are proposed; one will use laboratory rats and two will use college students transitioning from adolescence to young adulthood. Using neurochemical and electrophysiological techniques in rats as well as neuroimaging techniques in humans the basic neural mechanisms that mediate these different risk-related facets will be assessed. Humans varying in risk-related facets also will be tested for their response to drugs of abuse under controlled laboratory conditions. This basic research will be translated into the application of prevention in small-scale efficacy trials. An especially innovative aspect of the proposed work is that it will test the hypothesis that individuals high in urgency will be more responsive to an intervention that promotes emotional self-regulation (i.e. mindfulness training) relative to an intervention tailored to high sensation seekers. In addition to the specific researc proposed in the 3 research projects an administrative core a statistics/psychometrics core and a training/pilot program core will further synergize the projects. An outreach component also is proposed to enhance the bi-directional transfer of information between basic scientists and prevention practitioners. The long-range goal is to improve the design and implementation of targeted anti-drug preventive interventions.    
   
PUBLIC HEALTH RELEVANCE:  This research is relevant to public health because drug abuse continues to be a major preventable disorder. Intervening early in life prior to the beginning of dysfunctional drug intake would have life-long positive health consequences thus reducing health costs and the likelihood of early death.    
   
CENTERS CHARACTERISTICS:

public_health_relevance:
This research is relevant to public health because drug abuse continues to be a major preventable disorder. Intervening early in life prior to the beginning of dysfunctional drug intake would have life-long positive health consequences thus reducing health costs and the likelihood of early death.    
   
CENTERS CHARACTERISTICS:


application_id: 8351006
project_number: 261201000031C-4-0-3
project_title: SEER RRSS Using Multiple Imputation to Enhance the Utility of SEER Summary Stage
administering_ic: NCI
project_start_date: 2011-09-30
project_end_date: 2012-09-29
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Multiple Imputation (MI) methods have been widely used in many scientific fields to address missing data issues. Several statistical software packages have implemented MI procedures. However their performance varies. Attempts were made to compare performance of MI procedures in varying statistical packages. Because of the complexity of MI comparisons were made based on specific settings such as assuming missing patterns were monotonic missing the missing variable was semi-continuous or the missing data were simple artificial data. None of these comparisons addressed which methods are best used in a large data set such as the SEER registry data with non-monotonic missing pattern and many variables. This study will investigate issues more specific to the SEER registry data when using MI methods to handle missing data. Through this study guidance for researchers in the cancer registry community will be provided with regard to properly handling of the missing data issue in cancer registry data. Missing data is a frequent problem in most scientific studies and a common feature of large data sets in general and medical data sets in particular. It can cause bias or lead to inefficient analyses if not handled properly. Because of its high standard requirements the SEER data have only a small fraction of missing data for most of the variables collected. However one very important variable the SEER Summary Stage (1977 2000 and CS) contains a higher percentage of missing or unknown data especially for certain cancer sites. For example 9.8% of the lung cancer cases and 22% of the liver cancer cases were coded as unknown for the variable SEER Summary Stage 2000 for the 2001-2003 SEER data. The complete case method (listwise deletion) is the most commonly used method to address this missing data issue for data analysis among researchers in the cancer registry community. If missing data are not missing completely at random using the complete case method will introduce bias and generate incorrect results. For the same study data mentioned above the distributions of age at cancer diagnosis for cases with known stage and cases with unknown stage were significantly different  34% of cases were 75 years old or older for known stage while 54% of cases were 75 years old or older for unknown stage. This strongly suggests cases with unknown stage were not missing completely at random. Hence the complete case method is not an ideal method to analyze the data. Coding the cases with unknown stage as a separate sub-category will certainly include all cases in data analysis but unfortunately severe bias has been found for this type of analysis when data are not missing completely at random. Compared to the complete case method MI one of the more sophisticated methods to handle missing data provides superior estimates when data are missing at random. First proposed in 1978 MI has become an important and influential approach in the statistical analysis of missing data in recent years because it is easy to use and readily available in many statistical packages. MI replaces each missing value with a set of plausible values that represents the uncertainty about the most appropriate value to impute then combines results from separate data analyses for each complete dataset to generate the final estimates. It has been suggested that MI often provides valid and robust inferences even when assumptions were not met.

project_terms:
Address;Affect;Age Distribution;Categories;Code;Communities;Computer software;Data;Data Analyses;Data Set;Influentials;Lead;Malignant neoplasm of liver;Malignant neoplasm of lung;Medical;Methods;Pattern;Performance;Procedures;Research Personnel;Staging;Statistical Methods;Techniques;Uncertainty;base;cancer diagnosis;cancer site;data registry;high standard;meetings;neoplasm registry


application_id: 8350700
project_number: 275200800006C-7-0-1
project_title: NATIONAL CHILDREN'S STUDY
administering_ic: NICHD
project_start_date: 2008-09-26
project_end_date: 2013-09-25
contact_pi_person_id: 11143686
contact_pi: TOLLERUD, DAVID
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The National Children's Study (NCS) is prospective longitudinal cohort study of the individual and combined effects of environmental exposures and gene environmental interactions on child health and development in a representative sample of approximately 100000 children born in the United States. The children will be followed from before birth until age 21. The importance and timeliness of this study are based on many factors including past experiences demonstrating profound effects of environmental exposures such as exposures to alcohol during pregnancy and to lead in early childhood on child health and development; the special vulnerabilities of children to environmental exposures compared to adults; known ongoing exposures such as prevalent levels of non-persistent pesticides or hours of media exposure per day in young children; and evidence for environmental contributions or causes to such high-impact conditions as autism developmental delay and developmental disability asthma and obesity. The primary aim of the NCS is to investigate the separate and combined effects of environmental exposures (chemical biological physical psychosocial) as well as gene-environment interactions on pregnancy outcomes child health and development and precursors of adult disease. Unique features of the study include its focus on environmental exposures at the earliest stages of pregnancy (as well as thereafter) and the breadth of planned exposure and outcome measurements. The NCS responds to the Congressional mandate of the Children's Health Act of 2000 that the NICHD and a consortium of federal agencies plan and conduct a longitudinal study of the impacts of environmental exposures on children. The NCS will employ a national probability sampling approach to select locations and participants for conduct of the study. The sampling design utilizes a multistage clustered approach. In the first stage 105 locations (generally corresponding to single counties) were randomly selected from all U.S. counties. Seven of the locations serve as the initial or Vanguard Locations participating in the pilot phase of the NCS. Because the focus of the study includes assessment of the impact of exposures that occur early in pregnancy both pregnant women and their partners and women of childbearing age comprise the initial target population for enrollment. Data will be collected in combinations of face-to-face contacts and remote collection methods e.g. telephone computer or mail-in questionnaires. The expected frequency of contact (face-to-face or remote) is approximately every three months through age one every six months through age five years and annually thereafter. For a sample of children enrolled in the study visits will also be made to child care and school settings for collection of environmental samples and observational data. Anticipated biologic specimens include blood urine hair and nail clippings from mothers and children; blood urine and hair from fathers; cord blood umbilical cord and placental tissues and meconium collected at/around the time of delivery; vaginal swabs and breast milk from mothers. Anticipated environmental samples include air dust soil food and water.

project_terms:
21 year old;Address;Adolescent;Adult;Age;Air;Asses;Asthma;Autistic Disorder;Behavior Disorders;Biological;Birth;Blood;Chemical Exposure;Child;Child Care;Child Development;Child health care;Clip;Cohort Studies;Collection;Computers;County;Data;Databases;Developmental Delay Disorders;Developmental Disabilities;Disease;Dust;Enrollment;Environment;Environmental Exposure;Environmental Risk Factor;Fathers;Female of child bearing age;Food;Frequencies (time pattern);Future;Genes;Hair;Health;Hour;Human Milk;Individual;Infant;Injury;Lead;Location;Longitudinal Studies;Mails;Measurement;Meconium;Mental Retardation;Methods;Mothers;Nail plate;National Children's Study;National Institute of Child Health and Human Development;Obesity;Other Genetics;Outcome;Participant;Pesticides;Phase;Pregnancy;Pregnancy Outcome;Pregnant Women;Probability Samples;Questionnaires;Resources;Sampling;Schools;Severities;Sexual Maturation;Soil;Specimen;Staging;Swab;Target Populations;Telephone;Time;Tissues;Umbilical Cord Blood;United States;Urine;Vagina;Variation (Genetics);Visit;Water;alcohol exposure;base;design;early childhood;environmental chemical exposure;experience;gene environment interaction;prospective;psychosocial;repository;social;young adult


application_id: 8343890
project_number: 1R01NS079637-01
project_title: Vascular breakdown in Alzheimers Disease with cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2012-06-27
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 079637
program_official: CORRIVEAU, RODERICK A
project_start_date: 2012-07-01
project_end_date: 2017-04-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema.  Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice.  The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema and finally to establish the effect CBVD has on the response to A-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.   
   
PUBLIC HEALTH RELEVANCE: Cerebrovascular disease commonly occurs with aging as does Alzheimer's disease. In fact it is estimated that 40% of Alzheimer's patients also have cerebrovascular disease. Our research proposal will examine the impact cerebrovascular disease has on the progression of amyloid pathology a brain pathology in Alzheimer's disease. Our overall goal is to enhance our understanding of the relationship between cerebrovascular disease and Alzheimer's disease and how one can affect the other.


application_id: 8343492
project_number: 1R01AI101373-01
project_title: Role of Rapid IFNg Secretion by CD*+ T cells in Clearance of Food Borne Listeria
administering_ic: NIAID
award_notice_date: 2012-06-19
opportunity_number: PA-11-260
application_type: 1
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.   
   
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 resistant
individuals 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.

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 resistant
individuals 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: 8343314
project_number: 1R01HL114951-01
project_title: Enhancing the effectiveness of human cardiac stem cell therapy
administering_ic: NHLBI
award_notice_date: 2012-07-16
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 114951
program_official: BUXTON, DENIS B
project_start_date: 2012-07-16
project_end_date: 2017-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
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): Ischemic heart disease remains as the single largest cause of mortality in the United States. Delivery of c-kit positive human cardiac stem cells (hCSCs) is a very promising therapeutic approach in repairing the infarcted heart but is severely limited by the poor survival of donor cells. Carbon monoxide (CO) a byproduct of heme oxygenase 1 (HO-1) has a potent anti- apoptotic cytoprotective effect against ischemia/reperfusion injury to cardiomyocytes. However it is not known whether HO-1/CO is cytoprotective for hCSCs. Our pilot studies found that HO-1/CO plays an important role in mediating hCSC survival ability. Therefore this application focuses on testing our hypothesis that HO-1/CO promotes human cardiac stem cell survival vial the activation of survival signal pathways and the cytokine effects as well as enhances the stem cell therapy efficacy and heart function after transplantation into immunodeficient mouse heart following myocardial infarction. Thus we will examine whether hCSCs pretreated with an HO-1 inducer (CoPP) or a CO releasing molecule (CORM-3) will exhibit greater abilities in cell survival proliferation migration endothelial and cardiomyogenic differentiation (Aim 1) and understand the molecular mechanisms that underlie the effect of HO-1/CO on hCSC survival signal pathways resistance to apoptosis ROS generation and cytokine release (Aim 2). Aim 3 of this proposal will test whether transplantation of the preconditioned eGFP+-hCSCs will result in improvement in invivo hCSC survival and homing endogenous mouse CSC proliferation and differentiation and cardiac structure and function with immunodeficient mouse (SCID) model following myocardial infarction. Knowledge gained from the above experiments will provide the essential implications on the strategies to enhance hCSC survival after transplantation and therefore their efficacy in clinical repairing infarcted myocardium for the cell therapy of patients with ischemic heart disease.   
   
PUBLIC HEALTH RELEVANCE: Poor survival of donor cells is one of the major challenges in stem cell therapy for ischemic heart disease. This project investigates the effective strategies to
enhance the human cardiac stem cell therapy efficacy with small molecules including cobalt protoporphyrin (CoPP) a heme oxygenase 1 inducer which promotes endogenous carbon monoxide generation; or a carbon monoxide donor CORM-3. These studies will show how CoPP/CORM-3 affects the survival ability of human cardiac stem cells in an in vitro cell culture model and how intramyocardial injection of CoPP/CORM-3 pretreated human cardiac stem cells improve heart function in an in vivo immunodeficient mouse model following ischemia-reperfusion injury. The results and broad conclusions will be directly relevant to enhance the efficacy in clinical repairing the infarcted myocardium for the cell therapy of patients with ischemic heart disease.

project_terms:
Affect;Antibodies;Apoptosis;Apoptotic;Biological Assay;Carbon Monoxide;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cell Culture Techniques;Cell Proliferation;Cell Survival;Cell Therapy;Cells;Clinical;Clinical Research;Collaborations;Data;Discipline;Echocardiography;Effectiveness;Exhibits;Generations;Genes;Goals;Grant;Growth Factor;HLA-A gene;Heart;Heart Transplantation;Heme Oxygenase (Decyclizing);Homing;Human;Immunodeficient Mouse;Immunohistochemistry;In Vitro;Infarction;Infusion procedures;Injection of therapeutic agent;Knowledge;Laboratories;Left Ventricular Function;Letters;Mediating;Methods;Modeling;Molecular;Molecular and Cellular Biology;Mortality Vital Statistics;Mus;Muscle;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Oxidative Stress;Patients;Phosphorylation;Physiology;Pilot Projects;Play;Proteomics;Proto-Oncogene Protein c-kit;Reactive Oxygen Species;Regenerative Medicine;Reperfusion Injury;Reperfusion Therapy;Research;Research Personnel;Research Project Grants;Resistance;Role;SCID Mice;Signal Pathway;Staging;Stem cells;Structure;Testing;Therapeutic;Time;Training;Transplantation;Treatment Efficacy;United States;Up-Regulation (Physiology);Vial device;Western Blotting;angiogenesis;auricular appendage;base;cardiogenesis;cobaltiprotoporphyrin;cytokine;heart function;immunocytochemistry;immunodeficient mouse model;improved;in vivo;knock-down;migration;morphometry;preconditioning;repaired;research study;small hairpin RNA;small molecule;stem cell therapy

public_health_relevance:
Poor survival of donor cells is one of the major challenges in stem cell therapy for ischemic heart disease. This project investigates the effective strategies to
enhance the human cardiac stem cell therapy efficacy with small molecules including cobalt protoporphyrin (CoPP) a heme oxygenase 1 inducer which promotes endogenous carbon monoxide generation; or a carbon monoxide donor CORM-3. These studies will show how CoPP/CORM-3 affects the survival ability of human cardiac stem cells in an in vitro cell culture model and how intramyocardial injection of CoPP/CORM-3 pretreated human cardiac stem cells improve heart function in an in vivo immunodeficient mouse model following ischemia-reperfusion injury. The results and broad conclusions will be directly relevant to enhance the efficacy in clinical repairing the infarcted myocardium for the cell therapy of patients with ischemic heart disease.


application_id: 8341035
project_number: 1R01GM102129-01
project_title: In Search of Mannolipid Intermediate Flippases
administering_ic: NIGMS
award_notice_date: 2012-09-20
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: GM
serial_number: 102129
program_official: CHIN, JEAN
project_start_date: 2012-09-20
project_end_date: 2016-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 7875239
contact_pi: WAECHTER, CHARLES J
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): During the past 35 years this laboratory has been studying the function of polyisoprenol-linked intermediates in glycan synthesis in prokaryotes and eukaryotes. A long-standing interest in the topological issues involved in the biosynthesis of extracellular saccharides has led us to focus on the proteins that mediate the transbilayer movements of the lipid-linked intermediates utilized as glycosyl donors in these pathways. The current proposal is aimed at identifying the proteins that mediate the transbilayer movement of dimannosyldiacylglycerol and mannosylphosphoryldolichol two mannolipid intermediates in the assembly of the lipomannan of Micrococcus luteus. These studies will provide important clues to the identification of related proteins functioning in protein N-glycosylation C- and O-mannosylation of proteins and biosynthesis of glycosylphosphatidylinositol anchors in humans. The discovery of genes encoding membrane proteins functioning as flippases in these assembly processes will be valuable in the diagnosis of potential genetic errors referred to as Congenital Disorders in Glycosylation (CDGs).   
   
PUBLIC HEALTH RELEVANCE: This application proposes studies designed to identify the membrane proteins (flippases) in Micrococcus luteus that mediate the transbilayer movements of dimannosyl-diacylglycerol and mannosylphosphorylundecaprenol two mannolipid intermediates in bacterial lipomannan synthesis. These studies on micrococcal lipomannan assembly will provide important new clues to the identification of related membrane proteins functioning in protein N-glycosylation C- and O-mannosylation of proteins and the biosynthesis of glycosylphosphatidylinositol (GPI) anchors in humans. Since N-linked oligosaccharides play a key role in the proper folding and intracellular routing of important membrane glycoproteins e.g. rhodopsin voltage-sensitive sodium channels and the insulin receptor the identification of the genes encoding mammalian flippases is relevant to the diagnosis of potential genetic errors referred to as Congenital Disorders in Glycosylation (CDGs).


application_id: 8339914
project_number: 261200700019C-5-0-1
project_title: Development of Dosage Forms & Delivery Systems for Antitumor Agents
administering_ic: NCI
project_start_date: 2007-08-01
project_end_date: 2012-07-31
contact_pi_person_id: 11127579
contact_pi: BUMMER, PAUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Suitability for intravenous injection will be evaluated for all candidate compounds. Some compounds exhibit adequate pharmaceutical properties per se. However many others present significant solubility and stability problems that are not amenable to solvent approaches or pH adjustment. These compounds may require long range studies depending on program needs (potential of the compound) and judgment of the Project Officer. The new chemical entity is studied and its physicochemical characteristics elucidated. It may be necessary to conduct studies leading to non-traditional (alternate) dosage forms suitable for 'proof of concept' studies in animals and ultimately in human clinical trials. The Contractor is required to provide written final project reports which include recommendations for scale-up manufacturing. In some cases the contractor provides pilot-scale batches of finished dosage forms for evaluation in efficacy models.

project_terms:
Analytical Chemistry;Animals;Biological Assay;Cancer Patient;Characteristics;Chemicals;Clinical Trials;Contractor;Development;Dosage Forms;Drug Formulations;Evaluation;Exhibits;Experimental Animal Model;Human;Intravenous;Judgment;Modeling;Monitor;Oral;Parents;Pharmaceutical Resources;Pharmacologic Substance;Property;Recommendation;Reporting;Safety;Solubility;Solvents;System;Therapeutic;Writing;antitumor agent;intravenous injection;manufacturing scale-up;programs


application_id: 8339607
project_number: 1R01HG006838-01
project_title: Harmonizing Privacy Laws to Enable International Biobank Research
administering_ic: NHGRI
award_notice_date: 2014-09-04
opportunity_number: PA-11-250
application_type: 1
activity_code: R01
ic: HG
serial_number: 006838
program_official: MCEWEN, JEAN
project_start_date: 2014-09-05
project_end_date: 2016-07-31
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: KNOPPERS, BARTHA MARIA M.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In recent years researchers from around the world have begun developing repositories of tissues and socio-demographic data for genetics and other biomedical research. These biobanks often linked with patient health care records have been an invaluable resource in helping to understand cancer diabetes and various genetic-related disorders. The specimens and data are especially valuable when combined and analyzed with specimens and data from other countries because rare variations can be detected and examined. Sharing by researchers of specimens and data across international borders may be hampered by privacy laws in several countries that limit disclosure or receipt of certain specimens or health information. The study relying on a worldwide team of experts will compile and analyze the privacy laws in 23 countries undertaking substantial biobank development. It will then propose legal and technical strategies to accommodate important privacy interests while facilitating international access and use for research.   
   
PUBLIC HEALTH RELEVANCE: Biobanks often with linked clinical records have been established in numerous countries to facilitate genetic and genomic research. International collaborations of researchers using biobanks have been hampered by privacy laws in various countries. Developing an expert compilation of privacy laws in countries performing biobank-based research and recommending measures to harmonize these laws will enable international research cooperation and coordination.

project_terms:
Administrator;Affect;Area;Biomedical Research;Clinical;Code;Collaborations;Complex;Confidentiality;Consent;Country;Data;Databases;Development;Diabetes Mellitus;Disclosure;Disease;Ensure;Environment;Europe;European Union;Fostering;Genetic;Genome;Genomics;Growth;Health;Healthcare;Individual;Information Technology;International;Laws;Lead;Legal;Link;Malignant Neoplasms;Maps;Measures;Modeling;Monograph;Nature;Other Genetics;Participant;Patients;Policies;Policy Maker;Population Study;Privacy;Records;Regulation;Research;Research Methodology;Research Personnel;Resources;Role;Sampling;Security;Specimen;Structure;Tissues;Translational Research;Variant;Work;base;biobank;comparative;data integration;development policy;interest;next generation sequencing;public health relevance;repository;sharing data;tool

public_health_relevance:
Biobanks often with linked clinical records have been established in numerous countries to facilitate genetic and genomic research. International collaborations of researchers using biobanks have been hampered by privacy laws in various countries. Developing an expert compilation of privacy laws in countries performing biobank-based research and recommending measures to harmonize these laws will enable international research cooperation and coordination.


application_id: 8339229
project_number: 5F31AG039208-02
project_title: Emotion regulation and self-regulation in older adults
administering_ic: NIA
award_notice_date: 2012-08-14
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: AG
serial_number: 039208
program_official: NIELSEN, LISBETH
project_start_date: 2011-09-26
project_end_date: 2013-09-25
study_section: Special Emphasis Panel[ZRG1-F12A-R(20)L]
contact_pi_person_id: 10423010
contact_pi: EVANS, DANIEL REID
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Emotion regulation among older adults appears to be a relatively preserved capacity that is vital for wellbeing and successful aging. However the limits of this ability and the circumstances under which older adults might be less capable of regulating their emotions are unclear. Furthermore current theories that seek to explain how older adults regulate their emotions such as increased allocation of resources for emotion regulation or improved efficiency of emotion regulation have not been compared to each other. Therefore the aims of the proposed project are to 1) test the limits of older adults' emotion regulation capacity and 2) gain a better understanding of how older adults use their more limited resources to regulate their emotions. These aims are part of a long-term goal of producing a scientific knowledge base for improving the emotional health and wellbeing of older adults. The proposed project will use a paradigm from the strength model of self-regulation that posits a limited fatigable and common pool of self-regulatory resources that are drawn on by any act of self- regulation-controlling one's thoughts emotions and behaviors-such that performance on a subsequent but unrelated act of self-regulation tends to be impaired. An equal number of older and younger participants will be randomly assigned to one of four experimental groups involving an initial activity that is high or low in self- regulatory demand followed by a dependent task of emotion regulation or attention regulation. Comparing the performance of older and younger adults on the dependent emotion regulation task will provide results relevant to Aim 1. The proposed project will also include resting heart rate variability (HRV) a physiological measure that may provide an index of self-regulatory capacity. Examining the relationships between performance on the dependent self-regulation tasks and HRV will provide a measure of the extent to which participants are allocating self-regulatory resources for the different tasks results relevant to Aim 2. It is hypothesized that 1) older adults will perform better than younger adults on the emotion regulation task but worse on the attention regulation task and 2) older adults will allocate more resources than younger adults for the emotion regulation task. The proposed project would yield valuable information about the limits of emotion regulation in older adults provide more information about how older adults regulate their emotions and generate hypotheses for future research about the potential costs and benefits of different self-regulation strategies and priorities in older adults.

project_terms:
Affect;Aging;Area;Attention;Awareness;Behavior;Costs and Benefits;Elderly;Emotional;Emotions;Failure (biologic function);Fatigue;Goals;Health;Informal Social Control;Intervention;Life;Light;Literature;Maintenance;Measures;Modeling;Participant;Pattern;Performance;Physical Function;Physiological;Psyche structure;Randomized;Regulation;Resource Allocation;Resources;Rest;Role;Testing;Thinking function;Time;age group;base;emotion regulation;experience;heart rate variability;improved;indexing;knowledge base;theories;young adult

public_health_relevance:
The ability to control one's emotions is important for wellbeing especially for older adults who experience declines in many other areas of physical and mental functioning. Older adults seem to maintain their ability to control their emotions well yet the limits of this ability and the way they are able to do this is unclear. Therefore this project seeks to test those limits and shed light on the strategies older adults use to control their emotions so that better interventions can be developed to improve the wellbeing and emotional health of older adults.


application_id: 8337873
project_number: 1R56AI091766-01
project_title: Genetic analyses of salmonella-host interactions
administering_ic: NIAID
award_notice_date: 2011-09-27
opportunity_number: PA-10-067
application_type: 1
activity_code: R56
ic: AI
serial_number: 091766
program_official: ALEXANDER, WILLIAM A
project_start_date: 2011-09-30
project_end_date: 2013-09-29
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 2147829
contact_pi: WORLEY, MICAH
other_pis: Not Applicable
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Salmonella infection is a major public health problem with Salmonella spp. causing more than one billion new human infections each year that lead to more than three million deaths. The problem is greatly exacerbated by the emergence of multi-drug resistant strains. The public health threat of Salmonella is heightened by the fact that this NIAID Category B pathogen could be used as a weapon of bioterrorism given the ease with which it can be propagated and its environmental stability. In fact Salmonella is one of only a handful of pathogens that has been successfully used as a weapon. We have observed that Salmonella secretes the protein SrfH into infected cells to activate their motility by manipulating the host protein TRIP6 to accelerate the systemic spread of infection. At later stages of infection SrfH can bind the host protein IQGAP1 to inhibit productive infected macrophage motility perhaps to avoid interactions with immune system cells. The objectives of this work are to: understand mechanistically how SrfH subverts the host protein TRIP6 to accelerate productive infected macrophage motility early in infection understand the impact of the separable abilities of SrfH to promote and inhibit productive infected macrophage motility on Salmonella virulence in mouse models of infection disentangle spatial and temporal regulation models to account for the ability of SrfH to both promote and repress productive infected macrophage motility at different times during infection

project_terms:
Accounting;Acute;Affect;Alleles;Animal Model;Bacteria;Binding (Molecular Function);Bioterrorism;Blood;Blood Circulation;Categories;Cells;Cessation of life;Coupling;Data;Disease;Disease Reservoirs;Failure (biologic function);Gallbladder;Genetic;Goals;Health;Homologous Gene;Human;IQ motif containing GTPase activating protein 1;ITGB2 gene;Immune system;Infection;Intestines;Lead;Life;Liver;Logic;Lymphatic;Measures;Mediating;Microbe;Modeling;Molecular;Movement;Multi-Drug Resistance;Mus;National Institute of Allergy and Infectious Disease;Organ;Pathway interactions;Phagocytes;Phenotype;Property;Proteins;Regulation;Salmonella;Salmonella infections;Salmonella typhi;Salmonella typhimurium;Septicemia;Site;Spleen;Staging;T-Lymphocyte;Testing;Time;Tissues;Travel;Typhoid Fever;Video Microscopy;Virulence;Work;bile duct;cell motility;filamin;genetic analysis;human BCAR1 protein;in vitro Assay;in vivo;interest;intestinal epithelium;macrophage;microbial;migration;mouse model;mutant;pathogen;public health medicine (field);research study;resistant strain;weapons

public_health_relevance:
PROJECT NARRATIVE Salmonella infection is a major public health problem with Salmonella spp. causing more than one billion new human infections each year that lead to more than three million deaths1. The problem is greatly exacerbated by the emergence of multi-drug resistant strains2. It is the goal of this work to understand how when where and why pathogens move within their hosts. The answers to these questions may directly affect human health.


application_id: 8337872
project_number: 1R56AI091918-01A1
project_title: Systemic spread of Listeria monocytogenes after oral infection
administering_ic: NIAID
award_notice_date: 2011-09-27
opportunity_number: PA-10-067
application_type: 1
activity_code: R56
ic: AI
serial_number: 091918
suffix: A1
program_official: MILLS, MELODY
project_start_date: 2011-09-30
project_end_date: 2013-09-29
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
project_abstract:
Listeria monocytogenes (Lm) is important an important pathogen to study because: 1) it causes human food borne infections that are of significant public health concern 2) it is a genetically tractable organism with a unique intracellular lifestyle that serves 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 cellmediated immune responses. However due to the lack of a good animal model for oral transmission of Lm we still know very little about the infectious dose required to establish intestinal infection mechanisms of spread from the gut or why the innate susceptibility to developing systemic listeriosis seems to vary among individuals. We recently developed a new model of oral infection using mice fed Lm-contaminated food that shows 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 reseeding of peripheral tissues in susceptible mice that are 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 self-limiting gastroenteritis in resistant individuals. Our central hypothesis predicts that one such innate immune mechanism is the rapid secretion of IFN&#947; by a subset of memory phenotype CD8+ T cells. We postulate that this early IFN&#947; response can limit the growth and spread of Lm in resistant individuals and that susceptible mice or humans who lack this ability will be more likely to develop life-threatening systemic listeriosis. We have three specific aims: (1) to characterize the intestinal phase of infection after ingestion of Lm (2) to identify routes of primary dissemination from the gut and pathways of secondary spread that occur later in infection and (3) to identify IFN&#947;-dependent innate immune mechanisms that operate to limit the growth and spread of Lm in resistant but not susceptible mice. To study the role of CD8+ T cells in innate immunity we will use a unique adoptive transfer system wherein T cells from a responsive mouse are injected into a MHC-matched non-responsive strain. This powerful strategy will allow us to specifically isolate the function of IFN&#947; rapidly produced by CD8+ T cells while leaving all other innate immune mechanisms intact. These studies will have a large impact on both microbiologists and immunologists as we anticipate that our natural feeding model will be widely used by both groups in the future to identify mechanisms that promote either bacterial virulence or host resistance during infection.

