# projects

application_id: 7160750
project_number: 1P01HL080100-01A1
project_title: Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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: 2006-04-01
project_terms:
CD antigens;abdomen;alleles;angiotensin II;angiotensin receptor;aorta aneurysm;bone marrow transplantation;cardiovascular disorder epidemiology;cardiovascular disorder risk;gene expression;genetic polymorphism;genetically modified animals;hormone regulation /control mechanism;laboratory mouse;macrophage;monocyte;muscle cells;protein metabolism;receptor expression;tissue /cell culture;vascular smooth muscle


application_id: 7160748
project_number: 1P01HL080100-01A1
project_title: Androgen Regulation of Angiotensin Responses in Aneurysms
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
abdomen;androgens;angiotensin II;angiotensin receptor;aorta aneurysm;bone marrow;cardiovascular disorder risk;gender difference;genetic promoter element;hormone metabolism;hormone regulation /control mechanism;laboratory mouse;macrophage;male castration;mesenchyme;protein localization;receptor expression;testosterone;vascular smooth muscle


application_id: 7159343
project_number: 5R01NS045726-04
project_title: Calpain Inhibition Strategies for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2007-01-22
application_type: 5
activity_code: R01
ic: NS
serial_number: 045726
program_official: KLEITMAN, NAOMI
project_start_date: 2004-01-01
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-3(01)Q]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
DESCRIPTION (provided by applicant): Calcium-activated neutral proteases (calpains) are excessively activated soon after spinal cord injury (SCI) with elevated activity persisting for at least 24h postinjury. Calpain substrates include cytoskeletal proteins signaling proteins and cell life/death proteins. While calpains play normal roles in cell signaling and plasticity their over activation following SCI is strongly implicated in secondary neuron death axonal degeneration and oligodendrocyte death and demyelination. Calpain inhibition represents a rational and feasible therapeutic target for postinjury intervention following SCI. In previous studies postinjury administration of calpain inhibitors attenuated axonal damage and loss of neurofilament proteins but functional outcome was not examined and the magnitude of calpain inhibition was not measured. In some studies the inhibitors used were not cell permeable and in others the low inhibitor concentrations may not have inhibited calpain activity. Therefore the hypothesis that calpain inhibition is neuroprotective following SCI has not been tested. Effective calpain inhibition following SCI presents a number of challenges. Synthetic calpain inhibitors are not specific for calpain have relatively weak potency and have a plasma half-life of only 2h. While short-term calpain inhibition may be beneficial long-term inhibition can be detrimental to normal cell function. The first Specific Aim of this proposal will examine the hypothesis that postinjury administration of synthetic calpain inhibitors can significantly attenuate calpain activity and the proteolysis of calpain substrates following spinal cord injury. We will use both active site-directed peptide calpain inhibitors and a non-peptide inhibitor acting at the calcium-binding domain and will examine both intravenous intrathecal and intraspinal delivery of the calpain inhibitors. Having identified conditions that provide effective calpain inhibition the second Aim will examine the hypothesis that postinjury calpain inhibition can significantly attenuate lesion volume and improve functional outcome. The third Specific Aim will focus on the endogenous calpain inhibitor calpastatin and will examine the hypothesis that fusion proteins consisting of calpastatin and the Tat protein transduction domain will result in a potent and specific cell-permeable calpain inhibitor. The fourth Specific Aim examines the hypothesis that expression and secretion of the Tat-catpastatin will provide effective calpain inhibition in neighboring cells. Together the goal of the proposed studies is to develop effective strategies for calpain inhibition following SCI.

project_terms:
Amino Acids;Animals;Astrocytes;Attenuated;Calcium-Binding Domain;Calpain;Cathepsins B;Cell Line;Cell physiology;Cells;Cessation of life;Chimeric Proteins;Coculture Techniques;Condition;Contusions;Cysteine Protease;Cytoskeletal Proteins;Demyelinations;Development;Glioma;Goals;Gray unit of radiation dose;Half-Life;Hour;In Vitro;Infusion procedures;Injections Spinal;Injury;Intervention;Intravenous;Ischemia;Lesion;Life;Light;Localized;Locomotion;Measures;Membrane;Methods;Motor Neurons;Mus;Nature;Neurofilament Proteins;Neurons;Normal Cell;Numbers;Oligodendroglia;Pain;Peptides;Pharmaceutical Preparations;Plasma;Play;Proteins;Proteolysis;Range;Rattus;Role;Route;SJA6017;Signal Sequences Peptide;Signal Transduction;Signaling Protein;Site;Sites Active;Solubility;Specificity;Spectrin;Spinal Cord;Spinal cord injury;Testing;Therapeutic;Time;Tissues;Traumatic Brain Injury;Walking;aqueous;base;calpain inhibitor;calpastatin;design;desire;functional outcomes;gray matter;improved;in vivo;inhibitor/antagonist;injured;neurofilament;novel;tat Protein;tat Protein HIV;therapeutic target;uptake;white matter