project_terms:
Acute;Adoptive Transfer;Affinity;Age;Animal Model;Bacteria;Bacterial Proteins;Bile fluid;Blood;Bolus Infusion;Brain;Buffers;Bypass;CD8B1 gene;Cells;Cellular biology;Cheese;Disease;Dose;E-Cadherin;Eating;Face;Food;Future;Gastroenteritis;Genes;Growth;Host resistance;Human;Immune;Immune response;Immunologist;Individual;Infection;Inflammatory;Inflammatory Infiltrate;Inflammatory disease of the intestine;Ingestion;Interferons;Intestinal Mucosa;Intestines;Intravenous;Kinetics;Lamina Propria;Left;Life;Life Style;Listeria monocytogenes;Listeriosis;Liver;Mammalian Cell;Meat;Memory;Meningoencephalitis;Modeling;Mortality Vital Statistics;Mucous Membrane;Mus;Natural Immunity;Neuraxis;Oral;Organism;Outcome;Pathway interactions;Patients;Peripheral;Phagocytes;Phase;Phenotype;Predisposition;Pregnant Women;Process;Production;Resistance;Risk;Role;Route;Septicemia;Signal Transduction;Spleen;Stomach;Symptoms;System;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Time;Tissues;Virulence;bacterial resistance;cell type;cytokine;feeding;foodborne infection;human disease;improved;in vivo;insight;intestinal epithelium;neonate;novel;oral infection;pathogen;prevent;public health medicine (field);receptor;response;tool;transmission process

public_health_relevance:
Project Narrative: Listeria monocytogenes (Lm) infections occur following the ingestion of contaminated ready-to-eat food products such as unpasteurized cheeses and deli meats and have a high mortality rate particularly for some pregnant women/neonates and people over the age of 60. In this study we are testing the idea that Lm elicits a strong protective immune response in most individuals that will limit the infection to a mild gastroenteritis. We predict that in susceptible individuals who lack the ability to mount this innate immune response unrestricted growth of Lm will result in systemic spread and invasion of the central nervous system.


application_id: 8337749
project_number: 5R01ES019217-02
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2012-07-10
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)M]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylcholine;Acute;Admission activity;Adult;Affect;Air;Air Pollution;Animals;Antioxidants;Aorta;Arrhythmia;Atherosclerosis;Automobile Exhaust;Blood Cells;Blood Pressure;Blood Vessels;Bone Marrow;Breathing;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Coagulation Process;Coal;Defect;Deposition;Development;Endothelium;Epidemiologic Studies;Event;Exposure to;Flow Cytometry;Fossil Fuels;Free Radicals;Functional disorder;Generations;Goals;Health;Heart Arrest;Heart failure;Hematopoietic;Hematopoietic stem cells;Homing;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Intervention;Ischemic Stroke;Lead;Location;Maintenance;Measures;Mediator of activation protein;Mesenchymal Stem Cells;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Oxidation-Reduction;Oxidative Stress;Paper;Particulate;Particulate Matter;Plants;Plasma;Population;Reaction;Relaxation;Reporting;Risk;Smoke;Steel;Stem cells;Symptoms;Testing;Thrombosis;Time;Toxic effect;Ultrafine;Unstable angina;Wood material;Wound Healing;air filter;angiogenesis;atherogenesis;base;biomarker;cardiovascular disorder risk;cardiovascular risk factor;cell growth;human tissue;insight;novel;particle;peripheral blood;prevent;repaired;research study;response;stroke;tissue repair;young adult


application_id: 8337036
project_number: 2R01HL055477-15
project_title: Toxicity and Detoxification of 4 Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2012-07-27
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: HL
serial_number: 055477
program_official: WANG, LAN-HSIANG
project_start_date: 1998-12-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 CVRS-K (02)]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of lipid peroxidation products in inducing cardiac injury and dysfunction caused by chronic hemodynamic stress. Our working hypothesis is that the effects of reactive oxygen species generated in these hearts are in part mediated by 4-hydroxyalkenals produced as a result of lipid peroxidation. We propose that modification of myocardial proteins by these aldehydes is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress and therefore metabolic detoxification of these aldehydes diminishes myocardial hypertrophy and heart failure. To test this hypothesis we will examine 4-hydroxyalkenal formation and metabolism in hearts subjected to transverse aortic constriction (TAC) and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles such as reduced glutathione and carnosine. To identify changes in aldehyde metabolism metabolites of 4-hydroxy-trans-2-nonenal (HNE) generated in hypertrophic hearts perfused with radiolabeled HNE will be identified and quantified along with HNE metabolites generated in vivo in the blood and urine of mice subjected to TAC. To determine the role of aldehyde metabolism in regulating cardiac injury and dysfunction induced by pressure overload we will examine whether genetic deletion of aldose reeducates (which catalyzes the reductive metabolism of aldehydes) or cardiospecific overexpression of carnosine synthase (which generates the aldehyde-quenching dipeptide - carnosine in the heart) affects myocardial injury and dysfunction after TAC. To examine the mechanism by which aldehydes induce myocardial injury we will examine whether exposure to HNE triggers autophagy; whether the pathways of autophagy activated by HNE are also stimulated by TAC; and whether changes in aldehyde metabolism via aldose reductase and carnosine alter autophagic responses in hypertrophic and failing hearts. Completion of this project will lead to a better understanding of the role of oxidative stress in myocardial hypertrophy and heart failure as well as other chronic conditions associated with an increase in lipid peroxidation such as diabetes atherosclerosis and cardiovascular aging. Our results could provide novel insights into the mechanisms by which hemodynamic stress induces myocardial injury and dysfunction and how these changes could be attenuated. We expect that these findings will have wide mechanistic prognostic and therapeutic implications for diagnosis management and treatment of pathological hypertrophy and heart failure.     
   
PUBLIC HEALTH RELEVANCE: Exposure to environmental aldehydes through either pollution or diet is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress therefore determining how these aldehydes are removed from the system could lead to ways to reduce their effect. To test this hypothesis we will examine a specific aldehyde formation and metabolism in hearts subjected to reduced blood flow and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles in an effort to determine how to either block their damage or increase their metabolism to remove them prior to their causing injury.


application_id: 8336918
project_number: 5R00CA139050-04
project_title: KiSS1 treatment of pancreatic adenocarcinoma
administering_ic: NCI
award_notice_date: 2012-07-30
opportunity_number: PA-07-297
application_type: 5
activity_code: R00
ic: CA
serial_number: 139050
program_official: YOVANDICH, JASON L
project_start_date: 2011-09-21
project_end_date: 2014-08-31
study_section: NSS
contact_pi_person_id: 8230129
contact_pi: MCNALLY, LACEY R
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:
Currently pancreatic adenocarcinonna is the 4th leading cause of cancer death in the United States with a median survival of <6 month and a dismal 5-yr survival rate of 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using a metastasis suppressor to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor KiSS1 is a secreted protein that inhibits metastasis of human melanoma breast and ovarian cancer xenograft models. KiSSI expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarcinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSSI a metastasis suppressor. Preliminary studies indicate that restoration of KiSSI greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data the proposed in vitro and in vivo experiments will evaluate the efficacy of KiSSI treatment alone or combined with chemotherapy. Importantly since KiSSI is a secreted cytostatic protein this strategy does not depend on restoration of KiSSI in all cancer cells. Rather the effects of KiSSI are local including via a by-stander effect and systemic due to secretion of KiSSI. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSSI plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSSI delivery and enable testing of KiSSI in a model system by producing a KiSSI-expressing adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virusi Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy in established metastatic and primary tumors in a xenograft model.

project_terms:
Address;Adenoviruses;Animal Model;Animals;Apoptosis;Biological Models;Bioluminescence;Blood;Breast Melanoma;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Cherry - dietary;Chronic Disease;Clinical;Clinical Trials;Combination Drug Therapy;Cytostatics;Cytotoxic Chemotherapy;Data;Diagnosis;Diaphragm (Anatomy);Disease;Early treatment;Enzyme-Linked Immunosorbent Assay;Evaluation;Failure (biologic function);Future;Goals;Grant;Growth;Hematoxylin and Eosin Staining Method;Hepatic;Histology;Hour;Human;Image;Immunohistochemistry;Implant;In Situ Nick-End Labeling;In Vitro;Infection;Injection of therapeutic agent;Instruction;Investigation;Label;Liver;Luciferases;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Measures;Messenger RNA;Metastatic Lesion;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic Pancreatic Adenocarcinoma;Methods;Modeling;Monitor;Morphology;Mus;Neoplasm Metastasis;Organ;Pancreas;Pancreatic Adenocarcinoma;Patients;Pharmaceutical Preparations;Plasmids;Preparation;Primary Neoplasm;Principal Investigator;Progress Reports;Protein Analysis;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Research;Route;SCID Mice;Sampling;Signal Transduction;Staging;Subgroup;Survival Rate;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Transfection;Treatment Efficacy;United States;Update;Viral;Virus;Western Blotting;Xenograft Model;Xenograft procedure;base;cancer cell;chemotherapeutic agent;chemotherapy;conditionally replicative adenovirus;cytotoxic;design;fluorescence imaging;gene therapy;implantation;improved;in vivo;in vivo Model;mouse model;neoplastic cell;novel therapeutic intervention;p65;pancreas xenograft;pancreatic cancer cells;pancreatic neoplasm;prevent;programs;research study;response;restoration;tumor;tumor growth;tumor xenograft

public_health_relevance:
RELEVANCE (See instructions): These studies will be the first to examine KiSSI treatment on established metastasis and provide vital information on the potential benefits of this treatment for patients with pancreatic adenocarcinoma.


application_id: 8334921
project_number: 1R21DA034095-01
project_title: A Human Laboratory Study to Investigate Buspirone for Cocaine Use Disorders
administering_ic: NIDA
award_notice_date: 2012-07-30
opportunity_number: PA-10-269
application_type: 1
activity_code: R21
ic: DA
serial_number: 034095
program_official: HAMPSON, AIDAN
project_start_date: 2012-08-01
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce cocaine use however these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. In the central nervous system cocaine blocks the reuptake and induces release of dopamine and serotonin thus a successful cocaine pharmacotherapy will likely need to target both of those neurotransmitters. Buspirone an anxiolytic medication with limited abuse potential is an antagonist at dopamine autoreceptors and a partial agonist at serotonin 5- HT1A receptors; both of these receptors play crucial roles in the abuse-related effects of cocaine. Dopamine autoreceptors stabilize dopaminergic tone and antagonists at these receptors can increase dopamine release. Moreover medications with partial agonist activity 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). Although buspirone produces pharmacological effects that are likely beneficial for treating cocaine dependence we are unaware of any human laboratory research that has tested the influence of buspirone on the behavioral effects of cocaine a notable gap in the literature considering that such research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This study will assess the reinforcing subject- rated cognitive performance and physiological effects of cocaine during maintenance on buspirone. By determining how buspirone impacts the behavioral effects of cocaine we will provide important evidence regarding the potential efficacy of this compound for managing cocaine use disorders. These results will help to broaden the current clinical neuroscience paradigm of cocaine medications development efforts beyond a focus on dopamine 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.   
   
PUBLIC HEALTH RELEVANCE: A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone an anxiolytic with limited abuse potential is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.

project_terms:
12 year old;Abstinence;Agonist;American;Animals;Anti-Anxiety Agents;Autoreceptors;Basic Science;Behavior Therapy;Behavioral;Buspirone;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Cognitive;Data;Development;Disease;Dopamine;Dopamine Agonists;Dopamine Antagonists;Dose;Double-Blind Method;Drug usage;Health;Human;In Vitro;Intervention;Laboratories;Laboratory Research;Laboratory Study;Literature;Maintenance;Measures;Modeling;National Institute of Drug Abuse;Neuraxis;Neurosciences;Neurotransmitters;Nicotine Use Disorder;Opioid;Performance;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Physiological;Placebo Control;Placebos;Play;Receptor Serotonin 5-HT1A;Relative (related person);Reporting;Research;Role;Sample Size;Sampling;Schedule;Self Administration;Serotonin;Stimulus;Surveys;Synapses;System;Testing;Time;Translating;Treatment Efficacy;United States;Urine;cocaine use;dopamine system;effective therapy;in vivo;meetings;novel;pre-clinical;preclinical study;public health medicine (field);receptor;reinforcer;research study;reuptake;success;tool;treatment effect

public_health_relevance:
A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone an anxiolytic with limited abuse potential is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.


application_id: 8334625
project_number: 5R01DK091584-02
project_title: Novel biomarker validation and dosing algorithms for anemia management in ESRD
administering_ic: NIDDK
award_notice_date: 2012-09-05
opportunity_number: PA-09-204
application_type: 5
activity_code: R01
ic: DK
serial_number: 091584
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2011-09-20
project_end_date: 2016-08-31
study_section: ZDK1-GRB-G(O5)S
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: BRIER, MICHAEL E
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:
Address;Algorithms;Anemia;C-reactive protein;Chronic Kidney Failure;Clinical;Computer Assisted;Computers;Data;Decision Support Systems;Development;Dialysis procedure;Dose;End stage renal failure;Enrollment;Enzyme-Linked Immunosorbent Assay;Erythropoiesis;Erythropoietin;Goals;Grant;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Inflammatory;Investigation;Iron;Kidney Diseases;Kidney Failure;Knowledge;Laboratories;Methods;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Nutritional status;Outcome;Overdose;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Process;Protein Fragment;Proteins;Proteome;Protocols documentation;Publishing;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Research;Resistance;Risk;Sensitivity and Specificity;Serum;Serum Proteins;Surrogate Markers;Techniques;Testing;Treatment outcome;Validation;base;biomarker;cardiovascular risk factor;cost;cytokine;design;dosage;hepcidin;improved;indexing;novel;predictive modeling;prevent;response;tool;trend


application_id: 8334496
project_number: 5R21AA020188-02
project_title: Alcohol the vagus nerve and multi-organ inflammation
administering_ic: NIAAA
award_notice_date: 2012-07-26
opportunity_number: RFA-AA-10-008
application_type: 5
activity_code: R21
ic: AA
serial_number: 020188
program_official: WANG, JOE
project_start_date: 2011-09-20
project_end_date: 2014-08-31
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
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 tenth cranial nerve the vagus is distributed throughout the body including major divisions to all parts of the gut and to the liver. This cholinergic nerve restrains inflammation in all the organs to which the vagus is distributed by the tonic release of acetylcholine (ACh) onto nicotinic receptors (nicAChRs) of the alpha7- subtype. In addition to their presence on inflammatory cells alpha7-nicAChRs are also present on cell bodies of the vagus in the CNS where they cause vagal activation and neuroprotection. Since the presence of alcohol inhibits alpha7-nicAChRs and a known chronic effect is to cause vagal neuropathy these anti-inflammatory effects of the vagus are seriously compromised during alcohol exposure. The primary hypothesis is that this reduced vagal function contributes to the chronic inflammation following oxidative stress which is a common feature of alcohol-induced damage in many organs. If correct this predicts that compounds with alpha7- nicAChR agonist properties will protect against alcohol-induced tissue damage particularly if these compounds are also anti-oxidants. The first specific aim of this proposal is to test the primary hypothesis in vitro by studying the interactions of alcohol and alpha7-nicAChR ligands on endotoxin-induced release of mediators from inflammatory cells (splenic lung and peritoneal macrophages) from wild-type and alpha7-nicAChR knock-out C57Bl/6J mice. The second specific aim is to test the hypothesis in vivo by exposing C57Bl/6J mice (wild-type vagotomized and alpha7-nicAChR knockouts) chronically to alcohol by forced consumption and then evaluating endotoxin-induced release of inflammatory mediators in vivo. As part of these studies we will evaluate the therapeutic potential of the alpha7-nicAChR agonist choline and a methylquercetagetin which acts as a partial agonist at alpha7-nicAChRs. The latter was recently discovered by screening a native plant extract library and has potent anti-oxidant activity in addition to its action at nicAChRs where it has an affinity comparable to choline. The ability of these compounds to inhibit endotoxin-induced release of inflammatory mediators following alcohol exposure will be studied in vitro and in vivo using the same methods as above. This project therefore tests a novel hypothesis for alcohol-induced organ damage based on the interaction between brain gut and liver as represented by the vagus nerve and tests a novel therapeutic approach to this.

project_terms:
Acetylcholine;Acute;Affect;Affinity;Agonist;Alcohol-Induced Disorders;Alcoholism;Alcohols;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Brain;Cell physiology;Cells;Choline;Chronic;Consumption;Dependence;Development;Drug Evaluation;Endotoxins;Exploratory/Developmental Grant;Heart Rate;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Knock-out;Knockout Mice;Libraries;Ligands;Lipopolysaccharides;Liver;Lung;Mediator of activation protein;Medical;Methods;Mus;Nerve;Neuropathy;Nicotinic Receptors;Organ;Oxidative Stress;Peritoneal Macrophages;Pharmaceutical Preparations;Physiological;Plant Extracts;Population;Process;Property;Role;Screening procedure;Sum;Telemetry;Testing;Therapeutic;Tissues;Vagus nerve structure;Variant;Wild Type Mouse;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol research;alcoholism therapy;alpha-bungarotoxin receptor;base;cell body (neuron);cell type;cholinergic;cost;drug discovery;in vivo;macrophage;neuroprotection;novel;novel therapeutic intervention;prevent;receptor;research study;response;restraint;therapeutic target

public_health_relevance:
Alcoholism (either dependence or abuse) affects more than 8% of the population of the US and the societal costs approach $200BN annually. About half of this sum is medical cost much of which is accrued in treating alcohol-related organ damage. Despite this there are currently no accepted approaches to preventing or reversing this damage. This application proposes a novel hypothesis as to the cause of organ damage which has profound implications for treatment. If successful the project will establish a framework for drug discovery and evaluation in relation to this largely overlooked therapeutic target.


application_id: 8333969
project_number: 5R21NS077434-02
project_title: Inhibition of Lipid Peroxidation in SCI
administering_ic: NINDS
award_notice_date: 2012-07-27
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: NS
serial_number: 077434
program_official: HICKS, RAMONA R
project_start_date: 2011-09-16
project_end_date: 2013-08-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
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_abstract:
DESCRIPTION (provided by applicant): We have previously shown that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first hrs after spinal cord injury (SCI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have further shown that treatment with the potent LP inhibitor U-83836E can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results showing a partial attenuation of post-injury LP-related neural damage' even when the LP inhibitor is administered within the first 15 min. after injury strongly point to the logic of an antioxidant neuroprotective strategy that combines a LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a greater chance of translational success in future SCI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;3-nitrotyrosine;4 hydroxynonenal;Acute;Aldehydes;Antioxidants;Attenuated;Bladder Control;Brain;Brain Injuries;Buffers;Calcium;Calpain;Carbonates;Cell physiology;Clinical Trials;Contusions;Cytoplasm;Cytoskeletal Proteins;Dose;Early treatment;Elements;Failure (biologic function);Free Radicals;Functional disorder;Future;Generations;Goals;Hour;Hydroxyl Radical;Impairment;Injury;Lead;Lipid Peroxidation;Lipids;Locomotor Recovery;Logic;Mediating;Membrane Lipids;Mental Depression;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurologic;Neurological outcome;Nitric Oxide Synthase;Nitrogen Dioxide;Peroxonitrite;Pharmaceutical Preparations;Phenelzine;Post-Translational Protein Processing;Production;Proteolysis;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stress;Testing;Therapeutic;Thoracic spinal cord structure;Tissues;Traumatic Brain Injury;Treatment Efficacy;Tyrosine;Work;attenuation;controlled cortical impact;improved;lipid peroxidation inhibitor;mitochondrial dysfunction;neuroprotection;neurotoxic;nitration;oxidative damage;perhydroxyl radical;relating to nervous system;research study;respiratory;success;treatment strategy;uptake;white matter

public_health_relevance:
This project will examine the potentially greater benefits that might be obtained in the rat thoracic spinal cord contusion injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a dual treatment strategy involving the combination of the potent lipid peroxidation-inhibiting drug U-83836E with phenelzine a commercially available compound that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4-hydroxynonenal (4-HNE). Each of the compounds will also be tested by themselves in order for comparison to the combination treatments.


application_id: 8333731
project_number: 3R01AA018016-04S1
project_title: The Role of Alcohol in HIV Therapy Hepatotoxicity
administering_ic: NIAAA
award_notice_date: 2011-09-19
opportunity_number: RFA-AA-08-013
application_type: 3
activity_code: R01
ic: AA
serial_number: 018016
suffix: S1
program_official: WANG, JOE
project_start_date: 2008-09-30
project_end_date: 2013-08-31
study_section: ZAA1-BB(02)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: BARVE, SHIRISH S;EATON, JOHN W
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): It is clear that alcohol abuse can alter/suppress immune function including CD4 T-lymphocyte depletion which can accelerate HIV progression. Subjects who consume alcohol may be more likely to develop certain infectious diseases which can complicate HIV examples being various types of pneumonia and tuberculosis. Moreover subjects who consume alcohol are more likely to participate in high-risk behaviors that increase the likelihood of acquiring HIV. Patients who consume alcohol also may be less compliant with their HIV therapy which can affect disease progression. The research focus of this grant is the potential impact of alcohol use/abuse as a co-factor for HIV therapy-induced hepatotoxicity. Since the introduction of highly active antiretroviral therapy (HAART) in 1996 the life expectancy of patients with HIV has increased significantly. However HAART is associated with significant hepatotoxicity. The severity of liver toxicity ranges from the absence of symptoms to liver decompensation and the reported incidence of severe liver toxicity after initiating HAART ranges from 2% to 18%. The mechanisms involved in HAART-derived hepatotoxicity are not well understood which makes its management more difficult. Some likely mechanisms of hepatotoxicity include proinflammatory cytokine production mitochondrial toxicity hypersensitivity reactions steatosis and insulin resistance immune reconstitution in HCV or HBV co-infected patients and proteasome inhibition (with dysregulated cytokine metabolism and mitochondrial and proteasome dysfunction serving as the focus of this proposal). The long-term goals of this study are to: (1) define mechanisms of hepatotoxicity induced by a combination of drug therapy and alcohol abuse in HIV patients and (2) discover potential therapeutic interventions for HAART hepatotoxicity especially for patients in whom alcohol use/abuse may be a contributing factor. Specific Aims of this proposal are to: 1. Evaluate the potential hepatotoxic interactions of alcohol and HAART medications using rapid in vitro hepatocyte screening technology; 2. Determine the effects of anti- HIV drugs (selected agents based on preliminary toxicity studies from SO#1 and clinical hepatotoxicity risk) on the development and progression of hepatotoxicity in mice and the drug interactions with chronic alcohol intake; and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity and c) liver histology findings including markers of proteasome and mitochondrial function using a human translational approach from a cohort of HCV+HIV coinfected subjects enrolled in a prospective NIH study based at the University of Cincinnati. We postulate that the HAART and alcohol mediated metabolic complications of dysregulated proinflammatory cytokine production and mitochondrial and proteasome dysfunction converge on the liver in an overlapping fashion to induce hepatotoxicity. In this proposal we test that hypothesis in a novel translational approach and we evaluate unique therapeutic interventions for this hepatotoxicity.    PUBLIC HEALTH RELEVANCE: Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatotoxicity due to HAART is also common and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore hepatotoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure or more commonly AIDS following discontinuation of HAART. It is unknown why some but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through these and other mechanisms alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatotoxicity. Here we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.

project_terms:
Acetaminophen;Acquired Immunodeficiency Syndrome;Acute Liver Failure;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Anti-HIV Agents;Anti-HIV Therapy;Anti-Retroviral Agents;CD4 Positive T Lymphocytes;CYP2E1 gene;Cause of Death;Chronic;Clinical;Combination Drug Therapy;Communicable Diseases;Depressed mood;Development;Disease;Disease Progression;Drops;Drug Interactions;Enrollment;Enzymes;Fatty Liver;Functional disorder;Goals;Grant;HIV;HIV Infections;HIV therapy;Health;Hepatic;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Hepatocyte;Hepatotoxicity;Highly Active Antiretroviral Therapy;Histology;Human;Hypersensitivity;Immune;In Vitro;Incidence;Infection;Injury;Insulin Resistance;Killings;Lactic Acidosis;Life Expectancy;Lipodystrophy;Liver;Liver diseases;Lymphocyte Count;Lymphocyte Depletion;Lymphocyte Function;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Natural immunosuppression;Nucleosides;Opportunistic Infections;Outcome;Oxidative Stress;Patients;Pharmaceutical Preparations;Pneumonia;Population;Predisposition;Production;Protease Inhibitor;Proteasome Inhibition;Proteins;Reaction;Reporting;Research;Reverse Transcriptase Inhibitors;Risk;Role;Screening procedure;Series;Severities;Simulate;Symptoms;TNF gene;Technology;Testing;Therapeutic Intervention;Time;Toxic effect;Tuberculosis;Tumor Necrosis Factor-alpha;United States National Institutes of Health;Universities;Viral hepatitis;Work;World Health Organization;alcohol effect;base;cohort;cytokine;design;experience;feeding;high risk behavior;immune function;interest;mitochondrial dysfunction;multicatalytic endopeptidase complex;non-nucleoside reverse transcriptase inhibitors;novel;prospective;public health relevance;reconstitution;translational approach

public_health_relevance:
Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatoxicity due to HAART is also common and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore hepatoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure or more commonly AIDS following discontinuation of HAART. It is unknown why some but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through these and other mechanisms alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatoxicity. Here we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.


application_id: 8333414
project_number: 5R42DK074331-04
project_title: Induction of Donor Tolerance in Renal Transplants
administering_ic: NIDDK
award_notice_date: 2012-07-23
opportunity_number: PA-10-051
application_type: 5
activity_code: R42
ic: DK
serial_number: 074331
program_official: MOXEY-MIMS, MARVA M
project_start_date: 2005-06-03
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-G(11)B]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140644969
duns_number: 140644969
fips: US
organization_id: 10001459
organization_name: REGENEREX, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
budget_end_date: 2014-06-30
project_abstract:
DESCRIPTION: Renal transplantation is the preferred therapeutic approach for end organ failure. However the chronic use of immunosuppressive agents is critical to prevent rejection. The drugs are costly ($15000-25000/year) and have significant toxicities including opportunistic infection an increased rate of malignancy nephrotoxicity and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs. However the toxicity and complications associated with conventional hematopoietic stem cell transplants (HSCT) primarily graft-versus-host disease (GVHD) and the need for a matched donor has limited the therapeutic application of HSCT to tolerance induction. We have identified and patented a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of stem cells in mismatched recipients without causing GVHD. The discovery of FC opens the door to employing HSCT as a viable cell-based approach for tolerance induction. The product FCRx addresses the major challenges preventing the widespread use of HSCT for tolerance induction. FCRx is a bioengineered bone marrow product that includes hematopoietic stem cells (HSC) and FC but avoids GVHD in mismatched recipients. In phase I of this proposal we achieved our proposed milestones demonstrating that we could reliably produce and transport FCRx and safely infuse it into nonmyeloablatively conditioned renal transplant recipients. We demonstrated that the proprietary FCRx procedure can routinely produce a graft with defined 12-TCR+ T cell composition and enriched for HSC and engraftment-enhancing FC. The ultimate goal is the induction of immune tolerance and the elimination of or reduction in the need for expensive and harmful immunosuppressive drugs. We have developed a nonmyeloablative conditioning regimen with 200 cGy TBI/fludarabine/cyclophosphamide/MMF/prograf to avoid the toxicity of conditioning. Since completing Phase I we have addressed a major concern expressed by the reviewers regarding our ability to enroll subjects and have now successfully transplanted 6 living donor kidney patients all of whom demonstrated donor chimerism at one month post-transplant. The approaches for collection shipping and FCRx preparation have also been approved by the FDA. Three patients show laboratory evidence of donor-specific tolerance and immunosuppression is being weaned. The remaining subjects are early in follow-up. The reproducibility and quality assurance of the FCRx process will lead to its successful commercial launch. In phase II we will increase the pace of transplants and demonstrate that FCRx consistently achieves engraftment of HLA mismatched HSC in nonmyeloablatively conditioned kidney transplant recipients induces donor-specific tolerance without causing significant GVHD and reduces or eliminates the need for long-term immunosuppression. A recent meeting with FDA classified our product as Phase II another milestone that will enhance commercialization.

project_terms:
Address;Aplastic Anemia;Autoimmunity;Biological Assay;Biomedical Engineering;Biopsy;Blood;Bone Marrow;Bone Marrow Cells;Businesses;CD8B1 gene;Cell Transplants;Cells;Childhood;Chimerism;Chronic;Chronic Granulomatous Disease;Collection;Creatinine;Cyclophosphamide;Data;Diabetes Mellitus;Disease;Dose;Engineering;Engraftment;Enrollment;FDA approved;Face;Generations;Goals;Graft-vs-Host Disease;Grant;Hand;Health;Heart;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Hemoglobinopathies;Immune;Immune Tolerance;Immune system;Immunologic Monitoring;Immunosuppressive Agents;Inherited;Islets of Langerhans;Kidney;Kidney Failure;Kidney Transplantation;Laboratories;Lead;Legal patent;Life;Liver;Living Donors;Lupus;Macular degeneration;Malignant Neoplasms;Metabolic Diseases;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mucopolysaccharidosis II;Multiple Sclerosis;Myocardial Infarction;Natural immunosuppression;Natural regeneration;Opportunistic Infections;Organ;Organ Transplantation;Organ failure;Patients;Pharmaceutical Preparations;Phase;Population;Preparation;Procedures;Process;Prograf;Property;Protocols documentation;Psoriasis;Regimen;Regulatory T-Lymphocyte;Renal function;Reproducibility;Rheumatoid Arthritis;Safety;Serum;Shipping;Ships;Sickle Cell Anemia;Solid;Stem cell transplant;Stem cells;T-Lymphocyte;Technology;Testing;Thalassemia;Therapeutic;Therapeutic immunosuppression;Tissues;Toxic effect;Transplant Recipients;Transplantation;Universities;Weaning;base;commercialization;conditioning;cost;experience;fludarabine;follow-up;in vitro Assay;in vivo;islet;kidney allograft;large bowel Crohn's disease;leukemia;leukodystrophy;meetings;mouse model;nephrotoxicity;novel;prevent;quality assurance;regenerative;repaired;stem

public_health_relevance:
Life-long immunosuppressive therapy is necessary following solid organ transplant. These drugs are expensive and have significant toxicities including opportunistic infection an increased rate of cancer and kidney failure. Hematopoietic stem cell transplantation (HSCT) induces tolerance to transplanted organs and tissue eliminating the need for life-long immunosuppressive therapy. If successful the process proposed for commercialization called FCRx will produce a bioengineered HSCT graft-enriched for facilitating cells and stem cells that will safely induce tolerance eliminating the need for immunosuppressive therapy along with its high monetary and health-related cost.


application_id: 8333308
project_number: 5R34DE022274-02
project_title: Oral Health Intervention for Intellectually/Developmentally Disabled Persons
administering_ic: NIDCR
award_notice_date: 2012-07-23
opportunity_number: RFA-DE-12-001
application_type: 5
activity_code: R34
ic: DE
serial_number: 022274
program_official: CLARK, DAVID
project_start_date: 2011-09-15
project_end_date: 2014-02-28
study_section: ZDE1-JR(17)
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: JOHNSON, KNOWLTON WILLIAM
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): People with intellectual and/or developmental disabilities (IDD) living in family or group homes receive less preventive medical care than those living in institutions and are less likely to receive routine dental care. These individuals are more likely to have poor oral hygiene increased decay and periodontal disease than the general population-a significant health disparity. More importantly poor oral health in persons with IDD may also contribute to respiratory infections including aspiration pneumonia. The oral health of this population is compromised not only by the lack of preventive dental treatment every six months but also their inability to adequately brush and/or floss their own teeth. Many of the moderately to profoundly disabled are dependent on their caregivers to maintain oral health but there is evidence that caregiver psychosocial factors serve as barriers to optimal oral hygiene behavior  The proposed oral health planning grant is in conjunction with conducting a five-year randomized controlled trial with an oral health theory-based intervention delivered by case managers. The research will extend previous findings from a pilot study to a different population by using an empirical grounded theoretical framework refined intervention strategy larger sample size and pilot tested process and outcome measures. The U01 cooperative agreement trial would be the first outcome study properly powered to evaluate the effect of a dental case management strategy on oral health related quality of life and respiratory infections with caregivers and IDD participants in 124 community group homes.  The two-year planning grant is requested to pilot test recruitment strategies acceptability of the intervention fidelity monitoring methods and validity and reliability of study measures including intervention processes mediators moderators and outcomes. The pilot will be conducted with a sample of caregivers in 25 group homes with approximately 112 IDD participants. Upon completion of the planning grant a full protocol and manual of operations will have been developed for the clinical trial (U01 cooperative agreement) grant application. Personnel from the University of Louisville and the Pacific Institute for Research and Evaluation will participate in these activities.  The results of this study will impact the field of social and behavioral research by demonstrating whether dental case management improves the oral health and related quality of life of persons with IDD. If the results are positive we would advocate for a larger multi-site randomized controlled trial to produce results that may be generalized to different populations with oral health disparities in diverse geographic areas. Ultimately the results could impact healthcare reform and integrate dental case management into medical case management for disadvantaged persons.

project_terms:
Address;Administrator;Advocate;Applications Grants;Aspiration Pneumonia;Behavior;Behavior Therapy;Behavioral;Behavioral Research;Caregivers;Caring;Case Management;Case Manager;Child;Clinical Trials;Communities;Consent;Data;Data Analyses;Data Collection;Dental;Dental Care;Dental Hygiene;Dentists;Developmental Disabilities;Disabled Persons;Disadvantaged;Ensure;Evaluation Research;Exhibits;Family;Future;General Population;Geographic Locations;Grant;Group Homes;Health;Health Care Costs;Health Care Reform;Health Planning;Health Policy;Health Services;Health Services Accessibility;Health Status;Health behavior;Home environment;Housing;Human Resources;Impaired cognition;Individual;Institution;Institutional Review Boards;Insurance;Intervention;Intervention Trial;Kentucky;Learning;Letters;Life;Manuals;Measurement;Measures;Mediator of activation protein;Medicaid;Medical;Methodology;Methods;Modeling;Monitor;Oral Examination;Oral health;Outcome;Outcome Measure;Outcome Study;Parents;Participant;Patients;Periodontal Diseases;Persons;Pilot Projects;Population;Preparation;Preventive;Procedures;Process;Process Measure;Protocols documentation;Psychosocial Factor;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Reporting;Research;Research Institute;Respiratory Tract Infections;Risk;Safety;Sample Size;Sampling;Sedation procedure;Site;Support Groups;Target Populations;Testing;Tooth structure;U-Series Cooperative Agreements;Universities;Validity and Reliability;Vulnerable Populations;base;community setting;developmentally disabled;effective intervention;health disparity;health literacy;health related quality of life;improved;intervention effect;member;operation;prevent;public health medicine (field);respiratory;social;success;theories

public_health_relevance:
In the short term the results of the proposed study have the potential to provide evidence that public health policies should include dental case management especially for IDD participants living in the community. Additionally this study may show that a behavioral intervention targeting caregivers could produce a greater impact on oral health outcomes in other dependent populations. In the long term we hope this research can develop evidence for an oral health intervention for caregivers of cognitively impaired persons. We believe oral health can be positively impacted preventing poor oral health and oral health related quality of life and possibly respiratory infections in these vulnerable populations. Moreover if future studies show that oral health outcomes are positively impacted by this intervention then the overall healthcare cost could be reduced because cognitively impaired individuals will have less need for expensive procedures resulting from lack of proper oral health behaviors.


application_id: 8332626
project_number: 2R01AG026307-06
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2012-07-20
opportunity_number: PA-09-216
application_type: 2
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1 BBBP-T (02)]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Older adults are at high risk for a number of health problems including cardiovascular disease infectious disease and cancer. Underlying at least part of this risk is immunological aging but not all older adults experience immunological aging to the same degree nor do they experience the same health risk and health problems. The purpose of this project is to measure individual differences and changes in self-regulation over time in older adults and to link self-regulation to subjective health health risks and clinically
relevant markers of immunological aging including inflammation and markers of lymphocyte terminal differentiation and replicative senescence. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation neuropsychology autonomic and inflammatory biology immunology and longitudinal design and analysis. The first period of the study focused on risk factors especially stress and repetitive thought and their effects on psychological well-being subjective health and immune response to vaccination. The renewal continues assessment of these risk factors to provide continuity in this longitudinal dataset and adds innovation in the assessment of factors that may promote healthy aging and mitigate against effects of risks. Specifically the aims of the study are first to test the effects of a elf-regulatory constellation (comprising self-regulation executive cognitive function and heart rate variability [HRV]) on subjective psychological social and physical health and markers of immunological aging. Second we will test the relationships between this constellation and risk factors such as age and stress. Third we will test the ability of the constellation to moderate rik effects. A further aim is to support a "call for collaboration" in which we propose to work with other investigators whose hypotheses can be tested with study data from 2001 through the current renewal. At 6- month intervals older adults (N = 150) will complete measures of the self-regulatory constellation: behavioral emotional social and cognitive self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. They will complete measures of risk including stress pain physical activity BMI and waist circumference. Finally they will complete measures of psychosocial health including depression perceived cognitive and physical health and marital satisfaction. Blood draws will be synchronized with these visits and assays performed on these samples will capture two aspects of immunological aging: increases in serum proinflammatory cytokines and their soluble receptors and increases in markers of terminal differentiation and senescence in T cells and NK cells. This renewal will be innovative in its comprehensive assessment of self-regulation as well as risk; the longitudinal design that allows for the study of change and lagged mediational and bidirectional effects; and the focus on the role of self-regulation in healthy aging.   
   
PUBLIC HEALTH RELEVANCE: With age come changes in the immune system that can increase the risk of poor health. However not all older adults experience these changes to the same degree. This project will continue to track a cohort of older adults examining psychological factors that may be protective for psychological and physical health and delay immunological aging as well as those factors that may confer risk and the interactions between protective and risk factors.

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

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


application_id: 8332591
project_number: 1U01ES022564-01
project_title: Countermeasures for chlorine-induced airway fibrosis
administering_ic: NIEHS
award_notice_date: 2012-09-25
opportunity_number: PAR-11-155
application_type: 1
activity_code: U01
ic: ES
serial_number: 022564
program_official: NADADUR, SRIKANTH
project_start_date: 2012-09-25
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 MDCN-J (50)]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema inflammation airway obstruction and airway hyperreactivity within one day after exposure. In new studies related to the current application we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast portions of airways with few surviving epithelial cells are repaired inefficiently and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair airway fibrosis
and lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.   
   
PUBLIC HEALTH RELEVANCE: The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.

project_terms:
Acute;Adrenergic Agonists;Affect;Agonist;Airway Obstruction;Animals;Breathing;Cell Proliferation;Chemical Warfare;Chemicals;Chlorine;Chronic;Cyclic AMP;Development;Disease;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Ferrets;Fibrosis;Goals;Human;Hypoxemia;Iloprost;Impairment;Individual;Industrial Accidents;Inflammation;Irritants;Kinetics;Lesion;Lithium;Lithium Chloride;Lung;Measurement;Modeling;Mus;Non-Rodent Model;Phosphodiesterase Inhibitors;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Pneumonia;Poisons;Prevention;Production;Prostaglandins;Pulmonary Edema;Recording of previous events;Research;Resistance;Resolution;Respiratory System;Respiratory physiology;Rodent;Rolipram;Signal Pathway;Signal Transduction;Site;Structure;Structure of respiratory epithelium;Symptoms;Testing;Time;Toxic effect;Unconscious State;United States;Urokinase;airway epithelium;airway hyperresponsiveness;animal rule;butaprost;chlorin;chlorine gas;efficacy testing;formoterol;inhibitor/antagonist;injury and repair;lung development;lung injury;methacholine;novel;phosphoric diester hydrolase;prevent;prostaglandin EP2 receptor;pulmonary function;receptor;repaired;research study;respiratory;restoration

public_health_relevance:
The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.


application_id: 8330384
project_number: 3R43HG005799-02S1
project_title: Generation of Site-Specific Recombinase-Expressing Transgenic Rats using an Enhan
administering_ic: NHGRI
award_notice_date: 2011-09-16
opportunity_number: PA-09-080
application_type: 3
activity_code: R43
ic: HG
serial_number: 005799
suffix: S1
program_official: FLETCHER, COLIN F
project_start_date: 2010-09-09
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
DESCRIPTION (provided by applicant): The goal is to create site-specific recombinase (SSR)-expressing transgenic rats in an efficient and unbiased manner through a transposon-mediated in vivo gene trap. Rats are very relevant for modeling human biology and disease because rats unlike mice possess key biological similarities to humans. While in vitro gene trap mutagenesis is useful for gene discovery a rapid and efficient in vivo method is preferable for two key reasons: 1) an in vivo gene trap will reveal an authentic spatio-temporal expression pattern and 2) these genetic resources of can then be immediately employed for genome manipulations in the rat. Piecemeal promoter analysis in transgenic animals is clearly not sufficient for rapidly and economically generating effective tools for SSR-mediated tissue-specific genome manipulation. The generation of transgenic rats is simply too expensive and is performed at only a few institutions. Mouse promoter elements could be used to generate SSR-expressing transgenic rats but most promoter elements lack key regulatory sequences are sensitive to position effects at genomic insertion sites or will not necessarily produce identical expression patterns across species. Considering that tens of thousands of transcribed elements likely exist in the mammalian genome an efficient in vivo method is needed to authentically and rapidly recapitulate endogenous expression patterns to generate a diverse and effective set of transgenic tools. Furthermore a method to identify new transcribed elements would accelerate a comprehensive understanding of mammalian genomics. Gene trap mutagenesis is a standard approach for identifying and exploiting new transcription units but traditional strategies such as those targeting embryonic stem cells are simply untenable for a rapid and efficient in vivo screen. By using a PiggyBac (PB) transposon system that we have enhanced at Transposagen we will pursue an in vivo promoter trap in rats. Promoter traps will be visualized in live embryos and animals using bright fluorescent proteins (FPs). The primary reporter in this promoter trap is a Cre-EGFP fusion protein in which both Cre recombinase activity and EGFP fluorescence marks the expression domain of each trapped element. The Cre-EGFP cassette trap is delivered by a PB transposon that originates as a transgene concatemer in one transgenic line called the "donor." Another transgenic line the "driver" provides expression of the PB transposase in the germ line. Transposon mobilization is simply initiated by interbreeding driver and donor lines such that the PB transposase mobilizes the Cre-EGFP gene trap transposon within germ cells in double transgenic animals designated as "seed" rats. PB is the most efficient transposon yet described for gene mutagenesis in mammalian cells and by using an enhanced PB transposase we expect an insertion rate that should yield at least one gene trap event per gamete. As a result each G1 offspring bred from seed rats will display a unique expression pattern of the Cre-EGFP reporter. Because it is an insertional mutagen the integration site of the PB transposon is easily determined by simple PCR cloning techniques. EGFP fluorescence will be documented in E13.5 and E16.5 embryos and the identification of insertion sites will enable one to link a specific expression pattern with specific genomic locations. As noted above tools are needed for expanding the genetic resources of the rat. A strategy to accelerate the tools for genetic manipulations in the rat is integral to our approach here. By using a Cre-EGFP reporter we will be creating recombinase-mediated tools for conditional mutagenesis. To monitor Cre activity we will create transgenic rats that express a tdTomato fluorescent protein in cells following a Cre recombination event. The tdTomato protein exhibits very bright fluorescence and has proven useful for in vivo expression analysis. Using the rat ROSA26 promoter that drives ubiquitous expression tdTomato expression will be activated only following Cre-mediated removal of an intervening sequence. These transgenic rats will be mated to the G1 offspring described above that are obtained from seed rats. We will analyze live G2 embryos for EGFP and tdTomato fluorescence. By using these FPs each gene trap can be monitored in real-time; this will create the opportunity for a further in depth analyses in future investigations. We will identify at least 25 unique Cre- expressing elements in this screen in live embryos as a proof of concept. In addition to tdTomato Cre recombinase activity will also trigger FlpERT2 expression which is linked to the tdTomato open reading frame via an internal ribosomal expression sequence. FlpERT2 activity is dependent on 4-hydroxytamoxifen (4-OHT) and thus provides inducible Flp recombinase activity. Our design enables two key Flp-mediated manipulations: 1) Flp recombinase induction (via 4-OHT) removes the Cre-EGFP gene trap through flanking Flp recombinase target sites and 2) FlpERT2 expression will enable Flp-dependent conditional modification of FRT-containing alleles (generated through other efforts). The tools and resources generated here will provide great advances for rat genetics. This screen will identify at least 25 transcribed elements exhibiting a unique in vivo expression pattern of Cre-EGFP. Our strategy will provide the opportunity to easily generate hundreds of additional gene trap lines. Our investigation will generate valuable rat transgenic lines for recombinase-mediated conditional mutagenesis in future studies.

project_terms:
4-Hydroxy-Tamoxifen;Adult;Alkaline Phosphatase;Alleles;Animal Model;Animals;Biological;Breeding;Cancer Biology;Cells;Chimeric Proteins;Cloning;Communities;DNA Transposons;Development;Drug Industry;Elements;Embryo;Event;Excision;Exhibits;Fluorescence;Future;Gene Delivery;Generations;Genes;Genetic;Genetic Recombination;Genetic Transcription;Genome;Genomics;Germ Cells;Germ Lines;Germ-Line Mutation;Goals;Health;Human;Human Biology;Human Genetics;Human Pathology;Humulus;In Vitro;Indium;Individual;Inherited;Institution;Introns;Investigation;Jumping Genes;Knock-out;Lead;Life;Link;Location;Mammalian Cell;Mediating;Methods;Modeling;Modification;Monitor;Mus;Mutagenesis;Mutagens;Mutation;Neurology;Open Reading Frames;Organism;Partner in relationship;Pattern;Phase;Physiology;Positioning Attribute;Production;Promotor (Genetics);Proteins;Rattus;Reporter;Resources;Seeds;Site;Sleeping Beauty;Stem cells;System;Techniques;Technology;Time;Tissues;Toxicology;Transgenes;Transgenic Animals;Transgenic Organisms;Transposase;Validation;design;embryonic stem cell;falls;fusion gene;gene discovery;gene function;genetic manipulation;genetic resource;homologous recombination;human disease;in vivo;mammalian genome;mouse model;mutant;offspring;rapid technique;rat genome;recombinase;red fluorescent protein;retroviral transduction;sperm cell;success;tool;transposon/insertion element;vertebrate genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal describes a rapid method to discover and harness the power of tissue-specific expression patterns (where genes are turned "on") of a wide variety of genes in the rat genome in live animals. Using a mobile DNA element or "jumping gene" called piggyBac we will tag hundreds of genes in live rat embryos. The unique expression patterns that are revealed will then be exploited as tools for tissue-specific mutagenesis in future studies. The rat is highly suitable for seeking a better understanding of human genetics and biology because the rat in many ways better resembles human pathology physiology neurology and cancer biology than other popular animal models such as the mouse. The results from this study will generate valuable genetic tools for refined and subtle investigations of gene function in specific tissues.


application_id: 8329903
project_number: 2R56NS052292-06A1
project_title: Re-training locomotor circuitry in a rat model of spinal cord injury
administering_ic: NINDS
award_notice_date: 2011-09-22
opportunity_number: PA-10-067
application_type: 2
activity_code: R56
ic: NS
serial_number: 052292
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2005-07-01
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-Y(02)M]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Abstract: One of the most promising therapeutic approaches for clinical spinal cord injuries (SCI) is a form of activity-based rehabilitation known as body-weight supported step training. The fundamental concept underlying this approach is that the locomotor circuitry of the injured spinal cord remains responsive to the sensory inputs signaling loading of the limbs limb movement and contact with the ground. While a proportion of spinal cord injured individuals respond well to training many do not emphasizing the need for a greater understanding of the process. Importantly even those that respond well to training retain significant deficits especially when compared to the successful training in some animal models where the spinal cord is completely transected and training is initiated acutely (within a few weeks of injury). Unfortunately the majority of training in the clinical setting is not initiated until several months after injury primarily because current training strategies require the patients to stand on a treadmill in a body harness a process that would compromise their acute medical care. We have hypothesized based on findings from many laboratories including our own that early application of a simple but focused training strategy will fundamentally change the responsiveness of the spinal cord circuitry to more comprehensive training applied later when other medical complications have declined. Over the past several years we have developed a number of unique training tools that we will use to test this hypothesis and to develop training strategies that could be translated for bedside use in the clinic. We have also established a model of immobilization allowing us to mimic the lack of activity experienced by the majority of individuals with SCI thus providing a clinically relevant strategy where the experimental animals are treated more like we treat patients acutely after injury. We propose to use these models to answer the following specific questions: 1) Is there is a window of opportunity post-injury during which retraining of immobilized animals can be effective at improving functional recovery of locomotion? 2) What kinds of sensory input are necessary for optimal retraining? 3) Can simple and focused training strategies applied acutely improve the response of the spinal cord to more comprehensive training strategies applied at later time points? If successful the results from these studies will have the potential to fundamentally change how we approach clinical rehabilitation post-SCI.

project_terms:
Activities of Daily Living;Acute;Address;Animal Model;Animals;Biological Assay;Body Weight;Caring;Chronic;Clinic;Clinical;Early treatment;Frequencies (time pattern);Generations;Goals;Growth Factor;Hindlimb;Hindlimb Suspension;Immobilization;Individual;Injury;Label;Laboratories;Lead;Limb structure;Locomotion;Locomotor retraining;Lumbar spinal cord structure;Medical;Messenger RNA;Modeling;Molecular Profiling;Neurons;Pathway interactions;Patients;Pattern;Process;Rattus;Recovery of Function;Rehabilitation therapy;Sensory;Signal Transduction;Spinal Cord;Spinal Ganglia;Spinal cord injury;Step training;Swimming;Testing;Therapeutic;Time;Tissues;Training;Training Activity;Translating;Water;Weight;Wheelchairs;abstracting;base;clinically relevant;combinatorial;design;experience;functional improvement;functional outcomes;improved;limb movement;locomotor deficit;medical complication;neurotrophic factor;novel;prevent;research study;response;tool

public_health_relevance:
Project Narrative: The primary goal of this project is to determine if different kinds of simple and focused hindlimb activity (training) or hindlimb immobilization applied acutely can fundamentally change the responses of the injured spinal cord to more comprehensive training strategies applied later.


application_id: 8329734
project_number: 3R41DK081296-02S1
project_title: ApoFasL as a novel treatment for Type 1 Diabetes in Nonhuman Primates
administering_ic: NIDDK
award_notice_date: 2011-09-23
opportunity_number: PA-08-051
application_type: 3
activity_code: R41
ic: DK
serial_number: 081296
suffix: S1
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2010-09-05
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-G(10)B]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: ECKHOFF, DEVIN E;SHIRWAN, HAVAL
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Pancreatic islet transplantation is a viable approach for the treatment of type 1 diabetes (T1D). However this therapeutic approach suffers from graft rejection. Dr. Shirwan founder of ApoImmune has developed a novel immunotherapeutic approach aimed at tolerance induction to alloantigens without chronic use of general immunosuppression. This approach termed ApoFasL involves engineering pancreatic islets ex vivo using the Company's platform ProtEx(tm) technology in a rapid practical and nontoxic manner to efficiently display a novel form of Fas ligand (FasL) on the islet surface. Engineered islets transplanted into diabetic allogeneic mice recipients treated with a short course (15 days) of rapamycin resulted in 100% survival over an observation period of >200 days without any sign of rejection. Moreover since the last submission of this grant we have now followed these animals long-term. Recipients of FasL-engineered islet grafts enjoyed rejection-free survival unless their Treg cells were depleted. Some of these animals are over 500 (n=8) and 400 (n=12) days with functioning islets in the absence of any immunosuppression. These data demonstrate that tolerance induction is sufficient for long-term drug free survival.  Building on this and other strong data obtained in rodent models the primary objective of this proposal is to test the efficacy of this novel therapeutic approach ApoFasL for tolerance induction to allogeneic pancreatic islets in rhesus macaques. FasL will be displayed on rhesus macaque donor islets using ProtEx(tm) technology prior to transplantation into chemically-induced diabetic macaques. Transplants will be done under transient cover of rapamycin a pharmaceutical agent used in the clinic for the prevention of graft rejection. The rationale for using rapamycin in these experiments is two-fold. First it will face fewer regulatory hurdles and ease translation of the ApoFasL protocol into the clinic. And second it works in synergy with FasL to eliminate pathogenic T effector cells and generate/expand protective T regulatory cells thereby enhancing ApoFasL's efficacy. We hypothesize that islets engineered to display FasL on their surface will induce tolerance by physically eliminating alloreactive pathogenic lymphocytes responding to the transplanted islets through Fas/FasL interaction. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells thereby creating donor- specific immune tolerance leading to the survival of transplanted islets. Proof-of-principle in a nonhuman primate model will be followed by a Phase II SBIR application to further develop ApoFasL into a lead product. Tolerance to allogeneic islets in a nonhuman primate model will serve as the first step towards translation of this novel immunotherapy to the clinic for the treatment of T1D. If proven effective ApoFasL may improve the quality of life for millions of individuals worldwide with an economic impact in the billions of dollars.  PUBLIC HEALTH RELEVANCE: ApoFasL is a novel immunotherapy being developed for the treatment of Type 1 Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabetic nonhuman primate model will be a significant step toward developing ApoFasL for clinical trials. This novel therapy has the potential to break new grounds for the clinical treatment of T1D.

project_terms:
Acute;Alloantigen;Allogenic;Animals;Apoptosis;Apoptotic;Architecture;Autoantigens;Biotin;CD95 Antigens;Cell Maintenance;Cell surface;Cells;Chimeric Proteins;Chronic;Clinic;Clinical;Clinical Treatment;Clinical Trials;Critiques;Data;Diabetes Mellitus;Disease;Effector Cell;Engineering;Event;Extracellular Domain;Face;Freedom;Generations;Gold;Graft Rejection;Graft Survival;Grant;Harvest;Health;Homeostasis;Human;IL2RA gene;Immune;Immune Tolerance;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Implant;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Licensing;Lymphocyte;Macaca;Macaca mulatta;Metabolic;Modeling;Modification;Mus;Natural immunosuppression;Outcome;Peripheral;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiology;Play;Pre-Clinical Model;Prevention;Primates;Procedures;Proteins;Protocols documentation;Publishing;Quality of life;Recovery;Regulatory T-Lymphocyte;Replacement Therapy;Rodent;Rodent Model;Role;Series;Sirolimus;Small Business Innovation Research Grant;Streptavidin;Streptozocin;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Therapy Clinical Trials;Translating;Translations;Transplantation;Treatment Efficacy;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;base;commercialization;diabetic;economic impact;efficacy testing;immunogenicity;immunoregulation;improved;insulin secretion;islet;nonhuman primate;novel;novel therapeutic intervention;research study;response

public_health_relevance:
PROJECT NARRATIVE ApoFasL is a novel immunotherapy being developed for the treatment of Type 1Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabeticnonhuman primate model will be a significant step toward developing ApoFasL forclinical trials. This novel therapy has the potential to break new grounds for the clinicaltreatment of T1D.


application_id: 8329009
project_number: 5U01CA151648-04
project_title: RNA Nanotechnology in Cancer Therapy
administering_ic: NCI
award_notice_date: 2012-09-21
opportunity_number: RFA-CA-09-013
application_type: 5
activity_code: U01
ic: CA
serial_number: 151648
program_official: MORRIS, STEPHANIE A
project_start_date: 2010-08-25
project_end_date: 2015-07-31
study_section: ZCA1-SRLB-X(M1)
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: LI, HENRY ;ROSSI, JOHN JOSEPH
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): This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to cancer cells. RNA molecules can down-regulate specific gene expression in cancer cells. RNA is particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be manipulated as easily as DNA but possesses the versatility in structure and function similar to that of proteins. RNA contains single-stranded stem-loops for intra- or inter-RNA interactions which can serve as mounting dovetails providing advantages over external linking dowels in nanomachine assembly. This CNPP operation comprises of three major functions: the fundamental studies on therapeutic RNA nanoparticle construction; the conjugation and incorporation of therapeutic and targeting moieties to RNA nanoparticles; and the specific delivery of therapeutics to cancer cells. The team includes basic scientists with strong backgrounds in biomedical engineering chemistry and RNA and DNA nanotechnology; cancer biologists with extensive experience in ribozyme and siRNA delivery; and pharmaceutical cooperation focusing on RNA therapeutics with expertise in animal trials. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly using phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA oligomers containing aptamer siRNA ribozyme ligand imaging markers or drugs for cancer cell recognition and gene silencing. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that target and enter cancer cells specifically. Simultaneous delivery and detection will be designed combining therapy and detection of subsequent therapeutic effects on apoptosis. Approaches of crossover chemical modification and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industry scale production methods will be developed to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics bio-distribution toxicity gene silencing effects and cancer cell killing will be carried out on animal models of lung cancer ovarian cancer liver cancer and leukemia. RELEVANCE (See instructions): Cancer is a current and long term health care crisis and treatments necessitate the investigation of specific delivery to target cells. This application proposes to fabricate RNA nanoparticles to incorporate therapeutic SiRNA aptamers and ribosomes to accomplish targeted delivery. Therapeutic constituents will be selected for the treatment of lung cancer ovarian cancer liver cancer and leukemia.

project_terms:
Affinity;Animal Model;Animals;Apoptosis;Biodistribution;Biological Assay;Biological Models;Biomedical Engineering;Carcinoma;Catalytic RNA;Cell Culture Techniques;Cells;Chemicals;Chemistry;Chimera organism;Complex;DNA;Detection;Double-Stranded RNA;Drug Kinetics;Evaluation;Fermentation;Gene Expression;Gene Silencing;Healthcare;Image;Immunity;Industry;Instruction;Interferons;Investigation;Ligands;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of ovary;Methodology;Methods;Modeling;Modification;Motor;Nanotechnology;Ovarian;Pharmaceutical Preparations;Pharmacologic Substance;Primary carcinoma of the liver cells;Principal Investigator;Production;Proteins;RNA;RNA Stability;Ribosomes;Scientist;Screening procedure;Small Interfering RNA;Structure;System;Testing;Therapeutic;Therapeutic Effect;Time;Toxic effect;Work;Xenograft procedure;aptamer;cancer cell;cancer therapy;cancer type;cell killing;chemical synthesis;clinical application;crosslink;design;efficacy evaluation;experience;in vivo;leukemia;nanomachine;nanomedicine;nanoparticle;novel;operation;programs;scale up;stem;targeted delivery;therapeutic target


application_id: 8328713
project_number: 5K99CA158009-02
project_title: The role of the first mammalian N-term. methyltransferase NRMT in tumorigenesis
administering_ic: NCI
award_notice_date: 2012-08-21
opportunity_number: PA-10-063
application_type: 5
activity_code: K99
ic: CA
serial_number: 158009
program_official: SCHMIDT, MICHAEL K
project_start_date: 2011-09-05
project_end_date: 2013-08-31
study_section: ZCA1-RTRB-K(M1)
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): During my postdoctoral fellowship I successfully purified and identified the first mammalian N-terminal methyltransferase NRMT. Shown by microarray analysis to have reduced expression/copy number in human breast cancers I have also illustrated NRMT knockdown results in increased cell proliferation and a multi- spindle phenotype. Given that NRMT knockdown results in these two cancer prone phenotypes I intend to further study how it is regulated how N-terminal methylation affects substrate function and how NRMT misregulation leads to tumorigenesis. My goal after completion of my postdoctoral work is to obtain a tenure- track position at an academic research institution and establish an independent research program. Successful completion of my research goals includes training in a mouse mammary transplant model. As I have no previous mouse research experience the additional training time provided by a K99 will be imperative for learning these skills. Obtaining a K99 will also allow for further training in mass spectrometry fluorescent- activating cell sorting and FRET analysis. The long-term goal of my research is to use the NRMT mouse model to dissect the signaling pathways that lead to breast cancer. As personalized medicine treatments become increasingly necessary I want to create a model where combinations of genes can be easily manipulated simultaneously. These models can be used to test which current drug treatments are most effective for patients with specific combinations of mutations and to screen for new and more effective therapeutic agents. Research The list of genes involved in tumorigenesis is quite extensive however many of their biological functions remain unknown. One such gene Mettl11a (now renamed NRMT) has been shown to be under-expressed in breast cancers but has only recently been identified as the first mammalian N-terminal methyltransferase. Reduction of NRMT also results in a multi-spindle phenotype and the associated aneuploidy is often considered to contribute to cancer progression. As NRMT is a newly discovered protein the goals of this proposal are to understand the role of N-terminal methylation on protein and cellular function in order to study how its misregulation leads to tumorigenesis. The first two aims determining whether N-terminal methylation is constitutive and determining whether N-terminal methylation universally alters the DNA binding of its substrates are designed to better understand the basic biology of N-terminal methylation. These aims will involve mass spectrometry fluorescent-activating cell sorting FRET analysis and construction of a knockout mouse. The objective of the third aim is to determine the role of NRMT in development and tumorigenesis. A mouse mammary transplant model will be established for assaying if the multi-spindle NRMT knockdown phenotype leads to developmental defects and/or tumorigenesis. The key element of the career development aspect of this proposal will be learning the mouse system needed for successful completion of the third aim. The experiments of aims one and two have been designed for the downtime between surgeries and gland or tumor harvesting. Environment The University of Virginia is well equipped for completion of all three aims of this proposal. The on-campus mass spectrometry facility of advisory committee member Dr. Don Hunt has a Fourier transform mass spectrometer necessary for distinguishing N-terminal methylation from acetylation. The UVA Flow Cytometry Core will provide the training necessary for all fluorescent-activating cell sorting experiments. The UVA Gene Targeting and Transgenic Facility will create the NRMT knockout mouse. The Research Histology Core will paraffin embed and make slides of all normal mouse tissue and tumors. My advisory committee member Dr. Amy Bouton will aid in interpretation of the histology. The expertise and reagents of advisory committee member Dr. Todd Stukenberg will aid in characterization of the NRMT multi-spindle phenotype. The UVA W.M. Keck Center for Cellular Imaging supplies state-of-the art imaging facilities for immunofluorescent imaging of mouse tissue samples and training in FRET analysis. The Macara lab currently has three expert mouse biologists available for training in mouse handling and surgical techniques. In addition UVA offers numerous courses aimed at career development/training including the UVA transgenic methods and applications workshop the Flow Cytometry Training Workshop the Workshop on FRET Microscopy and a monthly career development seminar series offered by the Office of Postdoctoral Professional Development.

project_terms:
A Mouse;Acetylation;Advisory Committees;Affect;Aneuploidy;Antibodies;Apoptotic;Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Cell Cycle;Cell Line;Cell Proliferation;Cell Separation;Cell physiology;Chromatin;Committee Members;Consensus Sequence;Critiques;Cytoplasm;DNA;DNA Binding;DNA repair protein;DNA-Binding Proteins;Data;Defect;Development;Educational workshop;Elements;Embryo;Environment;Epithelial Cells;Exhibits;Fatty acid glycerol esters;Fellowship;Fibroblasts;Flow Cytometry;Fluorescence Resonance Energy Transfer;Fourier Transform;Future;Gene Combinations;Gene Targeting;Genes;Genetic;Gland;Glioblastoma;Goals;Growth;Harvest;Histology;Human;Image;Immunoprecipitation;In Vitro;Individual;Institution;Knockout Mice;Lead;Learning;Malignant Neoplasms;Mammary gland;Mass Spectrum Analysis;Measures;Medicine;Mentors;Methods;Methylation;Methyltransferase;Microarray Analysis;Microscopy;Mitotic;Modeling;Modification;Monitor;Mono-S;Mus;Mutation;N-terminal;Neoplasm Metastasis;Nuclear;Oncogene Proteins;Operative Surgical Procedures;Paraffin Embedding;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Positioning Attribute;Post-Translational Protein Processing;Process;Proteins;Reagent;Research;Retinoblastoma Protein;Role;Running;Series;Signal Pathway;Site;Slide;System;Techniques;Testing;Therapeutic Agents;Time;Tissue Sample;Training;Transgenic Organisms;Transplantation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Universities;Virginia;Work;Writing;career development;cellular imaging;chromatin immunoprecipitation;design;experience;in vitro Assay;in vivo;interest;leukemia;malignant breast neoplasm;mass spectrometer;meetings;mouse model;mutant;myosin light chain 2;programs;protein function;research study;skills;stoichiometry;tool;tumor;tumor progression;tumorigenesis

public_health_relevance:
The biological roles of many genes involved in tumorigenesis remain unknown. We need to study their functions in order to achieve a complete understanding of cancer progression and obtain an inclusive list of potential druggable targets. One such protein NRMT the newly identified mammalian N-terminal methyltransferase is under-expressed in breast cancers and its knockdown results in mitotic defects often considered to contribute to cancer progression. The goal of this proposal is to understand how NRMT is regulated and how its misregulation contributes to tumorigenesis.      The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" above summarizes the final opinions of the committee.


application_id: 8328062
project_number: 1K08DA032296-01A1
project_title: "African American Offenders: Drug Use Mental Health and HIV Risk"
administering_ic: NIDA
award_notice_date: 2012-04-26
opportunity_number: PA-11-193
application_type: 1
activity_code: K08
ic: DA
serial_number: 032296
suffix: A1
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: 03
department: PSYCHOLOGY
primary_duns: 081015281
primary_uei: J3KPEDNN74R6
duns_number: 081015281
uei: J3KPEDNN74R6
fips: US
organization_id: 1197801
organization_name: SPALDING UNIVERSITY
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 40203
organization_country: UNITED STATES
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.   
   