application_id: 7157566
project_number: 5R01CA035635-22
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2006-12-18
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: FU, YALI
project_start_date: 1984-03-01
project_end_date: 2009-06-30
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
DNA is an underrepresented target for small molecule therapeutic agents. One reason for thedearth of DNA-targeted drugs is that the fundamental molecular mechanisms that govern sequence-and structural-selective ligand binding to DNA are poorly understood. The rational design of newDNA-targeted drugs requires a thorough understanding of the binding mechanisms of existingcompounds that bind to DNA with unique types of specificity. The long-range goal of the proposedresearch is to understand the molecular mechanism of intercalation reactions with emphasis on theenergetic basis of their sequence and structural selective binding. Renewal is sought for asuccessful and highly productive basic science program that has produced several promisingavenues for DNA-targeted drug development. Research in the next funding period will focus oninnovative studies designed to clarify the mechanisms that govern structural and sequence selectiveligand binding to nucleic acids. Specific aims include: 1. Use and refinement of a high-throughput competition dialysis assay for the identification and characterization of structuralselective ligand binding to nucleic acids. 2. Characterization of ligand binding to DNA:RNA hybridstructures. 3. Characterization of regional-selective drug binding by a novel calorimetric"bootprinting" method.The results of these studies will: 1. Provide a definitive taxonomy of structural selective ligandbinding to nucleic acids along with a description of the energetic basis of that structural selectivity2. Provide fundamental information to guide the rational design of compounds targeted to DNA:RNAhybrid structures a target of enormous biological significance. 3. Provide a new tool for thequantitative study of drug-DNA interaction in long (genomic) pieces of DNA.

project_terms:
Affinity;Area;Basic Science;Binding (Molecular Function);Biological;Biological Assay;Calorimetry;Class;Condition;DNA;DNA Single-Stranded;Dependency (Psychology);Dialysis procedure;Drug Delivery Systems;Ellipticines;Ethidium;Fluorescence;Funding;Genomics;Goals;Hybrids;Ligand Binding;Ligands;Methods;Molecular;National Cancer Institute;Nucleic Acid Binding;Nucleic Acids;Nylons;Pharmaceutical Preparations;Physical Dialysis;Polynucleotides;Procedures;Propidium;RNA;Range;Reaction;Research;Research Design;Resolution;Score;Screening procedure;Series;Specificity;Structure;Taxonomy;Technology;Therapeutic Agents;Thermodynamics;Titrations;base;coralyne;design;drug development;ellipticine;innovation;intercalation;neglect;novel;nucleic acid structure;programs;small molecule;tool


application_id: 7157218
project_number: 1R41AA016500-01
project_title: Nasal Delivery of Naltrexone for Treatment of Alcoholism
administering_ic: NIAAA
award_notice_date: 2006-09-19
opportunity_number: PA-06-007
application_type: 1
activity_code: R41
ic: AA
serial_number: 016500
program_official: FERTIG, JOANNE
project_start_date: 2006-09-20
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 BST-Z (10)]
contact_pi_person_id: 6082060
contact_pi: WERMELING, DANIEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 039891606
duns_number: 039891606
fips: US
organization_id: 10005610
organization_name: INTRANASAL TECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111200
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-20
budget_end_date: 2008-08-31
project_abstract:
DESCRIPTION (provided by applicant): Alcohol abuse dependence and related societal effects exert a tremendous toll on world-wide and American health and economics. Given this devastating impact the significant lack of pharmaceutical intervention even for those patients seeking treatment is troubling. This phase 1 Small Business Technology Transfer Research (STTR) project will apply novel nasal drug delivery platform technologies to develop a nasally delivered pharmaceutical to acutely and rapidly attenuate drinking behavior and to curb alcohol craving. The general goal of this project is to create and develop a novel nasal delivery dosage form of naltrexone (NTX) hydrochloride useful in the pharmacologic treatment of alcoholism. The specific goals are to: 1) create a nasal spray producing improved biopharmaceutics over the oral tablet and 2) offer an adjunct novel therapeutic option of a rapid-acting interventional medication intended to acutely extinguish alcohol craving symptoms. The hypothesis of the proposed project is that nasally delivered NTX will have substantially improved biopharmaceutics over the FDA-approved oral tablet as demonstrated by attaining: 1) at least twice the mean systemic bioavailability (F=50%) 2) less than half the pharmacokinetic parameter variability (S.D. =30% of the mean) and 3) 1/3rd to 1/4th the absorption time (tmax =20 minutes). The project hypothesis will be tested by the following specific aims: 1) develop 2 pilot prototype formulations of NTX HCl meeting appropriate standards for potency and stability 2) demonstrate systemic exposure and assess bioavailability in an in vivo rat model for the 2 prototype formulations 3) manufacture a nasal spray batch of NTX HCl for human clinical testing and 4) conduct a pilot bioavailability study of the nasal spray system in human volunteers. Objectives 1 and 2 of this phase 1 STTR project will create a pharmaceutically appropriate NTX nasal spray that produces consistent absorption resulting in rapid systemic blood levels in animals. Objectives 3 and 4 will permit verification that an improved NTX delivery system is feasible for human use. Future STTR phase 2 clinical studies will address a hypothesis that a more completely consistently and rapidly absorbed anti-relapse drug can be a tool to acutely reduce alcohol craving in actively consuming and abstinent alcoholics and improve chronic treatment success rates by improved biopharmaceutics and decreased untoward effects. The long-term goal of this work is to develop and commercialize nasal delivered NTX for the treatment of alcoholism.