PUBLIC HEALTH RELEVANCE:  The proposed project has significant public health implications for reducing the spread of HIV among the African American community by offering testing and by targeting men exiting prison re-entering the community. The proposed project will generate an improved understanding of the complex relationship between drug use mental health and HIV risk among an at-risk group.

project_terms:
African American;Anxiety;Award;Biometry;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;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: 8327980
project_number: 3R01EY014701-06S1
project_title: Ganglion Cell Function in Retinal Disease
administering_ic: NEI
award_notice_date: 2011-09-09
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: EY
serial_number: 014701
suffix: S1
program_official: GREENWELL, THOMAS
project_start_date: 2004-02-01
project_end_date: 2015-03-31
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
project_abstract:
DESCRIPTION (provided by applicant): The goals of this research are focused on understanding signaling mechanisms that regulate the development of 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 of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result the pathways extend the dynamic range of information processing in the intensity domain and increase specialization of information processing for salient environmental features e.g. motion direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent 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 the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB) where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function.     PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of the parallel pathways of information processing in the retina. One focus is to understand the exact changes that occur in complete congenital stationary night blindness a retinal disease that does not involve photoreceptor dysfunction or morphological defects. A second focus is to understand the fundamental processes that regulate the development of normal retinal function particularly in the ganglion cells. We believe that our results will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant to other blinding diseases in people of all ages.

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;public health relevance;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: 8327334
project_number: 1R01DA032254-01A1
project_title: A Novel Anti Obesity Drug Combination as a Pharmacotherapy for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2012-09-05
opportunity_number: PA-10-268
application_type: 1
activity_code: R01
ic: DA
serial_number: 032254
suffix: A1
program_official: HAMPSON, AIDAN
project_start_date: 2012-09-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
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
project_abstract:
DESCRIPTION (provided by applicant): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence for example could yield treatments for managing COC dependence.  Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different maintenance doses of BUP (i.e. BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e. NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e. COC is a within-subject factor). COC (0 25 50 100 mg) will be tested with multiple dose combinations of BUP (0 100 200 300 mg/day) and NTX (0 25 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC.  This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination BUP and NTX for COC dependence which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies; 2) the use of a sophisticated drug self-administration procedure; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. In these ways the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of COC dependence.   
   
PUBLIC HEALTH RELEVANCE: The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination bupropion and naltrexone as
a pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.

project_terms:
Abstinence;Accounting;Admission activity;Adult;Adverse effects;Age Reporting;American;Anti-Obesity Agents;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Bupropion;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Combination Drug Therapy;Development;Disease;Dopamine Uptake Inhibitors;Dose;Drug Addiction;Drug Combinations;Enrollment;Epidemic;Evaluation;Food;Goals;Human;Hypothalamic structure;Inpatients;Investigation;Laboratory Study;Maintenance;Modeling;Mono-S;Naltrexone;Narcotic Antagonists;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Preventive Intervention;Probability;Procedures;Questionnaires;Randomized;Relative (related person);Research;Safety;Self Administration;System;Testing;United States;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;drug market;indexing;innovation;interest;novel;programs;public health medicine (field);reinforcer;research study;secondary outcome;success

public_health_relevance:
The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination bupropion and naltrexone as
a pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.


application_id: 8326543
project_number: 5R01HD061617-03
project_title: Function of RUNX transcription factors in COCs
administering_ic: NICHD
award_notice_date: 2012-06-06
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 061617
program_official: TAYMANS, SUSAN
project_start_date: 2010-09-24
project_end_date: 2014-05-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of the present proposal is to determine the molecular/cellular mechanism(s) involved in the maturation process of cumulus oocyte complexes (COCs). Proper maturation of the COC is critical to reproductive success in vivo and in vitro. Our lack of a complete understanding of this maturation process restricts our ability to manage fertility in vivo and hinders implementation of ART such as in vitro fertilization and in vitro maturation. Recent studies by our laboratory and others have begun to shed light on a small family of nuclear transcription factors RUNX1 and RUNX2 as key transcriptional regulators involved in COC expansion. Our preliminary data demonstrated that Runx1 and Runx2 expression is highly induced in cumulus cells of periovulatory follicles. We also found that RUNX1 and RUNX2 regulate the expression of Ptgs2 (a rate-limiting enzyme in the biosynthesis of prostaglandins) and Hapln1 (a stabilizer of cumulus matrix) in mural granulosa cells and/or cumulus cells. Both gene products are known to play crucial roles in COC expansion. Most importantly our pilot study demonstrated that over-expression of dominant negative RUNX in cumulus cells blocked COC expansion. Based on these novel findings we hypothesized that RUNX1/2 are essential transcriptional regulators necessary for the gonadotropin surge-induced COC expansion. This hypothesis will be tested by first demonstrating the functional significance of Runx1/2 expression in cumulus cells (Aim #1). Secondly we will determine the regulation action(s) of RUNX1 and RUNX2 on their target genes (Aim #2). Next we will determine the regulatory mechanism(s) of Runx1 and Runx2 expression in cumulus cells (Aim #3). These 3 Aims will be studied using rat COCs. To insure that the data obtained from rat studies is translatable to humans RUNX1/2 and their target gene expression profile will be also verified using human cumulus cells collected throughout the periovulatory period. We will also examine the correlation of the cumulus expression of RUNX1/2 and their target genes to oocyte quality fertilization and embryo development using COCs obtained from women undergoing IVF (Aim #4). These human studies will serve as a foundation for future translational/clinical application. The information obtained from the proposed studies will not only advance our understanding of the mechanism involved in COC maturation but also be instrumental for future translational/clinical application(s) thus leading to improved management of fertility in vivo and in vitro.    PUBLIC HEALTH RELEVANCE: Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COC expansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality and developmental competence. There are still huge gaps in our understanding of how the preovulatory gonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary data suggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating the transcription of specific periovulatory cumulus genes. Building upon these findings the present proposal will determine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s) of RUNX transcription factors during maturation of COCs. Information derived from the present proposal will provide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied for promoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility in vivo and in vitro.

project_terms:
Adenoviruses;Anabolism;Animal Model;Cells;Collecting Cell;Competence;Complex;Data;Development;Dominant-Negative Mutation;Embryonic Development;Enzymes;Female;Fertility;Fertilization;Fertilization in Vitro;Foundations;Future;GDF9 gene;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic Transcription;Goals;Gonadotropins;Hormonal;Human;In Vitro;Knowledge;Laboratories;Light;Link;Mediating;Mediator of activation protein;Molecular;Molecular Profiling;Mus;Nuclear Family;Oocytes;Ovarian;Ovulation;Peptides;Physiology;Pilot Projects;Play;Process;Promotor (Genetics);Prostaglandins;Proteins;RUNX1 gene;Rattus;Regulation;Role;Signal Transduction;Small Interfering RNA;Testing;Woman;base;clinical application;combinatorial;cytokine;granulosa cell;implantation;improved;in vivo;insight;novel;public health relevance;reproductive success;success;time interval;transcription factor

public_health_relevance:
Project Narrative Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COCexpansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality anddevelopmental competence. There are still huge gaps in our understanding of how the preovulatorygonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary datasuggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating thetranscription of specific periovulatory cumulus genes. Building upon these findings the present proposal willdetermine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s)of RUNX transcription factors during maturation of COCs. Information derived from the present proposal willprovide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied forpromoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility invivo and in vitro.


application_id: 8326437
project_number: 1R01AI095032-01A1
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2012-01-25
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AI
serial_number: 095032
suffix: A1
program_official: WALI, TONU M
project_start_date: 2012-01-01
project_end_date: 2016-12-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Toxoplasma gondii establishes an important chronic infection capable of causing life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The basis of persistence of the infection is the tissue cyst which remains largely quiescent for the life of the host but can reactivate and cause disease. This stage of the parasite is not affected by any of the current drug treatments and it has been generally regarded as untouchable. However our recent studies revealed that the immune T cells are able to eliminate T. gondii cysts from the brains of infected hosts when the T cells are transferred into infected immunodeficient animals that have already developed large numbers of the cysts. This T cell-mediated immune process is associated with accumulation of mononuclear cells primarily microglia and macrophages morphologically around tissue cysts. Since the accumulated phagocytes penetrate within the cyst these cells appear to be the main effector cells that destroy the cysts and eliminate them from the brain after initiation of this process by immune T cells. CD8+ immune T cells possess a potent activity to initiate this anti-cyst immune process and the protective activity of the T cells requires perforin. The overall goal
of this research project is to determine the molecular mechanisms by which perforin-mediated activity of CD8+ immune T cells cooperates with the phagocytes to remove T. gondii cysts from the brain. In the first aim we will determine if CD8+ immune T cells accumulate and attach to the cyst-containing cells in the brain. We will also determine if the CD8+ T cells lyse cyst-containing cells in a perforin-dependent manner in vitro and whether the perforin- mediated activity of CD8+ T cells induces the accumulation of phagocytes around the cysts in the brain. In the second aim we will determine the MHC class I molecule(s) critical for recognition of cyst-containing cells by CD8+ T cells. We will then determine the T. gondii cyst epitope(s) presented by the identified MHC class I molecule for recognition by the CD8+ T cells by screening predicted bradyzoite epitope peptides and/or bradyzoite cDNA library. The third aim is to determine the mechanisms by which phagocytes eliminate T. gondii cysts after initiation of the immune process by CD8+ T cells. We will examine the roles of inducible nitric oxide synthase and autophagy in killing of bradyzoites and elimination of cysts using mice lacking a molecule required for each mechanism. The information generated from the studies in these three specific aims all together will provide the essential basis for developing a novel method(s) to activate CD8+ T cells and phagocytes to eliminate T. gondii cysts that can reactivate and cause toxoplasmic encephalitis.    
   
PUBLIC HEALTH RELEVANCE: Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The proposed studies are to analyze how T cells and phagocytes cooperate to eliminate the persisting cyst stage of T. gondii which can reactivate and cause the disease. These studies will provide the information essential for developing a novel method(s) to eliminate the persisting cyst stage of the parasite and prevent or reduce the risk of developing toxoplasmic encephalitis.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Affect;Animals;Antigens;Autophagocytosis;Brain;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chronic;Cyst;Cytolysis;Cytotoxic T-Lymphocytes;Disease;Effector Cell;Encephalitis;Epitopes;Excision;Genes;Goals;Histocompatibility Antigens Class I;Hybridomas;Immune;Immune system;Immunocompromised Host;In Vitro;Inbred BALB C Mice;Individual;Infection;Interferons;Killings;Knockout Mice;Life;Mediating;Mediator of activation protein;Methods;Microglia;Microscopy;Molecular;Mononuclear;Mus;Nitric Oxide;Parasites;Patients;Peptides;Phagocytes;Pharmaceutical Preparations;Play;Process;Production;Research Project Grants;Resistance;Risk;Role;Screening procedure;Staging;Surface;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;base;cDNA Library;cytotoxic;human NOS2A protein;in vitro Model;in vivo;macrophage;novel;perforin;prevent;two-photon

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The proposed studies are to analyze how T cells and phagocytes cooperate to eliminate the persisting cyst stage of T. gondii which can reactivate and cause the disease. These studies will provide the information essential for developing a novel method(s) to eliminate the persisting cyst stage of the parasite and prevent or reduce the risk of developing toxoplasmic encephalitis.


application_id: 8326120
project_number: 5U01DA016205-10
project_title: Central States Criminal Justice Drug Abuse Center
administering_ic: NIDA
award_notice_date: 2012-08-13
opportunity_number: RFA-DA-08-002
application_type: 5
activity_code: U01
ic: DA
serial_number: 016205
program_official: JONES, DIONNE
project_start_date: 2002-09-30
project_end_date: 2014-03-31
study_section: ZDA1-MXS-M(01)
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
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): With 83% of state prisoners reporting drug use (Mumola & Karberg 2006) and 700000 prisoners re-entering U.S. communities annually (Glaze & Bonczar 2006) there is a need for organizational studies on how to design effective systems of continuous care for re-entering offenders. Kentucky provides an ideal setting to study re-entry because Kentucky is ranked in the top 3 states for increases in'the number inmates (Harrison & Beck 2006) as well as the number of parolees (BJS 2006). This continuation application is submitted by the University of Kentucky to further understand re-entry by continuing the Central States Center in CJ-DATS 2. Our CJ-DATS 1 Center successes include: Involvement in 7 protocols which exceeded the number by any other Center; Leading the only woman-focused protocol; Developing a true stakeholder-centered infrastructure which resulted in the innovative Kentucky Re-Entry Guidelines; Research activities which produced 26 manuscripts and 16 presentations by our team as well as data to allow other CJ-DATS 1 researchers to publish. CJ-DATS 1 also provided the infrastructure to develop a statewide outcome study and 2 NIDA grant applications. Our Center's innovative vision will uniquely contribute to the scientific knowledge on the organizational and system changes necessary to implement and sustain evidence-based interventions (APA 2006) across a continuum of care at re-entry in diverse criminal justice and community organizational settings. Our conceptual approach draws upon selected theoretical frameworks of organizational change to implement the Center's vision and our 3 Research Concepts. This application presents 4 established partner-rich Center Committees to: (1) Plan (2) Implement (3) Collect/Analyze Data and (4) Develop Publications in concert with our Center Steering Committee and the national CJ-DATS 2 Steering Committee. Letters of commitment include our states' Corrections Commissioner Director of Substance Abuse Commissioner of Public Health state substance abuse officials public safety officials and treatment organizations which support our innovative vision as well as our rural and urban interests.

project_terms:
Applications Grants;Caring;Communities;Continuity of Patient Care;Criminal Justice;Data;Data Analyses;Drug abuse;Drug usage;Evidence based intervention;Guidelines;Kentucky;Knowledge;Letters;Manuscripts;National Institute of Drug Abuse;Organizational Change;Outcome Study;Prisoner;Protocols documentation;Publications;Publishing;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Rural;Safety;Substance abuse problem;System;Universities;Vision;Woman;design;innovation;interest;offender;parolee;public health medicine (field);success;treatment organization


application_id: 8326075
project_number: 5R44HD062065-03
project_title: Active Distributed Electrode Array Network for Electrical Stimulation Therapy
administering_ic: NICHD
award_notice_date: 2012-08-14
opportunity_number: PA-10-050
application_type: 5
activity_code: R44
ic: HD
serial_number: 062065
program_official: CRUZ, THERESA
project_start_date: 2009-08-01
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-F(15)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-01
budget_end_date: 2015-08-31
project_abstract:
DESCRIPTION (provided by applicant):  Transcutaneous electrical stimulation applications involving high numbers of stimulated muscles have been an area of growing interest in recent years. customKYnetics has been approached by research groups and stimulation application developers requesting high channel count stimulation devices for use in their spinal cord injury rehabilitation research studies and products. Existing devices do not offer the features and/or number of stimulation channels required for these applications. Such high channel count devices are often cost prohibitive due to the size and complexity of the stimulator and the limited market for any particular configuration. Devices that are available lack the technological capability to coordinate the activity of the electrode pairs in an application-specific manner. Such applications have also lacked clinical acceptance because managing the large number of wires has been burdensome and impractical. We propose Active Distributed Electrode Array (ADEA) technology which offers two novel features that address these problems: network architecture and end-user programmability. With these features the ADEA system will be fully configurable (both in hardware and software) by the application developer (i.e. researcher specialized clinician or OEM company) to create application-specific stimulation/sensing networks and stimulation regimens. No end-user programming experience will be required. We successfully completed Phase I work including feasibility demonstration of the node concept. The goals of this Phase II SBIR project will be to develop clinically viable stimulation and sensing nodes an ADEA stimulator/controller module and an end-user programming suite and to demonstrate efficacy of the technology. The target markets for this device will be specialized clinics research groups and OEM companies. The target price for the system will be $3000 in volume for an 8-channel configuration (OEM market).

project_terms:
Address;Area;Characteristics;Clinic;Clinical;Clinical Research;Computer Architectures;Computer software;Data;Delaware;Development;Devices;Doctor of Philosophy;Electric Stimulation;Electrodes;Electromagnetics;Environment;Evaluation;Generic Drugs;Goals;Government;Human;Industry;Knowledge;Lead;Maintenance;Marketing;Muscle;Orthotic Devices;Performance;Phase;Physiologic pulse;Price;Progress Reports;Regimen;Rehabilitation Research;Rehabilitation therapy;Research;Research Personnel;Risk Management;Small Business Innovation Research Grant;Spinal cord injury;System;Technology;Testing;Therapeutic Intervention;Transcutaneous Electric Nerve Stimulation;Universities;Work;clinical application;clinical efficacy;commercial application;commercialization;cost;design;empowered;experience;improved;interest;meetings;novel;programs;prototype;public health medicine (field);research and development;research study;technology/technique;tool

public_health_relevance:
The proposed work may benefit public health through development of a clinically viable electrical stimulation technology for use in myriad rehabilitation applications. Compared to existing devices and techniques the technology may improve efficacy availability ease of use and reduce cost of the therapeutic interventions requiring high numbers of muscles to be activated using electrical stimulation in a well controlled/coordinated fashion.


application_id: 8325057
project_number: 5R01AG038651-02
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2012-08-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-01
project_terms:
Accounting;Age;Aging;Alzheimer's Disease;Americas;Asia;Autopsy;Biological Preservation;Brain Diseases;Brain Pathology;Caring;Clinical;Clinical Data;Clinical Research;Clinical assessments;Cognition;Cognitive;Cohort Studies;Communities;Complement;Complex;Consensus;Data;Databases;Dementia;Diagnostic;Disease;Elderly;Epidemiology;Evaluation;Funding;Gray unit of radiation dose;Health Care Costs;Health Sciences;Hippocampus (Brain);Impaired cognition;Incidence;Individual;Investigation;Kentucky;Lead;Lewy Bodies;Lewy Body Disease;Magnetic Resonance Imaging;Measures;Medical;Medical Genetics;Memory;Meta-Analysis;Minnesota;Modeling;National Institute on Aging;Oregon;Outcome;Participant;Pathology;Patients;Population;Prevalence;Prevention strategy;Registries;Religion and Spirituality;Research;Research Personnel;Resistance;Resources;Risk;Risk Factors;Role;Sample Size;Sampling;Sclerosis;Series;Statistical Methods;Statistical Models;Symptoms;Time;United States National Institutes of Health;Universities;Validation;Vascular Dementia;Washington;aging brain;base;biomarker;cohort;cooperative study;cost;demographics;design;disorder prevention;experience;follow-up;improved;innovation;insight;markov model;meetings;mild cognitive impairment;neuropathology;novel;pre-clinical;prevent;prevention clinical trial;public health medicine (field);skills;treatment strategy

other_pis:
KAYE, JEFFREY A;LIM, KELVIN O.;LIPTON, RICHARD B.;SCHMITT, FREDERICK ;TYAS, SUZANNE LEIGH;WHITE, LON RAY;XIONG, CHENGJIE ;YU, LEI


application_id: 8323651
project_number: 3R01EY020672-02S1
project_title: Endogenous Specific Inhibitor of Corneal Lymphangiogenesis
administering_ic: NEI
award_notice_date: 2011-08-26
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: EY
serial_number: 020672
suffix: S1
program_official: SHEN, GRACE L
project_start_date: 2010-04-01
project_end_date: 2014-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
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
project_abstract:
DESCRIPTION (provided by applicant): Absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity and optimal vision. Numerous pathological disorders result in corneal neovascularization that is responsible for blindness in hundreds of millions of individuals worldwide. The vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of the tightly regulated balance of endogenous angiogenesis stimulators and inhibitors which when disrupted results in neovascularization. The principal positive regulators of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) in the cornea are VEGF-A and VEGF-C respectively. Among the many inhibitors of hemangiogenesis that reside in the cornea we have shown that soluble VEGFR-1 (sVEGFR-1) by acting as a trap for VEGF-A is essential for corneal avascularity (Ambati et al. Nature 2006). In contrast the molecular basis of the alymphatic cornea has not been resolved; indeed no endogenous specific inhibitor of lymphangiogenesis in any tissue has yet been reported. In new and exciting studies we identified the existence of a novel secreted splice variant of VEGFR-2 in mouse and human (sVEGFR-2) (Albuquerque et al. Nature Medicine 2009). Surprisingly loss of sVEGFR-2 resulted in spontaneous invasion of lymphatic but not blood vessels into the mouse cornea at birth. sVEGFR-2 also specifically inhibited injury-induced corneal lymphangiogenesis and dramatically reduced corneal allograft rejection. This proposal will test the hypothesis that the lymphatic specificity of sVEGFR-2 is due to its existence as a monomer that interacts with and antagonizes VEGF-C but not VEGF-A. The Specific Aims of this proposal are to define the expression and function of sVEGFR-2 during mouse and human corneal development decipher the molecular mechanisms by which mouse and human sVEGFR-2 inhibit lymphangiogenesis but not hemangiogenesis and resolve the spatial and temporal expression and function of sVEGFR-2 in the mouse cornea following injury and allograft rejection. By providing clarifying insights into a critical endogenous regulator of lymphangiogenesis and identifying mechanisms that might serve as potential targets for advancing novel therapies for corneal neovascularization and transplant rejection these studies directly address the 5-year goals of the NEI Corneal Diseases program. The impact of these studies also extends to pathological states such as tumor metastasis lymphedema and lymphangioma which can be better studied and possibly treated by modulating the endogenous uncoupler of lymphatic and blood vessels we have discovered.    PUBLIC HEALTH RELEVANCE: Corneal neovascularization and transplant rejection which involve abnormal blood and lymphatic vessels lead to blindness in millions worldwide. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes we introduce a new research tool that can be used to specifically study lymphatic vascular biology and a new target that can lead to novel therapies for corneal blindness.

project_terms:
Accounting;Address;Adult;Allografting;Angiogenesis Inducing Agents;Angiogenesis Inhibitors;Binding (Molecular Function);Biochemical;Biology;Birth;Blindness;Blood;Blood Vessels;Cell surface;Cornea;Corneal Diseases;Corneal Neovascularization;Data;Dendritic Cells;Development;Disease;Elements;Equilibrium;Extracellular Domain;Family;Family member;Goals;Graft Rejection;Growth;Heterodimerization;Human;Immune;Individual;Inflammatory;Injury;Keratoplasty;Lead;Lymphangiogenesis;Lymphangioma;Lymphatic;Lymphatic Endothelial Cells;Lymphatic vessel;Lymphedema;Mediating;Medicine;Membrane;Modeling;Molecular;Mus;Nature;Neoplasm Metastasis;Optics;Organ;Pathology;Pharmaceutical Preparations;Process;RNA Interference;RNA Splicing;Recombinants;Regulation;Relative (related person);Reporting;Research;Risk;Signal Transduction;Source;Specificity;Surgical sutures;Testing;Tissues;Transplantation;Variant;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor C;Vascular Endothelial Growth Factor D;Vascular Endothelial Growth Factor Receptor-2;Vascular Endothelial Growth Factors;Vision;World Health;allograft rejection;angiogenesis;base;cell motility;corneal allograft;high risk;inhibitor/antagonist;insight;lymph nodes;monomer;neovascularization;novel;novel strategies;prevent;programs;public health relevance;receptor;tool;tumor

public_health_relevance:
Corneal neovascularization and transplant rejection which involve abnormal blood andlymphatic vessels lead to blindness in millions worldwide. We discovered a naturally occurringmolecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularlyuncoupling these intertwined processes we introduce a new research tool that can be used tospecifically study lymphatic vascular biology and a new target that can lead to novel therapiesfor corneal blindness.


application_id: 8323410
project_number: 5R01EY018830-05
project_title: MerTK regulation of the PTTG and RPE phagocytosis
administering_ic: NEI
award_notice_date: 2012-08-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 018830
program_official: NEUHOLD, LISA
project_start_date: 2008-09-30
project_end_date: 2014-08-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 8875628
contact_pi: LU, QINGXIAN
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): My long-term goal is to elucidate the cellular and molecular mechanism by which MerTK exerts its effects on phagocytosis of the retina pigmental epithelium (RPE) cell. MerTK is a receptor-type protein tyrosine kinase belonging to the TAM family. MerTK knockout mice develop autoimmune disease retinitis pigmentosa (RP) in adults with characterization of defective phagocytosis of the apoptotic lymphocytes and spent retinal outer segments (OS) by macrophage and RPE cells respectively. Photoreceptor degeneration caused by a failure of the RPE phagocytosis has been observed and intensively studied in the Royal College of Surgeons (RCS) rat a model in which the RPE cells carry a MerTK null mutation. MerTK null also causes human RP. Both in vivo and in vitro studies showed that the MerTK receptor participated during OS ingestion. However the molecular mechanism on how the MerTK regulate RPE phagocytosis is still not very clear. We have analyzed gene expression profile in MerTK mutant RPE and performed functional studies on the affected genes. Of those the PTTG was dramatically upregulated by MerTK mutation and knockout one copy of PTTG in the MerTK-/- RPE partially prevented photoreceptor degeneration in vivo. We will select and focus on MerTK mediated gene regulation to study its functional role in regulation of phagocytosis. In this proposal we project to study how the MerTK regulate PTTG and whether the PTTG affect RPE phagocytosis. We will also investigate whether structural preservation of the central photoreceptor by lower PTTG is corresponding to function recovery with ERG or OKR measurements. Our investigation will aid in one step forward to understand the molecular mechanism on the MerTK regulation of RPE functions. PUBLIC HEALTH RELEVANCE: Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with a worldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP is caused by mutation in a group of unrelated genes one of these is MerTK. Our experiments in this proposal aim to elucidate the molecular mechanism of the MerTK regulation on RPE phagocytosis through studies of one candidate gene under MerTK regulation which may in turn affect RPE function. The data from these studies is expected to provide us the new knowledge and understanding of the RPE function which will allow us to develop and implement new therapies for treatment of RP caused by RPE dysfunction.

project_terms:
Adult;Affect;Apoptotic;Autoimmune Diseases;Biological Preservation;Blindness;Candidate Disease Gene;Cell Nucleus;Cells;DNA Sequence Rearrangement;Data;Defect;Degenerative Disorder;Distal;Ectopic Expression;Epithelium;Failure (biologic function);Family;Fibroblast Growth Factor 2;Functional disorder;Gene Expression Profile;Gene Expression Profiling;Gene Expression Regulation;Gene Targeting;Genes;Goals;Health;Homeostasis;Human;IL8 gene;In Vitro;Ingestion;Inherited;Investigation;Knock-out;Knockout Mice;Knowledge;Lymphocyte;Measurement;Mediating;Metaphase;Mitosis;Modeling;Molecular;Morphology;Mus;Mutant Strains Mice;Mutation;One-Step dentin bonding system;PTTG1 gene;Patients;Phagocytes;Phagocytosis;Phenotype;Photoreceptors;Physiological;Pigments;Prevalence;Protein Tyrosine Kinase;RNA Interference;Rattus;Recovery of Function;Regulation;Retina;Retinal;Retinal Degeneration;Retinitis Pigmentosa;Rod Outer Segments;Role;Sister Chromatid;Spatial Distribution;Structure;Surgeon;Testing;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vision Tests;Visual;college;human MERTK protein;in vivo;macrophage;mutant;neovascularization;null mutation;overexpression;photoreceptor degeneration;prevent;receptor;research study;transcription factor

public_health_relevance:
Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with aworldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP iscaused by mutation in a group of unrelated genes one of these is MerTK. Ourexperiments in this proposal aim to elucidate the molecular mechanism of the MerTKregulation on RPE phagocytosis through studies of one candidate gene under MerTKregulation which may in turn affect RPE function. The data from these studies isexpected to provide us the new knowledge and understanding of the RPE functionwhich will allow us to develop and implement new therapies for treatment of RP causedby RPE dysfunction.


application_id: 8322333
project_number: 5R01DK083761-03
project_title: TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
administering_ic: NIDDK
award_notice_date: 2012-08-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 083761
program_official: RANKIN, TRACY L
project_start_date: 2010-08-15
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(03)M]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Transforming growth factor- (TGF-) is a negative regulator of normal benign and malignant prostate growth. While serving a growth-inhibitory/apoptotic role in the normal prostate overproduction of TGF-  1 in the aging prostate contributes to the development of benign prostate hyperplasia (BPH) and prostate cancer. We previously established that activation of TGF-s  signaling leads to apoptosis induction and loss of TGF  RII receptor (T2RII) contributes to prostate tumorigenic growth. Overexpression of T2RII in human prostate cancer cells enables apoptosis-mediated-growth suppression in response to TGF-  in vitro and in vivo. Using the LNCaP T2RII prostate cancer cells (androgen-sensitive and TGF-  responsive) as a model it was shown that TGF- 1 induces apoptosis and this effect was enhanced by androgens. Recent proteomic-based approaches identified two new intracellular effectors of TGF- pathway that act independent of Smads to regulate apoptotic outcomes in prostate cancer cells. In this proposal we hypothesize that TGF-  1 signaling via changes in Smad4-independent intracellular effectors and cross-talk with the androgen receptor (AR) regulates prostate growth and functional inactivation of this network accelerates the manifestation of the malignant phenotype and tumor progression. The following four Specific Aims will test this hypothesis: Specific Aim 1 will characterize the functional involvement of Smad- independent signaling effectors prohibitin and cofilin as novel mediators of TGF- action in prostate benign and malignant epithelial cells. Specific Aim 2 will identify the significance of the androgen receptor (AR) in the signaling interaction between TGF-1 and androgens towards apoptosis and epithelial to mesenchymal transition (EMT) of prostate tumor epithelial cells. Specific Aim 3 will establish the role of cofilin as a novel regulator of the ability of prostate (stroma) fibroblasts to direct TGF-  signaling in the context of the tumor microenvironment. Specific Aim 4 will characterize the in vivo physiological consequences of a functionally impaired TGF- signaling on prostate growth tumor initiation and progression using a conditional knockout mouse DNT2RII to generate double transgenics upon crossing with the TRAMP transgenic mouse model. These studies will provide new insights into the mechanistic deregulation of TGF signaling network that contributes to prostate growth and tumor progression. Understanding how cells read TGF-  will enable both the delineation of the transcriptional programs that mediate specific TGF-  effects and provide a framework for defining the mechanism via which TGF-  1 growth inhibitory/apoptotic responses in normal benign and pre-malignant prostate cells might be selectively replaced by invasive and metastatic responses in cancer cells.    PUBLIC HEALTH RELEVANCE: The long term objective of the application is to characterize the functional interplay between the TGF-  1 and androgen signaling pathways that independently of Smad effectors and in the context of tissue microenvironment contribute to deregulation of TGF  1 mediated effects on prostate growth during tumor initiation and progression. The application will also pursue the mechanism converting TGF-  from a tumor suppressor in normal and benign prostate growth to a tumor promoter in advanced metastatic cancer.

project_terms:
Actins;Adhesions;Aging;Androgen Receptor;Androgens;Apoptosis;Apoptosis Promoter;Apoptotic;Benign;Benign Prostatic Hypertrophy;Bypass;Cells;Complex;Cytoskeleton;Defect;Development;Disseminated Malignant Neoplasm;Dominant-Negative Mutation;Embryonic Development;Epithelial;Epithelial Cell Proliferation;Epithelial Cells;Event;Extracellular Matrix;Family;Fibroblasts;Genetic Transcription;Goals;Growth;Growth Factor;Human;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Knockout Mice;LNCaP;Laboratories;Ligands;Link;MAP Kinase Gene;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Modeling;Molecular;Neoplasm Metastasis;Outcome;Pathway interactions;Phosphotransferases;Physiological;Physiological Processes;Premalignant;Promotor (Genetics);Prostate;Prostatic Neoplasms;Proteins;Proteomics;Reading;Receptor Signaling;Regulation;Research;Resistance;Role;Signal Pathway;Signal Transduction;Testing;Tissues;Transforming Growth Factor beta;Transforming Growth Factors;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Suppressor Proteins;Tumorigenicity;Work;base;cancer cell;cell growth;cell motility;cofilin;epithelial to mesenchymal transition;evidence base;in vivo;insight;malignant phenotype;migration;mouse model;novel;overexpression;programs;prohibitin;public health relevance;receptor;response;tissue repair;trafficking;tumor;tumor initiation;tumor progression;tumorigenesis;tumorigenic

public_health_relevance:
NARRATIVEThe long term objective of the application is to characterize the functionalinterplay between the TGF-1 and androgen signaling pathways thatindependently of Smad effectors and in the context of tissue microenvironmentcontribute to deregulation of TGF1 mediated effects on prostate growth duringtumor initiation and progression. The application will also pursue the mechanismconverting TGF- from a tumor suppressor in normal and benign prostategrowth to a tumor promoter in advanced metastatic cancer.


application_id: 8322257
project_number: 1R21DA033796-01
project_title: Tonic and Phasic Glutamate Release from Psychomotor Stimulants
administering_ic: NIDA
award_notice_date: 2012-03-19
opportunity_number: PAR-09-222
application_type: 1
activity_code: R21
ic: DA
serial_number: 033796
program_official: PILOTTE, NANCY S
project_start_date: 2012-04-01
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZDA1 SXC-E (12)]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This CEBRA R21 application involves the further development characterization and use of an advanced technology to study second-by-second changes in L-glutamate in specific brain regions in rats using enzyme- based microelectrode arrays (MEAs) during self-administration of cocaine. This grant combines the strengths of a recently developed recording technology for glutamate measures (Gerhardt lab) with known expertise in drug self-administration (Bardo lab). This grant will adapt and further develop an innovative technique for addiction research as per the primary goals of the CEBRA program. The new technology can be potentially used by numerous investigators to better understand the role(s) of neuronal and possibly non- neuronal glutamate in addiction. The current proposal will develop and characterize a recently developed recording technology in awake and behaving rats to determine if cocaine self-administration is related to tonic and/or phasic release of glutamate in the nucleus accumbens core and infralimbic prefrontal cortex. The mechanistic framework for the proposed experiments rests on information about the homeostatic regulation of glutamate levels in critical reward-relevant brain regions. While a variety of neurotransmitter systems are involved in drug abuse particularly dopamine recent evidence indicates that glutamatergic tone in nucleus accumbens and related cortico-limbic structures is involved in the long-lasting consequences of stimulant exposure (Kalivas 2009). Our overarching hypothesis is that psychomotor stimulants lead to enhanced neuronal glutamate release in response to subsequent administration of drugs. The proposal is innovative from both health and technological perspectives. While the changes in glutamate homeostasis have been proposed to underlie cocaine self-administration and reinstatement (Kalivas 2009) extracellular glutamate measurements have been studied primarily by microdialysis which does not have the temporal and spatial resolution required to evaluate both tonic and brief phasic pulses of glutamate that characterize neuronal release. Our preliminary results show that the MEA methods in awake animals can measure both tonic and rapid phasic levels of glutamate and that the events may provide different and very important information regarding regulation of glutamate circuitry in the normal brain and in addiction.   
   
PUBLIC HEALTH RELEVANCE: These studies will adapt a new technology for investigating rapid tonic and phasic neurotransmitter signaling (glutamate) in an animal model of drug abuse. Studies will address slow and fast glutamate signals in brain areas critically involved with drug abuse and the effects of psychomotor stimulant drugs such as cocaine. This new technology once developed can possibly be used by many investigators to better understand changes to the brain that occur following repeated use of drugs of abuse.

project_terms:
Address;Animal Model;Animals;Area;Behavior;Brain;Brain region;Cocaine;Data;Development;Devices;Dopamine;Drug abuse;Enzymes;Event;Glutamates;Goals;Grant;Head;Health;Homeostasis;Impulsivity;Intravenous;Lead;Measurement;Measures;Methods;Microdialysis;Microelectrodes;Modification;Morphologic artifacts;Neurons;Neurotransmitters;Noise;Nucleus Accumbens;Pattern;Pharmaceutical Preparations;Physiologic pulse;Prefrontal Cortex;Rattus;Regulation;Research;Research Personnel;Resolution;Rest;Rewards;Role;Saline;Sampling;Self Administration;Self-Administered;Signal Transduction;Source;Staging;Stress;Structure;System;Tail;Techniques;Technology;Time;Training;Work;addiction;awake;base;drug of abuse;extracellular;improved;innovation;new technology;programs;prototype;research study;response;stimulant abuse

public_health_relevance:
These studies will adapt a new technology for investigating rapid tonic and phasic neurotransmitter signaling (glutamate) in an animal model of drug abuse. Studies will address slow and fast glutamate signals in brain areas critically involved with drug abuse and the effects of psychomotor stimulant drugs such as cocaine. This new technology once developed can possibly be used by many investigators to better understand changes to the brain that occur following repeated use of drugs of abuse.


application_id: 8322198
project_number: 5R00CA126161-05
project_title: Regulation of MAPK Activity by EGFR Endocytosis
administering_ic: NCI
award_notice_date: 2012-08-21
opportunity_number: PA-06-133
application_type: 5
activity_code: R00
ic: CA
serial_number: 126161
program_official: SPALHOLZ, BARBARA A
project_start_date: 2010-09-03
project_end_date: 2014-08-31
study_section: NSS
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mitogen-activated protein kinases (MARK) are major effector proteins involved in cell proliferation differentiation and apoptosis. Alterations in MARK signaling lead to development of various patho-physiological conditions. Signaling through MAPKs is predominantly controlled by growth factors in particular EGF. EGF receptor (EGFR) activation triggers a network of signal transduction events along with accelerated endocytosis of EGF-receptor complexes. It is proposed that endocytic trafficking regulates the intensity and duration of MARK signaling but the mechanisms of this regulation are not understood. Moreover both characteristics (signaling duration and intensity) have been shown to depend on the proper function of MARK scaffold proteins yet their role in signal propagation has not been fully elucidated. The main goal of this project is to identify the role of endocytosis in activation of the MARK cascade and to define the regulatory mechanisms of endocytosis and signaling that are critical for cancer development and progression. We will analyze how EGFR activation and endocytic trafficking provides spatial and temporal control of MARK pathway signaling. We will use a quantitative method of high-resolution microscopy fluorescence resonance energy transfer (FRET) that has been developed in our lab and has been previously used to demonstrate the presence of EGFR signaling complexes in endosomes of living cells. Here we propose a novel siRNA Knock Down And Rescue (KDAR) strategy to identify involvement of endocytic machinery in MARK activation. A number of reagents and new methodologies developed in our lab will allow us to characterize the localization of several components of MAPK1/2 module in time in living cells under conditions of physiological expression levels.

project_terms:
Affect;Apoptosis;Award;Binding (Molecular Function);Biochemical;Biological Assay;Cell Proliferation;Cell physiology;Cells;Characteristics;Colorado;Complex;Data;Development;Endocytosis;Endosomes;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Event;Fluorescence Microscopy;Fluorescence Resonance Energy Transfer;Goals;Growth Factor;HRAS gene;Health Sciences;Individual;Lead;Life;Location;MAP Kinase Gene;MAP2K1 gene;MAPK1 gene;MAPK3 gene;MEKs;Malignant Epithelial Cell;Malignant Neoplasms;Mentors;Methodology;Methods;Microscopy;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Normal Cell;Pathway interactions;Pattern;Physiological;Proteins;Publishing;RAF1 gene;Reagent;Receptor Activation;Receptor Signaling;Regulation;Research;Research Proposals;Resolution;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Son of Sevenless Proteins;Staging;Techniques;Testing;Time;Universities;Work;base;cancer cell;cell type;insight;knock-down;novel;novel diagnostics;overexpression;protein expression;receptor;reconstitution;research study;sensor;spatiotemporal;trafficking;tumor progression

public_health_relevance:
The research proposed here will provide new insight into the specific mechanisms of regulation of the signal-transduction events by endocytic trafficking. The purpose of this research is to understand the regulatory mechanisms of the molecular cascade that affect tumor progression. Results from this study will define requirements of this intracellular signaling pathway for normal cell function which will lead to development of new diagnostic markers work described in the Research Proposal will be conducted at the University of Colorado Health Sciences Center Aurora Colorado


application_id: 8322154
project_number: 8P20GM103538-09
project_title: Center for the Biologic Basis of Oral/Systemic Disease (CBBOSD)
administering_ic: NIGMS
award_notice_date: 2012-08-09
opportunity_number: RFA-RR-08-007
application_type: 8
activity_code: P20
ic: GM
serial_number: 103538
program_official: LIU, YANPING
project_start_date: 2004-09-23
project_end_date: 2014-07-31
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: 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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The link between chronic oral infections and general health has been recognized since the early 20th century. During the last 2 decades retrospective epidemiological studies and prospective longitudinal as well as intervention studies have supported that these chronic oral infections with accompanying chronic inflammation associate with various systemic diseases and their sequelae. This continuation application for the Center for the Biologic Basis of Oral/System Diseases (CBBO/SD) addresses major initiatives of the National Institute of Dental and Craniofacial Research (NIDCR) regarding improving oral and general health ofthe U.S. population. The CBBO/SD is organized into 3 cInical projects: Project 1: Chronic Inflammation at the Oral and Cervico/Vaginal Mucosa; Project 2: Physiology of the Stress Response in Patients with Temporomandibular Disorders and Fibromyalgia; Project 3: Coordinated Oral-Intestinal Immune Response in Patients with Inflammatory Bowel Diseases; and 2 translational science projects: Project 4: Ontogeny of Innate Immune Responses at Mucosal Surfaces; and Project 5: Gene Therapy for Orofacial Pain. These projects enlist junior investigators from the Colleges of Dentistry Nursing and Medicine as well as senior mentors/co-investigators from multiple colleges at UK. The thematic interface of the projects focuses on the contribution of chronic inflammation to oral and systemic diseases. They engage populations of expectant women patients with chronic orofacial pain and inflammatory bowel disease. These clinical projects interact with the translational projects at the level of a common understanding of innate immune responses and inflammation and novel therapeutic intervention strategies forthe chronic orofacial pain. The CBBO/SD provides an infrastructure for development of the junior faculty by providing grants management support educational opportunities a biostatistics/bioinformatics core and a clinical research center. The continuation of the CBBO/SD is supported by the success during the initial tenure of the center in transitioning junior investigators towards independent funding coupled with substantial investment from the university and individual colleges.

project_terms:
Acute Disease;Address;Advanced Glycosylation End Products;Aging;Aging-Related Process;Bacterial Infections;Biochemical;Bioinformatics;Biological;Biometry;Cardiovascular system;Cells;Chronic;Clinical;Clinical Research;Clinical Trials;Communication;Complex;Coupled;Culture Techniques;Data;Dental;Dental Plaque;Dental caries;Dentistry;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Discipline;Discipline of Nursing;Disease;Disease Progression;Documentation;Early Diagnosis;Ecology;Ensure;Epidemiologic Studies;Event;Faculty;Fibromyalgia;Focal Infection;Food Webs;Funding;Gene Expression Profile;Genetic;Genetic Structures;Genome;Goals;Grant;Growth;Health;Health Sciences;Immune response;Immunology;Individual;Infant;Inflammation;Inflammatory Bowel Diseases;Inflammatory Response;Institutes;Internet;Intervention;Intervention Studies;Intestines;Investigation;Investments;Kentucky;Link;Literature;Low Birth Weight Infant;Mediating;Medicine;Mentors;Methods;Microbial Biofilms;Microbiology;Molecular;Mouth Diseases;Mucous Membrane;National Institute of Dental and Craniofacial Research;Nature;Oral;Oral cavity;Oral health;Orofacial Pain;Osteoporosis;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Periodontium;Physiological;Physiology;Population;Population Group;Preventive;Process;Property;Proteome;Research;Research Design;Research Infrastructure;Research Personnel;Research Support;Research Training;Risk;Science;Scientist;Signal Transduction;Site;Specificity;Strategic Planning;Streptococcus mutans;Surface;System;Systemic disease;Temporomandibular Joint Disorders;Tissues;Translational Research;Underserved Population;Universities;Vagina;Validation;Viral;Virulence;Virus Diseases;Woman;base;biological adaptation to stress;biomarker;cerebrovascular;clinical practice;college;craniofacial;diabetes management;gene therapy;health disparity;improved;information gathering;infrastructure development;microbial;microorganism;new technology;novel strategies;novel therapeutic intervention;oral infection;oral tissue;prevent;programs;prospective;research clinical testing;response;success;tool;type I and type II diabetes


application_id: 8321988
project_number: 5R21AG038652-02
project_title: Aging related susceptibility to lung injury - remodeling and oxidative stress
administering_ic: NIA
award_notice_date: 2012-07-20
opportunity_number: PA-10-044
application_type: 5
activity_code: R21
ic: AG
serial_number: 038652
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2011-09-01
project_end_date: 2013-07-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Acute lung injury occurs in over 200000 subjects in the U.S. each year and over 40% of affected individuals succumb to this disease. Elderly patients represent a disproportionate number of afflicted individuals with acute lung injury but the factors responsible for this increased susceptibility remain unclear. We now have evidence suggesting that aging renders the lung susceptible to disrepair through the establishment of a 'pro-fibrotic' state that is unleashed only after exposure to an injurious agent. When comparing mice at 2 months and 24 months of age we found that at baseline the lungs of senescent mice show increased expression of the pro-fibrotic growth factor transforming growth factor beta its receptor TGF-RI and its main intracellular transducer Smad3; the fibronectin splicing variant EDA a matrix glycoprotein linked to lung fibrogenesis; and the proteases MMP2 and MMP9. We also found that fibroblasts harvested from the lungs of senescent mice show decreased expression of Thy-1; Thy-1 negative fibroblasts promote fibrogenic responses. Importantly when exposed to bleomycin elderly animals show greater fibrosis as demonstrated histologically and by quantification of hydroxyproline. In view of the importance of the above findings we turned our attention to the factors promoting these events. That search led us to investigate the role of oxidant stress. It has been shown that elderly animals (and humans) manifest oxidation of their plasma cysteine/cystine redox potential. We demonstrated that this type of oxidant stress promotes lung fibroblast proliferation myofibroblast transdifferentiation and expression of TGF- and fibronectin in vitro. Based on the above we hypothesize that aging through oxidation of the cysteine/cystine redox potential results in a 'pro- fibrotic' state that renders the host susceptible to disrepair and the development of acute lung injury after an insult. The hypothesis will be investigated by examining how oxidation of the extracellullar cysteine/cystine redox potential promotes a pro-fibrotic state in senescent murine lungs by determining the impact of nutritional interventions as preventive strategies and by testing for evidence of this pro-fibrotic state in the bronchoalveolar lavage fluid of young versus elderly humans who are otherwise healthy.

project_terms:
Acute respiratory failure;Adult Respiratory Distress Syndrome;Affect;Age;Age-Months;Aging;Alcohols;Animals;Antioxidants;Attention;Bleomycin;Bronchoalveolar Lavage Fluid;Collagen;Critical Care;Critical Illness;Cysteine;Cystine;Data;Development;Diet;Dietary Intervention;Dietary Supplements;Disease;Elderly;Endotoxemia;Endotoxins;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Funding;Glycoproteins;Growth Factor;Harvest;Histologic;Histology;Human;Hydroxyproline;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;Injury;Integration Host Factors;Investigation;Laboratories;Lead;Link;Lung;Lung Injury Acute;MMP2 gene;MMP9 gene;Mortality Vital Statistics;Mus;Myofibroblast;Nicotine;Nutritional;Organ;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peptide Hydrolases;Plasma;Predisposition;Prevention strategy;Preventive;Preventive Intervention;Process;Production;RNA Splicing;Reporting;Research;Role;Signal Transduction;Sirolimus;Surface;Testing;Tissues;Transducers;Transforming Growth Factor beta;Transforming Growth Factors;Variant;Virus;Work;age related;base;collagenase;design;fibrogenesis;human FRAP1 protein;improved;injured;lung injury;lung repair;novel;older patient;oxidant stress;oxidation;prevent;receptor;repaired;response;senescence;therapy design;transcription factor;transdifferentiation

public_health_relevance:
The incidence and mortality from acute lung injury are more common in elderly patients. Many reports suggest that senescent lungs are proned to disrepair after injury but the mechanisms responsible for this remain incompletely understood. We believe that a special kind of oxidant stress (oxidation of the cysteine/cystine redox potential) induce a 'pro-fibrotic' state in senescent lungs thereby increasing susceptibility to acute lung injury. This project seeks to explore this possibility with the hope of identifying dietary interventions that could serve as preventive therapy.


application_id: 8321445
project_number: 5R01AI050656-09
project_title: Molecular Mechanisms Controlling NK Receptors
administering_ic: NIAID
award_notice_date: 2012-08-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 050656
program_official: MOAYERI, MAHTAB
project_start_date: 2003-09-01
project_end_date: 2015-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: 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): Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. NK cells distinguish normal from aberrant cells largely via killer cell immunoglobulin-like receptors (KIR). Despite high homology between KIR genes individual NK cells express distinct numbers and combinations of clonally-restricted KIR (crKIR) genes. In contrast to crKIR KIR2DL4 is expressed by all NK cells preceding crKIR expression during NK development. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal the current objectives are to further characterize KIR expression control in normal physiology and during epigenetic therapy of lymphoma and myelodysplastic syndrome. The rationale for the proposed research is that once KIR gene regulation is better understood then KIR expression can be manipulated to make effective NK cells reagents in immunotherapy of cancer and infectious diseases. In this proposal 2DL4 and crKIR promoters will be investigated with special attention to mechanisms that overcome DNA methylation and repressive chromatin. Because so little is known about how lymphocyte-specific gene expression is influenced by cancer and by epigenetic therapy we will study how DNA methylation and histone deacetylase inhibitor drugs affect KIR promoter methylation KIR expression and NK cell activation in myelodysplastic syndrome and lymphoma patients. This work may explain why NK function is poor in cancer patients and might suggest strategies for boosting immunity in these patients. We will catalog NK cell microRNA expression and their target mRNAs and we will investigate the microRNA mechanisms that regulate "dangerous" cytotoxic NK cells and "unlicensed" inhibitory receptor- negative NK cells. This will provide the basic information needed for future studies on control of NK developmental decisions in health and disease. This study will 1) develop a clear understanding of the multiple layers of regulation that control the initiation and maintenance of KIR expression; 2) establish for the first time how epigenetic therapy affects nonmalignant human lymphocyte gene expression and function in vivo; and 3) reveal NK-specific microRNA patterns and elucidate how they control mRNA targets to regulate NK development and set NK cell activation thresholds. These results will be highly significant because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Such an understanding will suggest new ways to manipulate NK cells in the therapy of cancer and infectious diseases. PUBLIC HEALTH RELEVANCE: Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal the current objectives are to further characterize NK gene expression control in normal physiology and in cancers and pre-cancers such as lymphoma and myelodysplastic syndrome.

project_terms:
Abbreviations;Address;Affect;Aftercare;Alleles;Antibody -dependent cell cytotoxicity;Attention;Autoimmunity;B-Lymphocytes;Beryllium;Binding (Molecular Function);Bioinformatics;CREB1 gene;Cancer Patient;Cataloging;Catalogs;Cells;Chromatin;Co-Immunoprecipitations;Communicable Diseases;Complement;DNA;DNA Methylation;DNA Methyltransferase;DNA Modification Methylases;Data;Development;Disease;Distal;Double-Stranded RNA;Dysmyelopoietic Syndromes;EMSA;Electrophoretic Mobility Shift Assay;Elements;Epigenetic Process;Fluorescence;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Health;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Human;Human Herpesvirus 4;Immunity;Immunoglobulins;In Vitro;Individual;Interleukin-15;Interleukin-2;Investigation;Killer Cells;Knowledge;Lead;Licensing;Ligands;Lymphocyte;Lymphocyte Function;Lymphoma;Lysine;MHC Class I Genes;Maintenance;Malignant Neoplasms;Messenger RNA;Methods;Methylation;MicroRNAs;Molecular;Mus;NK Cell Activation;Natural Immunity;Natural Killer Cells;Non-Malignant;Nucleotides;Patients;Pattern;Pharmaceutical Preparations;Physiology;Production;Promotor (Genetics);Proteins;Quantitative Reverse Transcriptase PCR;RNA Polymerase II;Reagent;Receptor Gene;Regulation;Research;Research Technics;Retroviridae;Reverse Transcriptase Polymerase Chain Reaction;Role;Serum;Site;Stem cells;T-Lymphocyte;T-Lymphocyte and Natural Killer Cell;Testing;Time;Transcription Factor TFIIB;Transcriptional Regulation;Transfection;Untranslated Regions;Virus;Work;adaptive immunity;base;cancer cell;cancer immunotherapy;cancer therapy;cell killing;chemokine;chromatin immunoprecipitation;cytokine;cytotoxic;cytotoxicity;demethylation;effective therapy;expectation;gene function;histone modification;human disease;in vivo;innovation;insight;killer immunoglobulin-like receptor;novel;receptor;receptor expression;receptor function;response;transcription factor

public_health_relevance:
Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptiveimmunity. The long-range goal is to use NK cells as effective treatments of cancer andinfectious diseases. As the next logical step toward that goal the current objectives are to furthercharacterize NK gene expression control in normal physiology and in cancers and pre-cancerssuch as lymphoma and myelodysplastic syndrome.


application_id: 8321444
project_number: 5R03DE020839-02
project_title: Rank tests for clustered data with potentially informative cluster size: Novel st
administering_ic: NIDCR
award_notice_date: 2012-08-07
opportunity_number: PAR-09-182
application_type: 5
activity_code: R03
ic: DE
serial_number: 020839
program_official: HARRIS, EMILY L
project_start_date: 2011-09-01
project_end_date: 2014-12-31
study_section: ZDE1-LK(25)
contact_pi_person_id: 9020729
contact_pi: DATTA, SOMNATH
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): The overall goal of this proposal is to develop appropriate rank based tests for clustered data when the cluster size is potentially informative and apply the resulting methods for various marginal comparisons (e.g. average condition of teeth before and after treatment) using existing dental database resources specifically as obtained from the Piedmont 65 + Dental Study and Iowa Fluoride Study. Informative cluster size arises when the number of units in a cluster is non-constant/random and in correlation with the outcome of interest. In the context of dental data all teeth belonging to an individual will form a cluster. Since tooth loss (in adult) is correlated with two of the diseases we are planning to study namely periodontal disease and dental caries we have potentially informative cluster sizes in the Piedmont data sets. It is a methodological challenge to adapt a classical rank test to such situations. As for example the two sample Wilcoxon rank sum test has difficulty maintaining the correct size/significance level under informative clustering even if it is adjusted for cluster dependence through appropriate variance estimate.  This proposal has a goal of developing proper classes of rank based tests (and related R estimators) and studying their statistical properties for three classical problems adapted to marginal inference under cluster dependence with informative cluster size. These are the so called one sample location problem (Aim 1) the regression problem (Aim 2) and the association problem (Aim 3). In each of these problems we will obtain a class of test statistics using general score functions that maintain proper asymptotic size under the informative cluster size scenario. We will also study the properties of the related R estimates of marginal parameters. Multivariate extensions of the first two problems will also be considered (Aim 4). Another signification component of the proposed research will be to extend these procedures to handle missing data where the missingness mechanism can be modeled using observable covariates (Aim 5). Finally when the cluster size is not informative as in the case of Iowa Study which comprises of children only we will be able to increase the power of our tests by incorporating cluster specific weights in the construction of our test statistics (Aim 6).

project_terms:
Accounting;Adult;Aftercare;Data;Data Analyses;Data Set;Databases;Dental;Dental Hygiene;Dental Research;Dental caries;Dependence;Development;Disease;Environment;Fluorides;Goals;Individual;Iowa;Lead;Literature;Location;Measurement;Methods;Modeling;Only Child;Oral health;Outcome;Outcome Measure;Paired Comparison;Patients;Periodontal Diseases;Physiological;Population;Procedures;Property;Rank-Sum Tests;Research;Research Personnel;Resources;Sampling;Statistical Methods;Sum;Testing;Tooth Loss;Tooth structure;Weight;Work;base;improved;interest;novel;statistics

public_health_relevance:
The proposed research will lead to novel methodological and theoretical development in nonparametric/rank tests and estimators for clustered data that will have direct impact on the analyses of a dental data. The results from the proposed research have the potential to transform the way clustered data are handled in practice. Dental researchers and practitioners will be more aware of the informative cluster size issue and employ robust methods such as the ones developed here that accounts for the non-ignorability of the cluster size.    -cluster exchangeability remains an issue.


application_id: 8321393
project_number: 5R44HL090055-06
project_title: Personalized medicine informatics for anticoagulation therapy
administering_ic: NHLBI
award_notice_date: 2012-09-15
opportunity_number: PA-09-080
application_type: 5
activity_code: R44
ic: HL
serial_number: 090055
program_official: WARREN, RONALD Q
project_start_date: 2007-08-16
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: LINDER, MARK W;VALDES, ROLAND
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-08-15
budget_end_date: 2015-07-31
project_abstract:
DESCRIPTION (provided by applicant):   Improvements in the safety and efficacy of warfarin therapy will result from intelligent application of knowledge derived from inherited characteristics (CYP2C9 and VKORC1) of individual patients only when this knowledge is applied through a standardized interventional approach. The fundamental pharmacologic influences of CYP2C9 and VKORC1 have been unequivocally established and validated by numerous academic reports including those conducted by PGXL and its affiliated thought leaders. There is a clear cause and effect relationship between inherited variation in these enzymes and complications in warfarin management. Delayed metabolic clearance of S-warfarin (CYP2C9) and a lower concentration threshold for response (VKORC1) have a profound effect on the clinical pharmacology of warfarin and defeat the utility of standard dosing and monitoring practices. Current warfarin dosing practices which rely on standardized initiation dosing and INR-based dose adjustments are fundamentally flawed when applied to patients without regard to their unique metabolic and response characteristics. PGXL has developed a personalized medicine interface (PerMIT) which provides interpretive genotype-based guidance to facilitate appropriate clinical practice modifications accommodating patient individuality. PerMIT:Warfarin is the first HIPAA-compliant and secure pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin applies fundamental pharmacologic influences of inherited patient characteristics to individually tailor warfarin therapy. The mathematical operations that form the basis of PerMIT have been validated for accuracy and PGXL is now prepared for prospective interventional trials. PGXL Laboratories has engaged all of the key external resources necessary to construct a comprehensive strategic framework to gather compelling clinical evidence of improved outcomes and to move PerMIT:Warfarin through the regulatory and commercialization processes. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by federal regulatory bodies and the demands of the marketplace.    PUBLIC HEALTH RELEVANCE:   Individualised therapeutic management based on pharmacogenetic information requires a standardized interventional approach. PerMIT:Warfarin is the first pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin is a Class II device under FDA classification regulation 21 CFR 864.7750. The Center for Medicare and Medicaid Services (CMS) has established a standard for warfarin pharmacogenetics reimbursement calling for multi-site randomized controlled trials to assess the benefit of pharmacogenetics to warfarin therapeutic management. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by these regulatory bodies.

project_terms:
Address;Anticoagulation;CYP2C9 gene;Characteristics;Classification;Clinical;Clinical Pharmacology;Collaborations;Computational algorithm;Computer software;Consult;Development;Devices;Dose;Enrollment;Enzymes;Feedback;Funding;Genotype;Health Care Costs;Health Insurance Portability and Accountability Act;Individual;Individuality;Informatics;Inherited;Institutional Review Boards;Intellectual Property;Knowledge;Laboratories;Medical;Medicine;Metabolic;Methodology;Modification;Monitor;Online Systems;Outcome;Patients;Pharmacogenetics;Phase;Process;Randomized Controlled Trials;Records;Regulation;Reporting;Resources;Safety;Secure;Site;Small Business Innovation Research Grant;Software Design;Software Validation;System;Test Result;Testing;Therapeutic;Time;Translating;United States Centers for Medicare and Medicaid Services;United States National Institutes of Health;Universities;Variant;Warfarin;base;clinical practice;commercialization;design;improved;operation;pharmacogenetic testing;programs;prospective;public health relevance;response;standard of care;usability

public_health_relevance:
Project NarrativeIndividualised therapeutic management based on pharmacogenetic information requires astandardized interventional approach. PerMIT:Warfarin is the first pharmacogenetics-basedinterventional methodology for warfarin anticoagulation management. PerMIT:Warfarin is aClass II device under FDA classification regulation 21 CFR 864.7750. The Center for Medicareand Medicaid Services (CMS) has established a standard for warfarin pharmacogeneticsreimbursement calling for multi-site randomized controlled trials to assess the benefit ofpharmacogenetics to warfarin therapeutic management. This SBIR Phase II CompetitiveRenewal application is designed to achieve the regulatory compliance and medical evidentiarystandards set forth by these regulatory bodies.


application_id: 8321048
project_number: 5P20CA150343-03
project_title: Targeted Inhibition of P13K Pathway Components as Novel Treatment of Colectoral C
administering_ic: NCI
application_type: 5
activity_code: P20
ic: CA
serial_number: 150343
project_end_date: 2013-08-31
study_section: ZCA1
subproject_number: 5642
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2011-09-01
budget_end_date: 2012-08-31
funding_mechanism: Research Centers
project_abstract:
Colorectal cancer is the second leading cause of cancer deaths in the United States. When localized to the
mucosa and submucosa of the bowel wall (Stage I) the five year survival approaches 100%; however
metastasis to lymph nodes (Stage 111) results in a precipitous decrease in five year survival and systemic
metastasis to the liver (ie Stage IV) is associated with a five year survival that is less than 5%. Activation of
phosphatidylinositol 3-kinase (PI3K) a ubiquitous lipid kinase composed of an 85 kDa regulatory subunit
(p85) and a 110 kDa catalytic subunit (p110) and its downstream effector protein Akt is associated with
the growth and progression of a number of cancers including colorectal cancer. We have shown that
inhibition of PISK/Akt decreases viability and growth increases differentiation and apoptosis of human
colorectal cancer cells. Furthermore PISK/Akt inhibition decreases colon cancer xenograft growth in
athymic nude mice and sensitizes these cancers to the apoptotic effects of chemotherapeutic agents (eg 5-
FU). Moreover we have shown altered PISK/Akt expression in colorectal cancers and surrounding stroma
with increased expression of the p8Sa subunit and Akt2 in colorectal cancers of increasing stage. Targeted
inhibition of either p8Sa or p110a by RNA interference (RNAi) increased sensitivity of resistant colorectal
cancers to the effects of chemotherapy and significantly suppressed colorectal cancer metastasis to the
liver in preclinical animal models. The central hypothesis of this project is that colorectal cancer growth
and progression are augmented by increased p85a and Akt2 expression; the selective inhibition of PISK/Akt
components can suppress colorectal cancer growth and metastasis and can sensitize resistant colorectal
cancers to chemotherapeutic agents. The long-term qoai is to develop more selected therapies for
colorectal cancer progression and metastasis based on a systematic analysis of colorectal cancers tumor
stroma and surrounding mucosa for expression of piSK/Akt pathway components. To examine our hypothesis and address the long-term goal we have designed experiments with the following Specific
Aims: 1) To provide clinical validation of the pattern and significance of PISK/Akt/PTEN pathway component expression in polyps and colorectal cancers of different stages. 2) To assess novel strategies of selective PISK component inhibition on in vivo tumor growth and liver metastasis using preclinical animal models. 3) To evaluate the therapeutic efficacy of RNAi to the PISK pathway in combination with conventional chemotherapy. The cumulative information derived from ttiese studies will lead to better targeted therapeutics and treatment paradigms for colorectal cancer.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Animal Model;Apoptosis;Apoptotic;Cancer Etiology;Catalytic Domain;Cessation of life;Clinical;Colon Carcinoma;Colorectal Cancer;Fluorouracil;Goals;Growth;Human;Intestines;Lead;Lipids;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Metastatic Neoplasm to Lymph Nodes;Metastatic Neoplasm to the Liver;Mucous Membrane;Neoplasm Metastasis;Nude Mice;PTEN gene;Pathway interactions;Patients;Pattern;Phosphatidylinositols;Phosphotransferases;Polyps;Proto-Oncogene Proteins c-akt;RNA Interference;Resistance;Signal Pathway;Staging;Submucosa;Therapeutic Agents;Treatment Efficacy;United States;Validation;Xenograft procedure;base;cancer cell;chemotherapeutic agent;chemotherapy;design;in vivo;novel;novel strategies;pre-clinical;research study;therapeutic target;tumor;tumor growth;tumor progression


application_id: 8321047
project_number: 5P20CA150343-03
project_title: Hepatitis C and Tumor Suppressors in Hepatocellular
administering_ic: NCI
application_type: 5
activity_code: P20
ic: CA
serial_number: 150343
project_end_date: 2013-08-31
study_section: ZCA1
subproject_number: 5626
contact_pi_person_id: 1884112
contact_pi: LEMON, STANLEY M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-01
budget_end_date: 2012-08-31
funding_mechanism: Research Centers
project_abstract:
This project seeks to determine the clinical relevance and potential role in hepatic carcinogenesis of
interactions between host cell and hepatitis C virus (HCV) proteins that have been identified in previous cell
culture-based experiments. The retinoblastoma susceptibility protein (pRb) and the cellular DEAD-box RNA
helicase DDXS play critical roles in regulating the cell cycle. Our previous work indicates that the HCV RNA
polymerase NS5B fc^nns a complex with pRb targeting it for ubiquitination and proteasome-dependent
degradation activating E2F-responsive promoters and stimulating cell proliferation. Similarly HCV cofe
protein expression alters the cellular abundance and localization of DDX3. Our hypothesis is that these and
other interactions with host proteins (p53 and DDX5) promote proliferation of hepatocytes and impair DNA
damage responses tljiereby contributing to HCV carcinogenesis. In Aim 1 we will develop and validate
fluorescent quantum dot probes capable of sensitive detection of HCV proteins expressed in virus-infected
cells. We will also determine whether HCV protein expression conrelates with altered tumor suppressor
expression in transgenic mice. Aim 2 will utilize these novel probes in laser scanning confocal and multi
photon microscopy studies of liver tissue from patients with chronic hepatitis C and ask whether the
abundance and cellular localization of pRb p53 DDXS or DDXS is altered in infected hepatocytes. In Aim 3
we will determine whether HCV infection is associated on a single-cell basis with increased expression of the
proliferation markers Ki-67 and PCNA. We will also determine whether the proportion of cells displaying
proliferation markers is reduced after standard-of-care peg-IFN/ribavirin therapy. These results will be
correlated with oligonucleotide microarray and quantitative RT-PCR assays to determine whether liver
specimens with a high proportion of HCV-infected cells display transcriptional patterns indicative of
hepatocellular proliferation and/or E2F transcription factor activation. RELEVANCE TO PUBLIC HEATH:'
Liver cancer is one qf the most rapidly increasing types of cancers in the United States reflecting an
increased prevalence ^nd risk of liver cancer in persons with chronic hepatitis C. This project seeks a better
understanding of the interaction of HCV proteins with important regulators of cell proliferation (pRb p53
DDXS and DDXS) anc( the role of such interactions in liver cancer caused by HCV infection.
PERFORMANCE SITE

project_terms:
African American;Antiviral Therapy;Binding (Molecular Function);Biological Assay;Boxing;Cancer Etiology;Caring;Cell Culture Techniques;Cell Cycle;Cell Cycle Regulation;Cell Nucleus;Cell Proliferation;Cells;Chronic Hepatitis C;Complex;Cultured Cells;Cytoplasm;DNA Damage;DNA Modification Process;DNA-Directed RNA Polymerase;Detection;Diagnostic;E2F transcription factors;Event;Freezing;Goals;Hepatic;Hepatitis C;Hepatitis C virus;Hepatocyte;Hispanics;Human;In Vitro;Incidence;Interferons;Lasers;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Methods;Microscopy;Mitochondria;Oligonucleotide Microarrays;Oxidative Stress;Paraffin Embedding;Patients;Pattern;Persons;Play;Predisposition;Prevalence;Preventive;Principal Investigator;Proliferation Marker;Promotor (Genetics);Protein Binding;Protein p53;Proteins;Quantum Dots;RNA Helicase;RNA-Directed RNA Polymerase;Retinoblastoma;Reverse Transcriptase Polymerase Chain Reaction;Ribavirin;Risk;Role;Scanning;Semiconductors;Series;Specimen;Testing;Therapeutic;Tissues;Transgenic Mice;Tumor Suppressor Proteins;Ubiquitination;United States;Viral;Viral Core Proteins;Viral Proteins;Virus;Work;adduct;base;cancer type;carcinogenesis;clinically relevant;hepatitis C virus nucleocapsid protein;imaging modality;improved;in vivo;interferon therapy;liver cell proliferation;male;multi-photon;multicatalytic endopeptidase complex;novel;performance site;prevent;programs;protein expression;research study;response;viral RNA


application_id: 8320556
project_number: 1R01AR061939-01A1
project_title: BetaCatenin Regulation of Skeletal Muscle Hypertrophy
administering_ic: NIAMS
award_notice_date: 2012-06-28
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AR
serial_number: 061939
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-C (90)]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  As the "house-building" macromolecule of the cell ribosome biogenesis is essential for cell growth. Despite this central role in cell growth there remains a fundamental gap in our understanding of the role of ribosome biogenesis in adult skeletal muscle hypertrophy. Studies from our laboratory have provided evidence which supports a role for increased ribosome biogenesis in skeletal muscle hypertrophy. The current proposal will begin to directly examine the importance of ribosome biogenesis to muscle hypertrophy by testing the hypothesis that -catenin is necessary for muscle hypertrophy by increasing protein synthesis through c-myc activation of ribosome biogenesis. To conditionally manipulate -catenin or c-myc gene expression in adult skeletal muscle we generated the HSA-MerCreMer mouse. Aim 1 will determine if -catenin expression is necessary for skeletal muscle hypertrophy using a mechanical overload model of the plantaris muscle following catenin gene inactivation. Aim 2 will determine if increased expression of -catenin is sufficient to stimulate skeletal muscle hypertrophy. -catenin will be over-expressed in adult skeletal muscle by using the HSA- MerCreMer strain to generate a stabilized form of -catenin. Aim 3 will determine if c-myc expression is necessary for skeletal muscle hypertrophy following the conditional inactivation of c-myc in adult skeletal muscle using the HSA-MerCreMer strain. The effect of gene inactivation on the hypertrophic response will be assessed by measuring morphometric (muscle weight fiber CSA) biochemical (total protein RNA and DNA) molecular (Western blot RT-PCR promoter analysis chromatin immunoprecipitation (ChIP) and electrophorectic mobility shift assay (EMSA)) and metabolic (rates of protein synthesis and degradation) variables. The results of the proposed studies are expected to have important clinical implications by identifying new molecular targets for promoting skeletal muscle protein synthesis and hypertrophy. In the long- term the ability to manipulate ribosome biogenesis represents a promising novel strategy to attenuate or ameliorate muscle atrophy associated with aging bed rest and cachexia.   
   
PUBLIC HEALTH RELEVANCE:  Skeletal muscle mass makes up almost 50% of the total body weight in healthy adults and it is now recognized as an important health factor. The findings from the proposed research are expected to reveal whether or not b-catenin regulation of protein synthesis is necessary for muscle growth. If confirmed such results will be of medicinal value by providing new targets for promoting muscle growth during periods of muscle loss associated with inactivity cancer and aging.

project_terms:
Adult;Aging;Atrophic;Attenuated;Bed rest;Biochemical;Biogenesis;Biology;Body Weight;Cachexia;Cartoons;Catabolism;Cells;Clinical;Complement;DNA;DNA Polymerase I;DNA-Directed RNA Polymerase;Electrophoretic Mobility Shift Assay;Event;Fiber;Gene Expression;Gene Silencing;Genes;Genetic Transcription;Growth;Health;Hindlimb Suspension;Housing;Human;Hypertrophy;In Vitro;Insulin-Like Growth Factor I;Knowledge;Laboratories;Malignant Neoplasms;Measurement;Measures;Mechanics;Metabolic;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Outcome;Pathway interactions;Plantaris muscle;Promotor (Genetics);Protein Biosynthesis;Proteins;Publishing;Quality of life;RNA;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Ribosomal RNA;Ribosomes;Rodent;Role;Skeletal muscle structure;Stimulus;System;Testing;Translations;Weight;Western Blotting;Work;c-myc Genes;cell growth;chromatin immunoprecipitation;in vitro Model;in vivo;macromolecule;muscle form;muscle hypertrophy;muscle strength;novel;novel strategies;overexpression;prevent;protein degradation;research study;response;sedentary


application_id: 8320548
project_number: 1F31DA032496-01A1
project_title: Prolonged activation of endogenous opioid analgesia after inflammation
administering_ic: NIDA
award_notice_date: 2012-02-29
opportunity_number: PA-11-112
application_type: 1
activity_code: F31
ic: DA
serial_number: 032496
suffix: A1
program_official: AVILA, ALBERT
project_start_date: 2012-03-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZRG1 F02B-M (20)]
contact_pi_person_id: 10742197
contact_pi: CORDER, GREGORY
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Peripheral tissue inflammation can lead to maladaptive plasticity in the spinal cord and brain which contributes to persistent pain. The intensity and quality of pain is determined by the net balance between the activities of pronociceptive systems with compensatory endogenous inhibitory systems namely spinal opioid signaling. Interestingly a small set of studies indicate that endogenous opioid inhibition f acute nociception persists even after the initial signs of hyperalgesia have subsided. For example opioid receptor antagonists reinstate allodynia. This raises two intriguing questions. First opioid receptor subtypes and neural circuits remain unclear. Second does a latent nociceptive sensitization persist in the absence of overt behavioral signs of hypersensitivity? My preliminary data show that naltrexone when intrathecally administered weeks to months after intraplantar CFA reinstated behavioral signs of hypersensitivity and induced dorsal horn ERK phosphorylation. Both were blocked by spinal antagonism of NMDA receptors. My central hypothesis is that peripheral inflammation induces prolonged signaling of CNS opioidergic-circuits (Aim 1) that mask pronociceptive NMDA and AMPA signaling (Aim 2). This F31 proposal attempts to better characterize the mechanisms that underlie the latent sensitization that is masked by endogenous opioid activity. Aim 1 tests the hypothesis that spinal opioidergic signaling tonically masks nociceptive sensitization. Aim 1A investigates - - and ?-opioid receptor subtypes with the use of selective antagonists. Aim 1B and 1C test mechanisms of constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTP ?S35 binding assay and intrathecal sequestering opioid peptide antiserum respectively. Aim 1D tests the hypothesis that opioid receptor blockade disinhibits tonic afferent nociception. In Aim 2 I will test the idea that glutamatergic signaling drives the hypersensitivity that follows
spinal opioid receptor blockade with a focus on spinal NMDA (Aim 2A) and AMPA/kainate-receptors (Aim 2B). By better understanding long-lasting opioid antinociception this project could pave the way for future strategies to enhance endogenous opioid analgesia in humans with chronic pain and thus has the long-term potential to reveal novel targets to prevent the transition for acute to chronic pain. This F31 award will help me achieve my goals that will enable me to successfully compete for strong post-doctoral positions and ultimately a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment:   
   
PUBLIC HEALTH RELEVANCE: Sensitization of pain pathways in the setting of tissue inflammation leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.

project_terms:
6-Cyano-7-nitroquinoxaline-23-dione;Absence of pain sensation;Acute;Afferent Neurons;Agonist;Animal Model;Animals;Antibodies;Attenuated;Behavior;Behavioral;Binding (Molecular Function);Biological Assay;Brain;CTOP;Coupling;Cutaneous;Data;Dose;Dynorphins;Educational process of instructing;Endogenous Opiates;Enkephalins;Environment;Equilibrium;Female;Freund's Adjuvant;Future;GTP-Binding Proteins;Glutamates;Goals;Guanosine Triphosphate;Heating;Human;Hyperalgesia;Hypersensitivity;Immune Sera;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Intrathecal Injections;Kainic Acid Receptors;Lead;Light;Local anesthesia;Masks;Mechanics;Mediating;Medical Research;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NMDA receptor antagonist;Naltrexone;Neurons;Neurotransmitters;Nociception;Opioid;Opioid Peptide;Opioid Receptor;Pain;Pain quality;Pathway interactions;Peptides;Peripheral;Persistent pain;Phosphorylation;Positioning Attribute;Postdoctoral Fellow;Predoctoral Individual National Research Service Award;Presynaptic Terminals;Receptor Signaling;Research;Resolution;Science;Sensory Thresholds;Signal Transduction;Slice;Spinal;Spinal Anesthesia;Spinal Cord;Stimulus;Synapses;System;Testing;Therapeutic;Tissues;Touch sensation;Universities;allodynia;attenuation;career;central sensitization;chronic pain;design;dorsal horn;endomorphin 1;inflammatory pain;injured;kainate;male;meetings;naltrindole;neural circuit;neuronal excitability;norbinaltorphimine;novel;prevent;receptor;response;sciatic nerve;stressor;transmission process

public_health_relevance:
Sensitization of pain pathways in the setting of tissue inflammation leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.


application_id: 8320531
project_number: 1R21AI098371-01A1
project_title: Contribution of N-glycosylation to the Toxoplasma glycoproteome
administering_ic: NIAID
award_notice_date: 2012-02-23
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AI
serial_number: 098371
suffix: A1
program_official: MCGUGAN, GLEN C
project_start_date: 2012-03-01
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-S (02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The protozoan parasite Toxoplasma gondii is an important opportunistic infection causing life threatening disease in patients with HIV-AIDS and other immune compromising conditions. The high seroprevalence of the T. gondii worldwide but low incidence of symptomatic disease reflects the fact that the acute phase of infection is effectively handled by the immune response. Unfortunately a sterile cure is not achieved. Rather the parasite establishes a life-long chronic infections mediated by tissue cysts typically formed in the brain and muscle. The tissue cyst is protected by a heavily glycosylated cyst wall. Despite the importance of glycosylation little is known about these pathways in the parasite. With this work we address the contribution of N-linked glycosylation in Toxoplasma. We propose to use lectin affinity coupled with mass spectrometric identification to catalogue the diversity of N-glycosylated glycoproteins in tissue cysts. We further plan to conditionally knock out a key gene in the N-glycosylation TgALG7 in order to assess its role in parasite biology with a focus on protein targeting to its diverse unique secretory organelles. Given the central role for glycosylation in the tissue cyst we propose an experimental strategy to selectively knock out gene expression in the tissue cyst. This technology will be applied to establishing the contribution of TgALG7 and by extension N-glycosylation to tissue cyst formation and stability. This work represents the first in depth study of the cell biologic basis of protein glycosylation i Toxoplasma using state of the art approaches to modulate gene expression.   
   
PUBLIC HEALTH RELEVANCE: Toxoplasma gondii causes serious illness in immune compromised individuals including patients with HIV- AIDS. Our understanding of the role of glycosylation in parasite biology is very limited. With this work we directly explore N-glycosylation in the with a focus the dormant tissue cyst form. We hope to establish a strong foundation for future studies in this under explored area of investigation.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Affinity;Affinity Chromatography;Animals;Apicomplexa;Area;Asparagine;Bioinformatics;Biological Process;Biology;Blood;Brain;Cataloging;Catalogs;Cells;Chronic;Chronic Phase;Complex;Computer Simulation;Coupled;Cyst;Development;Disease;Elements;Enzymes;Exhibits;Foundations;Funding Mechanisms;Future;Gene Expression;Genes;Genetic;Genome;Glycoproteins;Golgi Apparatus;HIV;Homologous Gene;Immune;Immune response;Immune system;Incidence;Individual;Infection;Investigation;Knock-out;Knowledge;Lectin;Life;Light;Link;Maintenance;Mass Spectrum Analysis;Mediating;Methods;Muscle;Nature;Neospora;Opportunistic Infections;Organelles;Parasites;Pathogenesis;Pathology;Pathway interactions;Patients;Pattern;Phase;Play;Polysaccharides;Protein Glycosylation;Proteins;Proteome;Proteomics;Protozoa;Role;Seroprevalences;Site-Directed Mutagenesis;Sterility;Structure;System;Technology;Testing;Tetanus Helper Peptide;Tissues;Toxoplasma;Toxoplasma gondii;Vision;Work;asexual;base;genetic manipulation;glycosylation;high risk;infancy;knowledge base;member;microbial;rhoptry;sugar

public_health_relevance:
Toxoplasma gondii causes serious illness in immune compromised individuals including patients with HIV- AIDS. Our understanding of the role of glycosylation in parasite biology is very limited. With this work we directly explore N-glycosylation in the with a focus the dormant tissue cyst form. We hope to establish a strong foundation for future studies in this under explored area of investigation.


application_id: 8320477
project_number: 1T42OH010278-01
project_title: Central Appalachain Region Educational Research Center
administering_ic: NIOSH
award_notice_date: 2012-07-02
opportunity_number: PAR-10-217
application_type: 1
activity_code: T42
ic: OH
serial_number: 010278
program_official: SANDERSON, LEE M
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZOH1 GGB (50)]
contact_pi_person_id: 8433958
contact_pi: SANDERSON, WAYNE T.
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 Central Appalachian Regional Education and Research Center (CARERC) will provide graduate and continuing education for occupational safety and health professionals for the 3-year period July 2012-June 2015. Specifically we aim to (1) provide interdisciplinary occupational safety and health education for graduate students and occupational medicine residents; (2) enhance the research skills of students and faculty in the targeted disciplines; (3) encourage and conduct interdisciplinary research on a variety of occupational diseases and injuries; (4) deliver continuing education consultation and outreach to address environmental and occupational safety and health concerns; and (5) translate research into prevention practice. CARERC's scope includes counties in eastern Kentucky western North Carolina eastern Tennessee western Virginia and southern West Virginia where elevated rates of occupational injuries and fatalities persist particularly in production agriculture forestry mining and transportation. CARERC combines the resources of the University of Kentucky College of Public Health (Occupational Medicine Residency MPH and PhD in Occupational Epidemiology and Injury and MPH in Agricultural Safety and Health); the UK College of Nursing (PhD In Occupational Nursing); the UK College of Engineering (MS and PhD in Mine Safety & Health) and the Eastern Kentucky University College of Justice & Safety (MS in Occupational Safety). CARERC will collaborate with other regional institutions as well as industry labor and government in its Pilot Research Program (PRP) Outreach and Continuing Education (CE) programs to enhance research capacity and catalyze the translation of research to practice. We plan to support the following number of trainees each year: 3 occupational medicine residents; 6 doctoral students 6 MPH and 8 MS students across the core programs. Building on our existing strengths and stature CARERC will serve as a catalyst for interdisciplinary research in occupational safety and health and a centralized resource center for innovative education and training.    
   
PUBLIC HEALTH RELEVANCE: Building on the strengths of our existing research programs and responding to the need for innovative coordinated occupational safety and health training in central Appalachia the proposed Central Appalachian Regional Education and Research Center (CARERC) will provide unprecedented levels of targeted instruction training and applied research while serving as a recognized source of knowledge and expertise.


application_id: 8320092
project_number: 5R21NS071299-02
project_title: Electrophysiological reporter for monitoring gene manipulations
administering_ic: NINDS
award_notice_date: 2012-09-13
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: NS
serial_number: 071299
program_official: TALLEY, EDMUND M
project_start_date: 2011-09-01
project_end_date: 2014-08-31
study_section: Neurotechnology Study Section[NT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
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):  This proposal is an innovative effort to develop a novel tool that could revolutionize the execution and application of in vivo sharp electrode intracellular electrophysiology the fundamental approach for examining cellular and synaptic mechanisms of systems-level functions.  This tool is a reporter gene that will be detectible by electrophysiological methods in real-time by sharp electrodes in vivo without the need for secondary factors (i.e. light stimulus or exogenous ligands).  This could provide a necessary link to enable a more thorough incorporation of classic-type systems physiology with the reduced preparations and lower species that make up the majority of current experimental approaches used to understand genetic manipulations.  An ideal electrophysiological reporter is one that is genetically-encoded is "visible" to electrophysiological methods has a signal that is easily recognized and distinguished from native processes in real time and does not interfere with normal physiological function.  We have identified a lab-generated mutant ion channel that fits these criteria and appears to be an excellent candidate.  We will make use of new viral vector technology to deliver candidate gene to adult rats.  Aim 1 will use both in vivo and in vitro single-cell electrophysiological approaches to determine if the signal from the reporter gene can be detected against the well characterized background of the model systems (dorsal root ganglion sensory neurons and spinal motoneurons).  Aim 2 is hypothesis driven and will determine if constitutive signaling by trkC the receptor for neurotrophin-3 plays a necessary role in maintenance of the cellular and synaptic properties of adult motoneurons.  The issue of maintenance of cellular properties by target-derived factors is in a question of fundamental importance in terms of the principles of neuroscience/neurobiology and also in terms of biomedical issues in the adult nervous system such as aging neurodegeneration traumatic injury and learning and memory.

project_terms:
Address;Adult;Afferent Neurons;Aging;Animals;Biological Models;Candidate Disease Gene;Cell Line;Cells;Characteristics;Code;Complex;Data;Diabetes Mellitus;Diabetic Neuropathies;Disease;Electrodes;Electrophysiology (science);Functional disorder;Gene Delivery;Genes;Human;In Vitro;Individual;Information Systems;Injury;Ion Channel;Kinetics;Learning;Ligands;Light;Link;Locomotion;Maintenance;Mammalian Cell;Mediating;Memory;Mental disorders;Methods;Modeling;Molecular Genetics;Monitor;Motor;Motor Neurons;Nerve Degeneration;Nerve Growth Factor Receptors;Nervous System Trauma;Nervous system structure;Neurobiology;Neurodegenerative Disorders;Neurons;Neurosciences;Neurotrophic Tyrosine Kinase Receptor Type 3;Neurotrophin 3;Newborn Animals;Pathology;Physiologic pulse;Physiological;Physiology;Play;Preparation;Process;Production;Proline;Property;Publishing;Rattus;Receptor Signaling;Reporter;Reporter Genes;Reporting;Research;Research Personnel;Role;Signal Transduction;Spinal;Spinal Ganglia;Stimulus;Substance abuse problem;Synapses;System;Technology;Time;Viral Vector;Virus;Work;addiction;cell type;fighting;genetic manipulation;improved;in vivo;injured;innovation;interest;knock-down;mutant;nervous system disorder;neurophysiology;novel;receptor;relating to nervous system;research study;response;small hairpin RNA;therapeutic target;tool;voltage

public_health_relevance:
This project is aimed at developing a new tool for research - a gene that will report the status of genetic manipulations to electrophysiological probes.  If successful it will greatly facilitate the execution of and interpretation of data from systems-level in vivo neurophysiology an experimental approach that is particularly relevant to functional studies of the role of specific genes/cell-types in systems-level processes such as aging locomotion sensori-motor integration models of psychiatric disorders and addiction/substance abuse and nervous system disease/injury/insult and the responses to treatments.  This project also Aims to determine the effect of altering the expression of trkC (the receptor for neurotrophin-3) on the cellular and synaptic electrophysiological properties of a subpopulation of neurons which is relevant to conditions or disease states that may include reduced neurotrophin-receptor signaling in the pathophysiology such as aging diabetic neuropathy traumatic nervous system injury and neurodegeneration.


application_id: 8320014
project_number: 5U54CA153604-02
project_title: Research Project
administering_ic: NCI
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
study_section: ZCA1
subproject_number: 7548
contact_pi_person_id: 1878622
contact_pi: PASKETT, ELECTRA D.
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: 2011-09-01
budget_end_date: 2012-08-31
funding_mechanism: Research Centers
project_terms:
Address;Adult;Appalachian Region;Area;Behavior;Behavioral;Blood Pressure;Body mass index;Cancer Control;Centers for Disease Control and Prevention (U.S.);Cessation of life;Church;Colon Carcinoma;Communities;Community Networks;Computer Programs and Programming;Consumption;Country;County;Data;Diet;Direct Costs;Eating;Educational Status;Educational aspects;Effectiveness;Environment;Evaluation;Facilities and Administrative Costs;Female;Food;Frequencies (time pattern);Future;Goals;Health;Height;High Prevalence;Incidence;Individual;Intervention;Leisure Activities;Letters;Life;Life Style;Link;Low income;Malignant Neoplasms;Measures;Mortality Vital Statistics;Obesity;Outcome;Participant;Phase;Physical activity;Planets;Population;Process;Questionnaires;Randomized;Reporting;Research;Research Project Grants;Rural;Screening for cancer;Screening procedure;Technology;Testing;United States;Walking;Weight;Woman;base;community based participatory research;cost;design;disorder prevention;environmental change;faith-based intervention;follow-up;fruits and vegetables;health disparity;improved;intervention effect;intervention program;low socioeconomic status;male;medically underserved population;member;men;posters;prevent;programs;public health medicine (field);rural area;sedentary;social health determinants


application_id: 8319866
project_number: 1R13CA168316-01
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2012-04-19
opportunity_number: PA-10-071
application_type: 1
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZCA1 PCRB-G (F2)]
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
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): This R13 application requests support for the Kentucky Conference on Health Communication (KCHC)- District of Columbia Health Communication (DCHC) conference series which currently is planning its 13th meeting to be held April 19-21 2012. The overall goal of the annual KCHC-DCHC conference series is to promote health communication research and practice in order to advance our understanding of behavioral and communication science; such advanced understanding will through translational research subsequently enhance the effectiveness of interventions designed to promote health and prevent illness. The specific aims of this R13 are to increase the impact of KCHC-DCHC through 1) expanding dissemination; 2) increasing participation by early career researchers and graduate students; 3) increasing participation from underrepresented groups; and 4) continuing emphasis on scholarly excellence. Across all four aims our goal is to positively influence the field of health communication and increase its impact by enhancing dissemination of leading research and promoting the career development of early career scientists particularly those from underrepresented groups. Our emphasis on health message design and dissemination is relevant to the mission of the National Institutes of Health (NIH) given our goal to apply our knowledge "to enhance health lengthen life and reduce the burdens of illness and disability" [1]. This scientific focus is consistent with the aims of the U.S. government which has recognized the importance of communication in promoting the health and well-being of our nation in its Healthy People publications. The timeliness of our conference series is especially reflected by the theme the of 2012 conference Health Literacy Research and Practice a theme that addresses the number one Healthy People 2020 [2] health communication objective: health literacy. Our three- day international interdisciplinary conference encompasses several disciplines representing communication social behavioral and health sciences. Topics addressed at the conference include interventions designed for health risk behavior reduction in areas such as cancer diabetes substance abuse and HIV/AIDS; community media and technology-related issues; and methodological issues in behavioral/social science research. Such health communication-focused inquiry is now recognized as instrumental in promoting public health [3]. Past conference attendance has averaged approximately 200 participants. The audience primarily includes graduate postdoctoral and academic faculty researchers; we emphasize participation by graduate students and early career scientists. This audience composition allows the conference series to support one of NIH's goals: "to develop maintain and renew scientific human...resources that will ensure the Nation's capability to prevent disease" [1].   
   
PUBLIC HEALTH RELEVANCE: The Kentucky Conference on Health Communication (KCHC)-District of Columbia Health Communication (DCHC) conference series will advance health communication research and practice in order to reduce the burden of pressing public health problems such as cancer diabetes substance abuse and HIV/AIDS. The conference will promote career development in the social and behavioral sciences through support of early career researchers and graduate students increasing the number of professionals with expertise in health communication.

project_terms:
AIDS/HIV problem;Address;Area;Behavioral;Behavioral Genetics;Behavioral Sciences;Communication;Communication Research;Communities;Diabetes Mellitus;Discipline;Discipline of Nursing;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Goals;Government;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthy People 2020;Human Resources;Interdisciplinary Study;International;Internet;Kentucky;Knowledge;Life;Malignant Neoplasms;Medical Informatics;Medicine;Mission;Participant;Personal Satisfaction;Persuasive Communication;Process;Psychology;Publications;Publishing;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Scholarship;Science;Scientist;Series;Sister;Social Sciences;Sociology;Students;Substance abuse problem;Technology;Translational Research;Travel;United States National Institutes of Health;Work;behavioral/social science;burden of illness;career;career development;design;disability;disorder prevention;drug abuse prevention;graduate student;health information technology;health literacy;interest;meetings;member;prevent;public health medicine (field);skills;social;social science research;substance abuse prevention;symposium;therapy design


application_id: 8319607
project_number: 5K08CA155764-02
project_title: The Significance of Isocitrate Dehydrogenase Mutations in Gliomas
administering_ic: NCI
award_notice_date: 2012-08-10
opportunity_number: PA-10-059
application_type: 5
activity_code: K08
ic: CA
serial_number: 155764
program_official: JAKOWLEW, SONIA B
project_start_date: 2011-08-12
project_end_date: 2016-07-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 9285753
contact_pi: HORBINSKI, CRAIG MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this research proposal is to determine the mechanism(s) by which mutant isocitrate dehydrogenase 1 (IDH1) causes brain tumors to be less aggressive. The most common type of brain tumor is the diffusely infiltrative glioma; these tumors cannot be completely excised surgically and are difficult to treat with radiation and chemotherapy. Thus infiltrative gliomas are incurable. A specific point mutation in IDH1 (and a less common analogous mutation in IDH2) has been found to be quite frequent in these gliomas. When present it is a powerful favorable prognostic factor being strongly associated with longer patient survival. Mutant IDH1 has recently been shown to produce a novel compound 2-hydroxyglutarate (2-HG). However the effects of mutant IDH1 and 2-HG on glioma cells are unknown. Other work showed that 2-HG causes oxidative stress in nonneoplastic tissue models and our preliminary data indicate that 2-HG is toxic to glioma cells and induces autophagy ERK activation and reactive oxygen species production. We therefore hypothesize that the improved survival imparted by mutant IDH1 in diffuse gliomas is due to 2-HG-induced production of reactive oxygen species leading to oxidative damage and cell death. We also hypothesize that the cell death is primarily by autophagy a form of programmed cell death involving lysosomes that has been shown to be prominent in many gliomas. To test these hypotheses glioma cells will be treated with 2-HG or transfected with mutant IDH1 and multiple well-described markers of autophagy and reactive oxygen species will be measured. Response of glioma cells to autophagy and reactive oxygen species modulation will be assessed. For patient-derived tumor biopsies and human-mouse xenografts immunohistochemical markers of autophagy and oxidative stress will be quantified and correlated with IDH mutation status. Success in this project would determine whether mutant IDH1 causes increased oxidative stress and autophagy in gliomas thereby producing a less aggressive glioma compared to tumors that are wild type for IDH1. This knowledge could then be exploited to develop novel ways of treating gliomas. I am fortunate to have been mentored by exceptional scientists and physicians thus instilling in me a desire to pursue a career that synthesizes what I have learned as a scientist and neuropathologist.My graduate and postdoctoral work in neuroscience and my work in neuro-oncology have given me a diverse array of techniques and approaches that will be used in this project. My current position as an Assistant Professor in the Department of Pathology in the University of Kentucky offers the ideal opportunity to pursue my goal of being an independent investigator. I have nine person-months (75%) of guaranteed protected time for research separate laboratory space that has been fully equipped a full-time technician to increase output and sufficient funds to conduct experiments for the next four years. All this has been put in place by my chairman Dr. Paul Bachner independent of my success in securing extramural funding. I also benefit from a collaborative environment superb mentorship by Drs. Natasha Kyprianou Arie Perry and Jeremy Rich and excellent technical resources. Now that I have completed my clinical training the funding provided by this K08 award would allow me to develop as an independent investigator. Furthermore the project described in this proposal provides a superb opportunity to discover why mutant IDH1 imparts a more favorable survival in patients afflicted with gliomas in turn helping to identify pathways and targets for effective therapeutic interventions.

project_terms:
3-methyladenine;Abbreviations;Affect;Analysis of Variance;Antioxidants;Apoptosis;Arginine;Autophagocytosis;Award;Binding Sites;Biology;Biopsy;Brain Neoplasms;Bromodeoxyuridine;Cell Death;Cell Survival;Cells;Cessation of life;Chairperson;Clinical;Codon Nucleotides;Critiques;Data;Detection;Diffuse;Environment;Enzymes;Epidermal Growth Factor Receptor;Extramural Activities;Formalin;Funding;Future;Genetic;Glioma;Gliomagenesis;Glutathione Disulfide;Goals;Green Fluorescent Proteins;Human;In Vitro;Individual;Isocitrate Dehydrogenase (NAD+);Isocitrates;Kentucky;Knowledge;Laboratories;Lead;Learning;Lesion;Light;Lysosomes;MAP1 Microtubule-Associated Protein;MGMT gene;Manganese Superoxide Dismutase;Measurement;Measures;Mentors;Mentorship;Metabolic;Methods;Mus;Mutate;Mutation;NADP;Neurosciences;O(6)-Methylguanine-DNA Methyltransferase;Output;Oxidative Stress;Paraffin Embedding;Pathology;Pathway interactions;Patients;Persons;Phosphatidylethanolamines;Physicians;Point Mutation;Positioning Attribute;Primary Neoplasm;Production;Prognostic Factor;Radiation;Reactive Oxygen Species;Research;Research Personnel;Research Proposals;Resources;Scientist;Secure;Techniques;Testing;Tetrazolium Salts;Therapeutic Intervention;Time;Tissue Model;Tissues;Training;Tumor-Derived;Universities;Work;World Health Organization;Writing;Xenograft procedure;alpha ketoglutarate;career;chemotherapy;clinically relevant;clinically significant;dichlorofluorescin;expectation;glioma cell line;improved;inhibition of autophagy;isocitrate;meetings;monodansylcadaverine;mutant;neuro-oncology;novel;outcome forecast;oxidative damage;phosphatidylethanolamine;professor;prognostic;research study;response;success;tumor

public_health_relevance:
This research explores why mutant isocitrate dehydrogenase 1 an abnormal enzyme found in many brain tumors is such a powerful marker of longer patient survival. Discovering why this is so will help find new ways to treat these incurable tumors.      The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.


application_id: 8319328
project_number: 5R21EY021584-02
project_title: 14-3-3?? and epithelial differentiation in the eye and other tissues
administering_ic: NEI
award_notice_date: 2012-08-08
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: EY
serial_number: 021584
program_official: MCKIE, GEORGE ANN
project_start_date: 2011-09-01
project_end_date: 2013-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
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): Epithelial differentiation has been widely studied and the process can be divided into two general steps: generation of proliferating progenitors from resident stem cells and the subsequent arrest and differentiation of these progenitors. Oscillation of the transcription factor TCF3 between activator and repressor is key to both maintaining a resident stem cell population and generating pulses of progenitor cells for these stem cells. These progenitors proliferate to fill the tissue field and then the Notch pathway triggers their cell cycle arrest and differentiation. Accordingly when Notch1 is mutated progenitors in the cornea meibomian gland and hair follicles fail to differentiate and they proliferate beyond the tissue fields leading to pathologic loss of function. The timing of Notch1 signal initiation in proliferating progenitors is critical to define the precise number of cells and thus tissue topology. Insight into to how Notch1 signaling is initiated in this process is only now emerging. Epithelial tissue fields are established by cell-cell contact inhibition as proliferating progenitors come in contact. Mutations in cell contact inhibition signaling lead to progenitor outgrowth beyond normal tissue fields (as with Notch1 mutation) loss of tissue function and ultimately cancer. But how might onset of Notch1 signaling be linked to such cell-cell contact? Cadherin-initiated junctional complexes not only mediate apical polarity in epithelial cells they also initiate a kinase cascade known as Hippo which phosphorylates a set of transcription factors that regulate both the cell cycle as well as differentiation programs. This phosphorylation provides a binding site for 14-3-3 which in turn sequesters the factors in an inactive form in the cytoplasm. Recent results demonstrate that mutations in components of the cell contact inhibition kinase cascade lead to loss of Notch 1 activity and likewise we have found that mutation of 14-3-3s in this pathway also leads to loss of Notch1 expression. Taken together such results imply that as progenitors expand in tissues their eventual cell contact signals 14-3-3s -dependent expression of Notch1 thereby signaling arrest and differentiation. In support of this hypothesis we have found that mutation of 14-3-3s in mice leads to accumulation of proliferating progenitor cells and a phenotype indistinguishable from that of Notch 1 in the cornea hair follicle and ductal structures such as those in the meibomian gland. This loss of 14-3-3s or Notch1 causes severe corneal defects ductal obstruction leading to loss of terminal ascini and abnormal hair follicles leading to hair loss. Importantly we demonstrate that expression of activated Notch1 rescues the differentiation defect in 14-3-3s mutant epithelial progenitors in culture. Here we propose a series of studies designed to further establish linkage between 14-3-3s and the Notch1 pathway in epithelial differentiation in the cornea meibomian gland and hair follicles and to development mouse model systems which can be used as a basis for a future R01 proposal examining the molecular details of the pathway through which 14-3-3s and Notch1 regulate the onset of epithelial differentiation.

project_terms:
Anterior;Apical;Binding Sites;Biological Models;Cadherins;Cell Count;Cell Cycle;Cell Cycle Arrest;Cell Cycle Regulation;Cell Differentiation process;Cells;Cellular Structures;Complex;Contact Inhibition;Cornea;Corneal Diseases;Corneal Intraepithelial Neoplasia;Cyclin E;Cytoplasm;Defect;Detection;Development;Ductal;Epithelial;Epithelial Cells;Epithelium;Eye;Eye Part;Future;Gene Expression;Generations;Genes;Genetic;Hair;Hair follicle structure;Histocompatibility Testing;Homeostasis;Individual;Intestines;Lead;Link;Malignant Neoplasms;Mediating;Microarray Analysis;Molecular;Mus;Mutate;Mutation;Normal tissue morphology;Obstruction;Pathologic;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Physiologic pulse;Process;Proliferating;Regulation;Research Design;Role;Series;Signal Pathway;Signal Transduction;Skin;Squamous cell carcinoma;Stem cells;Structure;TCF3 gene;Time;Tissues;Transcription Coactivator;Transgenes;Vision;base;blind;corneal epithelium;in vivo;insight;loss of function;meibomian gland;mouse model;mutant;notch protein;prevent;progenitor;programs;research study;stem cell population;transcription factor

public_health_relevance:
The integrity of the cornea the most anterior part of the eye is indispensable for vision as evident by the facts that more than forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of the loss of corneal transparency. Our proposed experiments aim to uncover the essential role of 14-3-3s and the signaling network in controlling the corneal epithelial homeostasis. Our studies will elucidate the molecular mechanism underlying the corneal disease development such as corneal intraepithelial neoplasia and squamous cell carcinoma; and provide new strategies for detection and treatment.


application_id: 8318954
project_number: 3R01EY016155-05S1
project_title: Signal Transfer in the Tectothalamic Pathway
administering_ic: NEI
award_notice_date: 2011-09-05
application_type: 3
activity_code: R01
ic: EY
serial_number: 016155
suffix: S1
program_official: STEINMETZ, MICHAEL A
project_start_date: 2007-09-01
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(02)M]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: PETRY, HEYWOOD M
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 the applicant): Parallel visual pathways from the retina to the cortex via the lateral geniculate nucleus (LGN) or via the superior colliculus (SC) and pulvinar nucleus likely serve distinct functions in the coding of form movement and spatial location signals. In the LGN further segregations of anatomically and physiologically distinct visual pathways have been identified and extensively characterized. Likewise studies in a variety of species have noted the existence of multiple pathways from the SC to the thalamus although these pathways are largely uncharacterized and their functions remain unknown. The tree shrew with its expanded tectopulvinar system is an ideal species to begin to understand how pathways from the SC influence cortical activity via their projections to the pulvinar nucleus. Previous studies characterized two distinct zones in the tree shrew pulvinar nucleus a dorsal region (Pd) which receives diffuse convergent input from the SC and projects to the posterior temporal cortex (Tp) and a central region (Pc) which receives specific topographic projections from the SC and projects to the dorsal temporal cortex (Td). We propose to test the idea that separate tectopulvino- cortical pathways are organized to code distinct features of visual movement. To examine this hypothesis we will 1) use in vivo extracellular recordings to compare the activity of Pd and Pc neurons during the presentation a variety of computer generated stimuli designed to test responses to simple and complex visual motion 2) use in vitro whole cell recordings to compare the membrane properties of Pc and Pc neurons and their responses to stimulation of the SC 3) use tract tracing immunocytochemistry and electron microscopy to anatomically characterize the connections between the Pd and Pc and temporal cortex and 4) use in vivo intrinsic optical imaging to examine temporal cortex response pattern changes following deactivation of the SC Pd or Pc. Given the similarities between the tree shrew and primate visual pathways the results should further our understanding of human motion processing particularly within the tectopulvinar pathway and cortical area MT. Therefore the proposed studies should provide information relevant to the treatment of disorders of motion processing such as dyslexia schizophrenia autism and Williams Syndrome. The proposed studies may also provide insight into "blindsight" the ability of some patients to detect visual motion in the absence of visual perception.

project_terms:
Autistic Disorder;Axon;Cell Nucleus;Cells;Code;Complex;Diffuse;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Excitatory Postsynaptic Potentials;Frequencies (time pattern);GABA Agonists;Human;Image;In Vitro;Injection of therapeutic agent;Label;Lateral Geniculate Body;Light;Location;Mediating;Membrane;Methods;Microelectrodes;Microscopic;Motion;Movement;Neurons;Pathway interactions;Patients;Pattern;Physiology;Preparation;Primates;Process;Property;Pulvinar structure;Research Personnel;Retina;Schizophrenia;Signal Transduction;Slice;Speed (motion);Stimulus;System;Techniques;Tectum Mesencephali;Temporal Lobe;Testing;Thalamic structure;Tracer;Trees;Tupaiidae;Visual;Visual Motion;Visual Pathways;Visual Perception;Whole-Cell Recordings;Williams Syndrome;area MT;computer generated;design;extracellular;immunocytochemistry;in vivo;insight;optic imaging;programs;receptive field;response;segregation;superior colliculus Corpora quadrigemina;visual stimulus


application_id: 8318674
project_number: 5R01AG034605-04
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2012-08-01
opportunity_number: RFA-AG-09-010
application_type: 5
activity_code: R01
ic: AG
serial_number: 034605
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: ZAG1-ZIJ-5(M2)
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 application proposes to address a fundamental unresolved question in the field of cognitive aging the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased 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 correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices concomitant Ca2+ imaging in recorded neurons extensive immunohistochemistry with a battery of stains diffusion tensor imaging (MRI/DTI) separate microarray analysis of each individual rat and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral electrophysiological microarray and immunohistochemical analyses to test the proposition that conversion to UCA has been slowed and if it has to determine through which hippocampal pathways this occurred. Overall these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA and should importantly determine the role of myelinogenic programs in cognitive aging. Further the proposed longitudinal studies should have direct translational relevance.  PUBLIC HEALTH RELEVANCE: This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

project_terms:
Address;Age;Age-Months;Aging;Anemia;Animal Feed;Animal Model;Animals;Astrocytes;Behavioral;Binding (Molecular Function);Bioenergetics;Bioinformatics;Brain;Cholesterol;Cognition;Cognitive;Cognitive aging;Corpus Callosum;Cuprizone;Data;Diet;Dietary Iron;Diffusion Magnetic Resonance Imaging;Elderly;Electrophysiology (science);Event;Exhibits;Fostering;Gene Expression;Genes;Genomics;Guanosine Triphosphate Phosphohydrolases;Health;Hemochromatosis;Hippocampus (Brain);Human;Image;Immune;Immunohistochemistry;Impaired cognition;Individual;Inflammation;Inflammatory;Intake;Intervention;Investigation;Iron;Left;Link;Lipids;Liver;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Memory;Methods;Microarray Analysis;Modeling;Monkeys;Myelin;Nature;Neurites;Neurobiology;Neurons;Oligodendroglia;Oxidative Stress;Pathway interactions;Performance;Phase;Play;Process;Protocols documentation;Rattus;Regulation;Research;Resources;Role;Sampling;Serum;Signal Transduction;Slice;Staining method;Stains;Stimulus;Structure;Techniques;Testing;Therapeutic;Translating;Up-Regulation (Physiology);Validation;Work;age related;aged;aging brain;base;behavior test;biological adaptation to stress;biomarker;cognitive function;density;indexing;insight;interest;iron deficiency;middle age;morris water maze;multidisciplinary;myelination;programs;protein degradation;response;trafficking;young adult

public_health_relevance:
This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.


application_id: 8318099
project_number: 5R21CA139359-02
project_title: Mechanisms of Wnt/beta-catenin inhibition by resveratrol and its derivatives
administering_ic: NCI
award_notice_date: 2012-09-10
opportunity_number: PA-10-088
application_type: 5
activity_code: R21
ic: CA
serial_number: 139359
program_official: KIM, YOUNG S
project_start_date: 2011-08-10
project_end_date: 2014-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This is a revised application in response to PA-10-088 "Exploratory Cancer Prevention Studies Involving Molecular Targets for Bioactive Food Components (R21)". In this project we will characterize a novel molecular target of resveratrol for colorectal cancer prevention. Colorectal cancer is the second leading cause of cancer-related mortality in the United States and accounts for more than 56000 deaths per year. Colorectal cancer is initiated by mutations of adenomatous polyposis coli (APC) and 2-catenin genes which result in abnormal activation of Wnt signaling. Inhibition Wnt signaling is essential for colorectal cancer chemoprevention. Resveratrol is found in the skin of red grape and also present in the red wine. Resveratrol and many of its analogs have anti-cancer activity. We found several resveratrol analogs including pterostilbene found in blueberry can strongly inhibit Wnt signaling while cis-resveratrol cannot. We have designed and synthesized a panel of novel resveratrol analogs and have identified several novel inhibitors for Wnt/2-catenin signaling. Our central hypothesis is that resveratrol and its analogs inhibit Wnt signaling thus prevent of 2-catenin-induced cancers particularly colorectal cancers. To further understand the molecular mechanisms of resveratrol in Wnt/2-catenin inhibition and to develop better inhibitors for chemoprevention we will pursue the following two specific aims: 1) to delineate the mechanisms of how resveratrol inhibits Wnt signaling using cell models; and 2) to investigate how resveratrol and its analogs inhibits Wnt signaling using a novel inflammation-related mouse colon cancer model.

project_terms:
APC gene;Accounting;Adenomatous Polyposis Coli;Biological Factors;Biometry;Blueberries;CTNNB1 gene;Cancer Center;Cancer Etiology;Cancer Model;Cell Proliferation;Cell model;Cessation of life;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Research;Colitis;Colon;Colon Carcinoma;Colorectal Cancer;Dimethylhydrazines;Exhibits;Future;Genes;Goals;Grapes;Growth;Hand;In Vitro;Inflammation;Interdisciplinary Study;Lead;Malignant Neoplasms;Modeling;Modification;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;New Agents;Nude Mice;Pathology;Pathway interactions;Pharmaceutical Preparations;Physicians;Plants;Proteomics;Publications;Research;Resveratrol;Signal Transduction;Skin;Staging;Stilbenes;Testing;Toxic effect;United States;Universities;Work;Xenograft procedure;adenoma;analog;base;beta catenin;bioactive food component;cancer cell;cancer chemoprevention;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;in vivo;inhibitor/antagonist;insight;mouse model;novel;phytoalexin;phytoalexins;prevent;red wine;response;trans-resveratrol;tumor;tumor growth

public_health_relevance:
Colorectal cancer is the second leading cause of cancer death in the United States. This project is to explore a novel mechanism of cancer prevention by resveratrol a product from red grapes. We found that resveratrol blocks Wnt signaling a key pathway in colon cancer formation. The studies in this project will provide a better understanding of resveratrol function in cancer prevention and will lead to better chemoprevention agents in the future.


application_id: 8317644
project_number: 8P20GM103527-05
project_title: Center of Research in Obesity and Cardiovascular Disease (1P20 RR021954-01A1)
administering_ic: NIGMS
award_notice_date: 2012-07-02
opportunity_number: PAR-07-229
application_type: 8
activity_code: P20
ic: GM
serial_number: 103527
program_official: LIU, YANPING
project_start_date: 2008-09-08
project_end_date: 2013-09-14
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_abstract:
The objective of this revised application is to create a Center of Biomedical Research Excellence in Obesity and Cardiovascular Disease (COCVD) to identify mechanisms linking the epidemic of obesity to the high incidence of cardiovascular diseases in the obese population and to use this focus as a platform to develop promising junior investigators and enhance their success at competing for NIH grant support. We will achieve this objective by (1) assembling a group of established extramurally-funded scientists who will mentor faculty serving as principal investigators on research projects that address timely and significant questions related to obesity and cardiovascular disease (2) providing a variety of mentoring approaches that will facilitate the development of research projects by investigators leading to independent NIH-funded research (3) developing and supporting shared use core facilities that support and extend research methods critical to the study of obesity and cardiovascular disease (4) providing pilot grants for new projects focused on obesity and cardiovascular diseases (5) facilitating symposia seminars and meetings of participants researching obesity and cardiovascular diseases (6) focusing on the research of the center at retreats dedicated to evaluating progress by investigators studying obesity and cardiovascular diseases (7) strategically hiring promising new faculty to develop a critical mass of productive physician and basic scientists studying obesity and cardiovascular diseases. Five investigators representing both physician and basic scientists will serve as principal investigators on research projects that address a central hypothesis and that utilize a common model of diet-induced obesity to study obesity-induced hypertension atherosclerosis and platelet dysfunction/vascular inflammation. The central hypothesis of this revised proposal is that obesity induces changes in the production and release of adiopkines and other inflammatory mediators to promote cardiovascular diseases. Each project addresses aspects of this hypothesis using a common model of diet-induced obesity and the projects synergize through their focus on adipokines inflammation and through coordinate development of multiple cardiovascular diseases. The proposed structure and mentoring mechanisms will meet the need of increasing NIH funded research and will develop a multi-disciplinary Center around the clinically significant area of obesity and cardiovascular disease.

project_terms:
Address;Area;Atherosclerosis;Blood Platelets;Cardiovascular Diseases;Centers of Research Excellence;Core Facility;Development;Diet;Epidemic;Faculty;Functional disorder;Funding;Grant;Hypertension;Incidence;Individual;Inflammation;Inflammation Mediators;Kentucky;Link;Mentors;Methods;Modeling;Obesity;Obesity associated disease;Participant;Physicians;Pilot Projects;Principal Investigator;Production;Program Research Project Grants;Publications;Research;Research Methodology;Research Personnel;Research Project Grants;Resources;Scientist;Structure;Training Support;United States National Institutes of Health;Universities;adipokines;clinically significant;interest;meetings;member;programs;research and development;success;symposium;vascular inflammation


application_id: 8317628
project_number: 5R01HD064993-04
project_title: Aging of Frontal Structure and Function in Down Syndrome and Dementia
administering_ic: NICHD
award_notice_date: 2012-07-30
opportunity_number: RFA-HD-09-028
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: OSTER-GRANITE, MARY LOU
project_start_date: 2009-09-30
project_end_date: 2014-08-31
study_section: ZHD1-MRG-C(28)
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractDown syndrome (DS) is the major cause of intellectual disability in humans and it is estimatedthere are over 300000 individuals with this genetic disorder in the United States. Virtually all DSindividuals have sufficient neuropathology for a diagnosis of AD in their 40th year. Howeverdementia may not develop until up to a decade later and some people remain cognitively intact.Thus we seek to follow a group of adults ranging in age from 20-40 years over a 5 year periodof time to identify age and dementia-associated changes in cognition and in particular focus onfrontal lobe function. Our aims are four-fold. Aim 1 will cognitively characterize a cohort ofadults with DS and follow individuals for a period of 5 years. Aim 2 will use magnetic resonanceimaging to measure white matter integrity on an annual basis in longitudinally followed people.Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changesto identify biomarkers of AD development and that are also correlated with cognition. Aim 4 willstudy archived and new autopsy brain samples from DS adults to identify molecular pathwaysthat change prior and during AD development. The outcomes of the proposed studies willcontribute to the development of noninvasive biomarkers that will assist in early AD diagnosis inDS and monitor disease progression. Further novel biomarkers that are mechanistically relatedto aging AD neuropathology and dementia will also provide outcomes for the design of futuretherapeutic clinical trials to treat or prevent dementia in DS.

project_terms:
Accounting;Activities of Daily Living;Adult;Affect;Age;Age of Onset;Age-Years;Aging;Alzheimer's Disease;Anisotropy;Archives;Autopsy;Biological Assay;Blood;Brain;Caring;Categories;Cell Adhesion Molecules;Chromosomes Human Pair 21;Clinical;Cognition;Cognitive;Color;Data;Dementia;Development;Diagnosis;Diffusion Magnetic Resonance Imaging;Digit structure;Disease;Disease Progression;Dissociation;Down Syndrome;Elements;Event;Evolution;Fiber;Functional disorder;Future;Genes;Growth Factor;Hereditary Disease;Human;Image;Impaired cognition;Impairment;Individual;Intellectual functioning disability;International;Intervention;Intervention Studies;Lead;Link;London;Magnetic Resonance Imaging;Measures;Medial;Memory impairment;Methods;Modeling;Molecular;Monitor;Myelin;Neurobiology;Neurofibrillary Tangles;Oligodendroglia;Outcome;Parietal Lobe;Pathogenesis;Pathology;Pathway interactions;Pattern;Performance;Persons;Phase;Plasma;Plasma Proteins;Prevalence;Process;Proteins;Quality of life;Raven;Reaction Time;Receptor Signaling;Risk;Sampling;Scanning;Senile Plaques;Short-Term Memory;Signaling Protein;Sorting - Cell Movement;Structure;Testing;Therapeutic;Therapeutic Clinical Trial;Time;United States;Vaccination;abstracting;age related;aging brain;base;biomarker;chemokine;cognitive function;cohort;cytokine;design;disease diagnosis;early onset;executive function;frontal lobe;frontal lobe function;functional decline;high risk;improved;in vivo;indexing;inhibitor/antagonist;insight;interdisciplinary approach;middle age;nervous system disorder;neuropathology;novel;novel therapeutics;overexpression;prevent;secretase;skills;therapeutic development;tool;visual search;white matter;white matter change

public_health_relevance:
Project NarrativeThe proposed study will identify new ways in which to detect Alzheimer disease (AD) in adultswith Down syndrome (DS) by monitoring changes in cognitive function measuring brainchanges by magnetic resonance imaging and profiling patterns of proteins in the plasma. Inparallel autopsy studies of brain samples will help us to understand how noninvasive cognitiveimaging and blood measures reflect the development of AD in DS. Treatments for AD in DS willbe more effective if the disease is detected early and identifying biomarkers will greatly facilitatethe development of therapeutics.


application_id: 8317500
project_number: 261201000031C-4-0-2
project_title: TAS::75 0849::TAS SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PROGRAM
administering_ic: NCI
project_start_date: 2011-09-30
project_end_date: 2012-09-29
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program was established by the National Cancer Institute (NCI) to collect and report periodically on population-based cancer incidence and survival data. It is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. Objectives of the SEER Program include:  1. Assemble and report on a periodic basis estimates of cancer incidence. 2. Monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. Provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival.  4. Identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy.  5. Serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as issues related to the operation of the SEER Program which may lead to improved and/or more cost-effective operating procedures.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Breast;Cancer Patient;Characteristics;Colorectal;Communities;Comorbidity;Data;Diagnostic tests;Division of Cancer Control and Population Sciences;Early treatment;Educational process of instructing;Ethnicity aspects;Geographic Locations;Hospitals;Laws;Link;Malignant Neoplasms;Medical Surveillance;Medicare;National Cancer Institute;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Pattern;Patterns of Care;Physicians;Race;Radiation therapy;Reporting;SEER Program;Staging;Time;United States;Work;biomarker;cancer diagnosis;cancer therapy;chemotherapy;clinical practice;hormone therapy


application_id: 8316612
project_number: 1F31AA020767-01A1
project_title: Sexual Assault Personality and Problem Drinking in College Women
administering_ic: NIAAA
award_notice_date: 2012-08-30
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: AA
serial_number: 020767
suffix: A1
program_official: FREEMAN, ROBERT
project_start_date: 2012-09-09
project_end_date: 2014-09-08
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 10747927
contact_pi: ROHR, JESSICA COMBS
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
project_abstract:
DESCRIPTION (provided by applicant): I propose to address the significant impact that sexual assault has on the mental health of college-aged women integrating personality factors and trauma to predict maladaptive behavioral consequences. One important and unexplained phenomenon is that some women respond to the trauma of sexual assault with symptoms of externalizing disorders most notably heavy alcohol consumption but others respond to the trauma with increases in internalizing dysfunction such as major depression and generalized anxiety disorder (Kilpatrick et al. 2003; Ullman & Nadjowski 2009a). It is crucial to identify which women are likely to respond to the trauma in which way given that (a) heavy alcohol consumption is associated with many problems including increased risk of re-victimization (Ullman & Nadjowski 2009b); and (b) there are different empiricallysupported treatments for the two different kinds of dysfunction (Hayes et al. 1999; Linehan 1993; Zapolski et al. 2010). The intent of the proposed research is to test this theoretical model: Women with elevations in personality traits that dispose them to engage in rash action when distressed (i.e. the trait of negative urgency) are more likely than other traumatized women to respond to the trauma with increases in rash actions such as heavy drinking. In contrast women with elevations in personality traits that dispose them to internalizing dysfunction are more likely than other traumatized women to respond to the trauma with increased symptoms of depression and anxiety but they are less likely to engage in increased heavy drinking. To date there are no longitudinal studies that measure personality functioning prior to sexual assault victimization and
investigate personality-based prediction of different forms of post-trauma distress. The proposed study fills this important gap in the literature. I will assess the personality functioning drinkig behavior and sexual trauma histories of 1000 women prior to their first year of college and then again at the end of their first semester and then at the end of their first year in school. Pror research at my university suggests that approximately 17% of these women will experience sexual assault during their first year in college (Wilcox et al. 2007). Using a three-wave   
longitudinal design I will conduct several regression equations using difference scores as dependent variable. In the first the interaction of negative urgency with sexual assault will predict increased problem drinking across the first year of college and that effect will be above and beyond the effect of initial problem drinking and initial trait depression. In the second the interaction of personality traits that dispose individuals to internalizing dysfunction with victimization will predict increased depression and anxiety across the first year above and beyond initial depression and anxiety and initial negative urgency. I will also test whether sexual assault is associated with increases in traits within the Neuroticism domain across the first year of college. A successful model test will guide clinical researchers to apply different interventions to different assault victims based on their personality characteristics.

project_terms:
Address;Admission activity;Alcohol abuse;Alcohol consumption;Alcohols;Anxiety;Behavior;Behavioral;Binge Eating;Characteristics;Clinical;Development;Disease;Distress;Drug usage;Eating Behavior;Equation;Exanthema;Female;Functional disorder;Generalized Anxiety Disorder;Heavy Drinking;Individual;Intervention;Kentucky;Lead;Literature;Longitudinal Studies;Major Depressive Disorder;Measures;Mental Depression;Mental Health;Modeling;Moods;Neurotic Disorders;Outcome;Pathology;Pathway interactions;Personality;Personality Traits;Play;Process;Recording of previous events;Reporting;Research;Research Personnel;Research Proposals;Risk;Role;Schools;Specific qualifier value;Students;Symptoms;Testing;Theoretical model;Time;Trauma;Universities;Victimization;Woman;aged;assault;base;college;depressive symptoms;drinking;drinking behavior;effective intervention;experience;falls;high risk sexual behavior;longitudinal design;response;service intervention;sexual assault;sexual trauma;theories;trait

public_health_relevance:
For some women the experience of being sexually assaulted leads to increases in problem drinking behavior which is associated with many problems including increased risk for re-victimization. At present researchers are unable to predict which women will respond to the trauma in that way; as a result clinicians lack the capacity to identify which sexual assault victims would benefit most from alcohol-related interventions. The proposed research will test a model specifying premorbid personality characteristics that are proposed to interact with victimization to lead to problem drinking; a successful model test will enable clinicians to identify those women most likely to respond to their trauma with problem drinking behavior and thus permit the timely implementation of appropriate intervention services.


application_id: 8316321
project_number: 5U24HL094373-03
project_title: Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies
administering_ic: NHLBI
award_notice_date: 2012-07-31
application_type: 5
activity_code: U24
ic: HL
serial_number: 094373
program_official: EVANS, FRANK
project_start_date: 2010-08-01
project_end_date: 2015-07-31
study_section: ZHL1-CSR-H(O1)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-08-01
project_abstract:
DESCRIPTION (provided by applicant):     Ischemic heart disease causes -600000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately due to methodological problems this enormous investment has not produced any notable clinical application and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded randomized and adequately powered studies using a rigorous design full dose-response analyses optimal statistical methods independent data analysis and statistical Cores histology plasma biomarkers and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse rabbit pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry) thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and thus most likely to be effective in patients the consortium will dramatically advance our ability to rationally translate basic findings into clinical use.     This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large namely the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct reducing infarct size will have a major impact on their morbidity and mortality and thus enormous implications for public health. (End of Abstract)

project_terms:
Academia;Acute myocardial infarction;Address;American;Americas;Animal Model;Basic Science;Blast Cell;Blinded;Carbon Monoxide;Cause of Death;Cessation of life;Clinical;Clinical Trials;Clinical Trials Network;Communities;Comorbidity;Conscious;Doctor of Medicine;Dose;Educational workshop;Electronic Mail;Ensure;Evaluation;Experimental Models;Failure (biologic function);Family suidae;Funding;Future;Goals;Healthcare;Histology;Individual;Industry;Infarction;Institution;Intervention;Investments;Ischemic Preconditioning;Journals;Laboratories;Letters;Logistics;Mind;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial tissue;National Heart Lung and Blood Institute;Oryctolagus cuniculus;Participant;Patients;Phase;Plasma;Pre-Clinical Model;Probability;Protocols documentation;Publishing;Randomized;Recommendation;Reperfusion Therapy;Reporting;Reproducibility;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Review Committee;Role;Screening procedure;Sodium Nitrite;Statistical Data Interpretation;Statistical Methods;Structure;System;Testing;Therapeutic Intervention;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Work;abstracting;biomarker;clinical application;design;disability;interest;meetings;member;myocardial infarct sizing;novel strategies;operation;outcome forecast;pre-clinical;pre-clinical research;preclinical evaluation;preclinical study;programs;public health medicine (field);research study;response;sildenafil;success;web site;working group


application_id: 8316114
project_number: 5K08EY021757-02
project_title: Endothelial Cell Dysregulation in Neovascular AMD
administering_ic: NEI
award_notice_date: 2012-08-16
opportunity_number: PA-10-059
application_type: 5
activity_code: K08
ic: EY
serial_number: 021757
program_official: AGARWAL, NEERAJ
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: ZEY1-VSN(11)
contact_pi_person_id: 8784086
contact_pi: KLEINMAN, MARK E
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_terms:
Ablation;Accounting;Advisory Committees;Affect;Age related macular degeneration;Aging;American;Animal Model;Architecture;Area;Automobile Driving;Award;Basic Science;Biological;Biology;Biomedical Research;Blindness;Blood;Blood Vessels;Bone Marrow Transplantation;Cell Line;Cells;Chairperson;Choroidal Neovascularization;Chromatin Remodeling Factor;Clinical;Clinical Research;Complement Activation;Coupled;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Drusen;Dyes;Early Diagnosis;Early treatment;Endothelial Cells;Engineering;Environment;Experimental Designs;Exudative age-related macular degeneration;Eye;Faculty;Fellowship;Fluorescein Angiography;Funding;Future;Gene Expression Profile;Genetic;Goals;Grant;Growth;Human;Hypersensitivity;Image;Imaging Techniques;Immune;Immune system;Immunoglobulin Fragments;Immunologic Receptors;In Vitro;Inflammation;Interleukins;Invaded;Investigation;Journals;K-Series Research Career Programs;Kentucky;Knowledge;Laboratories;Lead;Legal;Legal Blindness;Lesion;Leukocytes;Ligands;Malignant Neoplasms;Maps;Mediating;Medicine;Mentors;Methods;Molecular;Molecular Profiling;Molecular Target;Mus;Nature;Nonexudative age-related macular degeneration;Ophthalmic examination and evaluation;Ophthalmology;Outcome;Oxidative Stress;Pathogenesis;Pathologic Processes;Pathway interactions;Patient Care;Patients;Pattern;Physicians;Positioning Attribute;Prevalence;Principal Investigator;Process;Progressive Disease;Quality of life;Regulation;Relative (related person);Reporting;Research;Research Personnel;Research Project Grants;Research Training;Retina;Retinal Diseases;Risk Factors;Role;Running;Safety;Scientist;Sensitivity and Specificity;Signal Pathway;Signal Transduction;Signaling Molecule;Specialist;Specimen;Staging;Structure of retinal pigment epithelium;Sum;Surface;Symptoms;Techniques;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxicology;Training;Training Programs;Transgenic Mice;Treatment Efficacy;Treatment Failure;United States;Universities;Uveal Melanoma;Vascular Diseases;Vascular Endothelial Growth Factor A;Vision;Visual;Work;allergic response;base;biomarker;career;career development;cell type;chemokine;chemokine receptor;cost;cytokine;cytotoxicity;design;disorder of macula of retina;experience;imaging probe;immune activation;improved;in vivo;insight;molecular marker;mouse model;nanocrystal;neutralizing antibody;next generation;normal aging;ocular angiogenesis;pre-clinical;prevent;professor;programs;research study;response;skills;small molecule;therapeutic development;therapeutic target;vision science


application_id: 8315740
project_number: 5R01CA138688-04
project_title: Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co
administering_ic: NCI
award_notice_date: 2012-04-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 138688
program_official: JOHNSON, RONALD L
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2378- tetrachlorodibenzo--dioxin (TCDD) have been closely correlated to MM by epidemiologic studies yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor guardian of the human genome. Genomic instability (chromosome translocation aneuploidy and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis reporter expression and immunoblotting analyses; second we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays; third we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA that is upregulated by dioxin will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis. PUBLIC HEALTH RELEVANCE: TP53 gene alterations are rare and late events in multiple myeloma (MM) the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.

project_terms:
101 Mouse;ARNT gene;Aneuploidy;Antisense RNA;Apoptosis;Apoptotic;Aromatic Hydrocarbons;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Binding Sites;Biological;Biological Assay;Biological Process;Bone Marrow;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cell Death;Cell Line;Cells;Cellular Assay;Cessation of life;Characteristics;Chromosomal translocation;Clinical;Code;Collaborations;Computing Methodologies;Cytoplasm;Development;Diagnosis;Diagnostic;Diagnostic Neoplasm Staging;Dioxins;Disease Progression;Double Minutes;Drug Delivery Systems;Elements;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epigenetic Process;Etiology;Event;Exposure to;FDA approved;Gene Expression;Gene Library;Gene Mutation;Gene Targeting;Genes;Genome;Genomic Instability;Hematologic Neoplasms;Human;Human Genome;Immunoblotting;Immunoglobulins;Incidence;Infiltration;Laboratories;Lead;Little's Disease;MDM2 Gene Amplification;Malignant Neoplasms;Mediating;Messenger RNA;Methods;MicroRNAs;Molecular;Molecular Profiling;Monitor;Multiple Myeloma;Mus;Mutagenesis;Mutate;Mutation;Neoplasms;Neoplastic Plasma Cell;Nucleotides;Oncogene Activation;Onset of illness;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Physiological;Plasma Cells;Process;Promotor (Genetics);Protein p53;Proteins;RNA;Regulation;Reporter;Reporting;Research;Role;Sampling;Signal Transduction;Small RNA;Specimen;TP53 gene;Testing;Therapeutic Intervention;Time;Tumor stage;Tumor-Suppressor Gene Inactivation;Universities;Untranslated RNA;Untranslated Regions;Viral Proteins;Wisconsin;antiangiogenesis therapy;base;biomarker;clinically significant;mutant;novel;overexpression;p14ARF Protein;prevent;prognostic;public health relevance;research study;response;stressor;tool;tumor;tumorigenesis;vector

public_health_relevance:
Project NarrativeTP53 gene alterations are rare and late events in multiple myeloma (MM) the second most commonhematological malignancy constituting about 1% of all human cancers. It is critical to explore whether thereare unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MMdevelopment. The proposed research plan is to test the hypothesis that TP53 is negatively regulated bymicroRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNAdysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxinmodulates p53 signaling through upregulating miRNA expression.


application_id: 8315726
project_number: 5U01CE001675-04
project_title: Green Dot across the Bluegrass: Evaluation of a primary prevention intervention t
administering_ic: NCIPC
award_notice_date: 2012-08-30
opportunity_number: RFA-CE-09-003
application_type: 5
activity_code: U01
ic: CE
serial_number: 001675
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: ZCE1-JXS(09)
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
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: 2012-09-01
project_abstract:
DESCRIPTION (provided by applicant):     Problem Statement: While rates of lifetime forced sexual intercourse have increased in Kentucky over the past five years among high school students Kentucky is working to reduce this trend. Through CDC assistance Kentucky Association of Sexual Assault Programs Inc. (KASAP) is ready to implement the "Green Dot" bystander intervention program for primary prevention of sexual violence (SV). Importance: We now have the unique and time-sensitive opportunity to evaluate a statewide bystander intervention which will be implemented by KASAP Educators across Kentucky through high schools beginning in 2010. Green Dot empowers students to actively question peer support for SV and become change agents who can play a significant role in ending SV. Innovation: While several bystander intervention programs have been implemented few been empirically evaluated and none have been evaluated on a statewide basis using the same intervention protocol. Purpose: To evaluate the statewide application of Green Dot among high schools students. We hypothesize that students in high schools with Green Dot will over time report lower rates of SV compared with students in comparable high schools randomized not to have Green Dot. This reduction in SV will be mediated through a reduction in social norms supporting SV and an increase in bystander behaviors. Specific Aims: To prospectively determine whether relative to students in high schools without Green Dot those in schools with Green Dot (Aim 1) report lower rates of SV (Aim 2) a greater frequency of bystander behaviors and (Aim 3) fewer social norms supporting SV. Finally because Green Dots draws on social diffusion of innovation theory we propose (Aim 4) to determine how Green Dot influences bystander behaviors in the first and second order social networks of students who do and do not receive Green Dot training. Methods: A population-based controlled intervention trial will be used to test the efficacy of Green Dot. Both panel and web-based cohort survey methods will be used to provide baseline and prospective data on student's attitudes supporting SV bystander behaviors and SV experiences. Setting: In each of the 13 KASAP regions 2 demographically comparable high schools with at least 200 students per grade will be recruited to participate in Green Dot either as the intervention or control site. Schools will be randomly assigned to the intervention. Study Population: All students in participating high schools will be invited to complete anonymous panel surveys beginning spring 2010 through 2014; we anticipate that 6500 students in Green Dot and 6500 in control schools will complete surveys each year. We estimate that 650 students receiving Green Dot training and 650 students not so trained will complete the web-surveys (2011-2014). External sources of data to document SV will be obtained from high schools. Implications for Prevention: This state-wide population-based multi-site controlled intervention trial will provide an empirical test of a promising intervention which if proven effective could result in the primary prevention of SV and a reduction in the health and academic consequences of SV.    PUBLIC HEALTH RELEVANCE:     Determining whether a promising primary prevention intervention to reduce sexual violence perpetration is effective in reducing violence in a real world setting (high schools across Kentucky) can result in an important opportunity to prevent the short and longer term health consequences of sexual violence. Sexual violence defined to include physically forced sexual activity coerced sexual activity and sexual harassment is common (~25%) has health and academic consequences and is preventable; thus this form of violence can be a high impact target for primary prevention efforts.

public_health_relevance:
Determining whether a promising primary prevention intervention to reduce sexual violenceperpetration is effective in reducing violence in a real world setting (high schools acrossKentucky) can result in an important opportunity to prevent the short and longer term healthconsequences of sexual violence. Sexual violence defined to include physically forced sexualactivity coerced sexual activity and sexual harassment is common (~25%) has health andacademic consequences and is preventable; thus this form of violence can be a high impacttarget for primary prevention efforts.


application_id: 8315000
project_number: 1F31DA033728-01
project_title: Individual Differences in Escalation of Tobacco Use: Impulsivity and Alcohol Use
administering_ic: NIDA
award_notice_date: 2012-04-02
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: DA
serial_number: 033728
program_official: BJORK, JAMES M
project_start_date: 2012-04-22
project_end_date: 2014-04-21
study_section: Special Emphasis Panel[ZRG1 F16-B (20)]
contact_pi_person_id: 11038716
contact_pi: LEE, DUSTIN CLARK
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): Like adolescents young adults are at risk of initiating tobacco use and escalating to daily use and tobacco dependence. However not every young adult who uses cigarettes intermittently becomes tobacco dependent and the time-course of those who transition to daily use varies widely. Individual differences likely contribute to the variability observed in patterns of tobacco use. This project will use a multi-modal research approach to examine dimensions of impulsivity and characteristics of alcohol that are associated with vulnerability for escalation of cigarette smoking and how alcohol interacts with behavioral inhibition to increase cigarette consumption. Furthermore this project will support the
applicant's career goal of becoming an independent investigator in the field of behavioral pharmacology capable of identifying and understanding risk factors associated with vulnerability to drug use and dependence. Impulsivity is a multidimensional construct that can be assessed using trait measures and tasks of behavioral inhibition and it is likely that these assessments inform drug use vulnerability. Dimensions of impulsivity are differentially associated with tobacco
initiation escalation and dependence. Moreover behavioral inhibition is altered as a consequence of acute and chronic drug exposure. Alcohol is also closely associated with vulnerability to escalating tobacco use and acute alcohol exposure is associated with decrements in behavioral inhibition. Thus it is likely that impulsivity and alcohol use have separate and combined influences on vulnerability to tobacco use. The first study will utilize data
from a longitudinal study to identify trajectories of tobacco use in young adults in order to determine 1) which dimensions of impulsivity and alcohol use inform vulnerability to escalating tobacco use and 2) if measures of behavioral inhibition are altered as a consequence of escalating cigarette use. The second study will utilize a laboratory design to examine whether alcohol-induced impairments in behavioral inhibition mediate the relationship between acute alcohol administration and increases in ad-libitum cigarette consumption. Results from these studies will improve scientific knowledge by elucidating the relationship between individual differences in both impulsivity and characteristics of alcohol use and escalation of cigarette smoking and identifying the mechanism(s) responsible for alcohol-induced escalation of tobacco use. This knowledge will help inform screening and prevention efforts aimed at reducing the amount of young adults who escalate to daily smoking.

project_terms:
Acute;Adolescent;Alcohol consumption;Alcohols;Behavior;Behavioral;Behavioral inhibition;Cessation of life;Characteristics;Chronic;Cigarette;Cigarette Smoker;Consumption;Cues;Data;Dependence;Development;Dimensions;Drug Addiction;Drug Exposure;Drug usage;Early treatment;Goals;Impairment;Impulsivity;Individual Differences;Knowledge;Laboratories;Longitudinal Studies;Measures;Mediating;Modeling;Monitor;Non-smoker;Patient Self-Report;Pattern;Personality;Placebos;Population;Prevalence;Prevention;Preventive Intervention;Relative (related person);Reporting;Research;Research Personnel;Risk;Risk Factors;Screening procedure;Self Administration;Smoker;Smoking;Smoking Behavior;Time;Tobacco;Tobacco Dependence;Tobacco smoking;Tobacco use;United States;alcohol effect;alcohol exposure;base;behavior measurement;behavioral pharmacology;career;cigarette smoking;design;improved;non-smoking;public health research;trait;university student;young adult

public_health_relevance:
Young adults are at risk for escalating patterns of tobacco use and individual differences in impulsivity and alcohol use likely are associated with vulnerability of smoking escalation. This multi-modal project will examine dimensions of impulsivity and characteristics of alcohol use to determine which factors alone or in combination are associated with the escalation of tobacco smoking and how alcohol interacts with behavioral inhibition to increase cigarette consumption. This research will help inform screening treatment and prevention efforts aimed at reducing the number of young adults who become daily smokers.


application_id: 8314487
project_number: 1R43HL114235-01
project_title: A NEW TECHNIQUE FOR TREATING HEMORRHAGIC SHOCK
administering_ic: NHLBI
award_notice_date: 2012-04-19
opportunity_number: PA-10-122
application_type: 1
activity_code: R43
ic: HL
serial_number: 114235
program_official: PUCIE, SUSAN
project_start_date: 2012-04-19
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1 SBIB-V (12)]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The specific aims of this proposal are to use a newly developed intracellular energy delivery technique to enhance resuscitation and to study the relationship between tissue high-energy phosphate supplementation and tissue necrosis and apoptosis during hemorrhagic shock.  In most western countries trauma/hemorrhage is the leading cause of death up to the age of 40. The most common consequence of severe trauma and hemorrhage is shock which is a hypovolemic condition in which oxygen delivery to the body is inadequate for the generation of the adenosine triphosphate (ATP) and adenosine diphosphate (ADP) necessary to maintain the function and structural integrity of tissues. Treatment strategies for shock have changed very little in the past half century and the incidence of mortality and morbidity remains very high. Depletion of high-energy phosphates during hemorrhagic shock was described decades ago and direct administration of free Mg-ATP was reported to increase tissue ATP concentrations tissue and mitochondrial Mg levels and cellular functions by some authors. However this approach is controversial not only because the protective effects cannot always be duplicated by other scientists but also because the half life of ATP is very short in the blood circulation-less than 40 seconds. Furthermore it i well known that highly charged molecules like ATP do not normally cross the cell membrane. We have developed a technique for intracellular Mg-ATP delivery (named ATP- vesicles or VitaSolTM). Preliminary results have indicated a very promising effect in several models of tissue hypoxia and ischemia including shock. Our hypothesis is that the replenishment of intracellular ATP levels alleviates or eliminates many of the detrimental effects caused by hemorrhagic shock thereby increasing survival time.  This Phase I proposal has two aims: 1) To establish the effect of VitaSolTM treatment on hemorrhagic shock; and 2) To investigate the relationship between tissue high- energy phosphate contents and necrosis and apoptosis during hemorrhagic shock and the effect of VitaSolTM treatment on these changes. These studies have not been performed in the past. The success of this project will likely provide a totally new therapeutic approach for treatment of severe trauma and shock. Further study of this new energy delivery technique may also benefit various clinical conditions such as coronary heart disease stroke spinal cord injury cardiopulmonary bypass organ transplant chronic wounds and many other conditions where ischemia is involved. The potential impact on medicine is high.   
   
PUBLIC HEALTH RELEVANCE: Trauma/hemorrhage is the leading cause of death up to the age of 40 in most western countries but no effective treatment has been developed and mortality remains very high. This proposal is to use our newly developed intracellular energy delivery technique to enhance resuscitation in hemorrhagic shock. The success of this project will likely have a major impact on medicine.

project_terms:
Adenosine Diphosphate;Adenosine Triphosphate;Age;Apoptosis;Blood Circulation;Blood Substitutes;Blood Transfusion;Brain Hypoxia-Ischemia;Cardiopulmonary Bypass;Cause of Death;Cell membrane;Cell physiology;Charge;Chronic;Clinical;Colloids;Coronary heart disease;Country;Generations;Half-Life;Hemorrhage;Hemorrhagic Shock;Hypovolemics;Incidence;Intervention;Ischemia;Medicine;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Names;Necrosis;Organ Transplantation;Outcome;Oxygen;Patients;Phase;Reporting;Resuscitation;Scientist;Shock;Solutions;Spinal cord injury;Supplementation;Techniques;Time;Tissue Model;Tissues;Trauma;Vesicle;base;crystalloid;effective therapy;inorganic phosphate;novel therapeutic intervention;protective effect;restoration;stroke;success;treatment strategy

public_health_relevance:
Trauma/hemorrhage is the leading cause of death up to the age of 40 in most western countries but no effective treatment has been developed and mortality remains very high. This proposal is to use our newly developed intracellular energy delivery technique to enhance resuscitation in hemorrhagic shock. The success of this project will likely have a major impact on medicine.


application_id: 8314246
project_number: 1R43HL110562-01A1
project_title: Development of Double Lumen Cannula for Percutaneous Right Heart Support
administering_ic: NHLBI
award_notice_date: 2012-08-31
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: HL
serial_number: 110562
suffix: A1
program_official: BALDWIN, TIM
project_start_date: 2012-09-05
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1 SBIB-V (12)]
contact_pi_person_id: 10756458
contact_pi: SIDOR, BILL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Left ventricular assist devices (LVADs) are increasingly applied to treat advanced heart failure demonstrating improvement of morbidity/mortality and quality of life. Right heart failure (RHF) affects up to 40% of LVAD patients and significantly contributes to their morbidity and mortality. One third of them require  right ventricular assist device (RVAD) which needs a second open chest procedure for installation and a third one for its removal. A percutaneous RVAD (pRVAD) is required to eliminate these two major surgeries. The current TandemHeartTM Cannula-based pRVAD requires two major venous cannulations and a high resistance long circuit resulting in restricted patient mobility and compromised blood flow affecting RVAD performance.  Our ultimate goal is to develop a single-site percutaneous RVAD (pRVAD) system that achieves full right heart support avoiding two additional open chest surgeries. The enabling technology will be a percutaneous double lumen cannula (DLC) that will drain venous blood from the right atrium (RA) and infuse blood directly into the pulmonary artery (PA). Our objective in this Phase I SBIR is to develop and fabricate a working prototype of a DLC assembly for pRVAD and to test prototype performance in adult sheep. We hypothesize that the pre-curved DLC coupled with any commercially available blood pump can be easily deployed in the right heart and the PA for percutaneous total right heart support reversing RHF.  The Specific Aim will be to develop a DLC Assembly for RVAD/OxyRVAD and to test our prototype pRVAD DLC for percutaneous deployment and 6h in vivo performance. In this SBIR I proposal we will design and fabricate a working prototype of a percutaneous DLC to assist RHF and design and fabricate a working prototype of the balloon guided introducer to facilitate DLC deployment. The DLC consists of main DLC body extension infusion cannula. The drainage lumen opens in the RA to drain total venous return from both the SVC and IVC while the infusion cannula extends from the main DLC membrane sleeve infusion lumen. The bench test measurements will include how well the introducer fits inside the infusion lumen/extension infusion cannula and in vitro DLC flow dynamic performance. The in vivo sheep experiments (n=5) are designed to test the DLC assembly for percutaneous insertion advancement and deployment and for in vivo hemodynamic performance. Upon this SBIR grant completion the commercialized DLC will provide pRVAD to RHF patients. This minimally invasive technology will lower the threshold of RVAD application and have significant impact on LVAD application in advanced heart failure by decreasing RHF associated mortality and mobility. pRVAD can also be applied to other RHF patients secondary to pulmonary hypertension right heart infarction induced carcinogenic shock and postcardiotomy. Furthermore addition of an artificial lung to the circuit will convert pRVAD to OxyRVAD for combined RHF and lung failure. Such wide application will benefit patients around the world as well as the American economy.   
   
PUBLIC HEALTH RELEVANCE: We are proposing to develop a double lumen cannula for percutaneous right ventricular assist device to bridge critical right heart failure patient to recovery transplantation and advance treatment.

project_terms:
Adult;Affect;Alloys;American;Animal Testing;Applications Grants;Area;Biomedical Engineering;Blood;Blood flow;Businesses;Cannulas;Cannulations;Carbon Dioxide;Cardiac;Cardiopulmonary;Catheters;Chest;Complex;Coupled;Development;Device or Instrument Development;Devices;Distal;Drainage procedure;Excision;Failure (biologic function);Gases;Goals;Grant;Heart;Heart failure;In Vitro;Infusion procedures;Kentucky;Label;Laboratory Animal Production and Facilities;Left;Liquid substance;Lung;Measurement;Medical Device;Membrane;Memory;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Myocardial Infarction;Operative Surgical Procedures;Outcome;Patients;Performance;Phase;Polyurethanes;Positioning Attribute;Procedures;Publications;Pulmonary Hypertension;Pulmonary artery structure;Pulmonary valve structure;Pump;Quality of life;Recovery;Research Support;Resistance;Right atrial structure;Secondary to;Shapes;Sheep;Shock;Site;Small Business Innovation Research Grant;Stainless Steel;Surgeon;System;Technology;Testing;Thoracic Surgical Procedures;Transplantation;Universities;Venous;Work;artificial lung;base;blood pump;commercialization;design;experience;hemodynamics;improved;in vivo;minimally invasive;multidisciplinary;pressure;prototype;research and development;research study;respiratory;ventricular assist device

public_health_relevance:
We are proposing to develop a double lumen cannula for percutaneous right ventricular assist device to bridge critical right heart failure patient to recovery transplantation and advance treatment.