project_terms:
alcoholism /alcohol abuse chemotherapy;clinical research;craving;dosage forms;drug design /synthesis /production;drug screening /evaluation;human subject;inhalation drug administration;laboratory rat;naltrexone;pharmacokinetics;substance abuse related behavior


application_id: 7155575
project_number: 1R43MH078437-01
project_title: Genetic Test for Schizophrenia Susceptibility: Targeted
administering_ic: NIMH
award_notice_date: 2006-09-26
opportunity_number: PA-06-016
application_type: 1
activity_code: R43
ic: MH
serial_number: 078437
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2006-09-26
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 GGG-J (10)]
contact_pi_person_id: 8483374
contact_pi: BRENNAN, MARK DAVID
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 609831222
duns_number: 609831222
fips: US
organization_id: 10007145
organization_name: SUREGENE, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402992882
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-26
budget_end_date: 2007-08-31
project_abstract:
DESCRIPTION (provided by applicant): The long term objective of this project is to develop validated genotype-based biomarkers to aid in more accurate diagnosis of schizophrenia and related schizophrenia spectrum disorders including bipolar disorder. SureGene LLC is developing two novel genetic tests one based on the SULT4A1 gene on chromosome 22q (which is supported by a multipoint LOD score of 4.78 assuming genetic heterogeneity in NIMH family samples) and another involving proprietary genetic markers in conjunction with novel microdeletions elsewhere in the genome (odds ratio of approximately 15). These tests need to be further refined before they are ready for general clinical and research use. Additionally SureGene plans to determine if chromosomal linkages called quantitative trait loci (QTL) that significantly affect behavioral variation in the human population can be used to define novel genes influencing diagnostic components of schizophrenia spectrum disorders. First to test the hypothesis that chromosomal regions contributing to schizophrenia-related phenotypes in an unselected population contain one or more genes influencing susceptibility to spectrum disorders we will perform targeted microsatellite and single nucleotide polymorphism genotyping with NIMH schizophrenia and bipolar family samples and evaluate the results by linkage analyses and transmission disequilibrium testing. Second we will determine the frequencies of putative susceptibility haplotypes for novel loci in populations of schizophrenia subjects and control African American and European American populations in order to get a more complete picture of the relative risks or odds ratios associated with these genetic tests. Finally we will analyze the molecular nature of a targeted set of putative susceptibility alleles. Using quantitative polymerase chain reaction methods we will find the end points of the novel deletions and describe the region of overlap. Also we will perform targeted resequencing of novel positional candidate genes with the goal of better understanding the molecular mechanisms contributing to increased risk. We anticipate that intellectual property (IP) will come out of the proposed research in the form of genotype-based diagnostic products and services. Such products should be helpful to individuals suffering from schizophrenia and related disorders their families and health care providers and researchers seeking to improve diagnosis and treatment.

project_terms:
African American;alleles;behavioral /social science research tag;behavioral genetics;biotechnology;bipolar depression;caucasian American;clinical research;diagnosis design /evaluation;family genetics;genetic disorder diagnosis;genetic markers;genetic screening;genetic susceptibility;human genetic material tag;human population genetics;human tissue;linkage disequilibriums;mental disorder diagnosis;quantitative trait loci;schizophrenia;twin /multiplet


application_id: 7154383
project_number: 1R43NS051878-01A2
project_title: Peptidomimetics for Manipulation of Growth Cone Motility and Axon Regeneration
administering_ic: NINDS
award_notice_date: 2006-09-15
opportunity_number: PA-06-006
application_type: 1
activity_code: R43
ic: NS
serial_number: 051878
suffix: A2
program_official: RIDDLE, ROBERT D
project_start_date: 2006-09-15
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1 MDCN-L (10)]
contact_pi_person_id: 8497567
contact_pi: WILSON, MARK THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 146134833
primary_uei: CSYMMBCEGFE5
duns_number: 146134833
uei: CSYMMBCEGFE5
fips: US
organization_id: 10004863
organization_name: ECM BIOSCIENCES
organization_city: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403831214
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Thousands of people every year experience long-term or lifelong disabilities in motor sensory and cognitive function as result of central nervous system (CNS) injuries. There has been little hope for recovery from these dysfunctions because axons from injured neurons in the brain and spinal cord do not regenerate. A major impediment to regeneration is the formation of a glial scar that expresses axon growth inhibiting molecules like chondroitin sulfate proteoglycans (CSPGs). Novel technologies that can overcome the inhibitory effects of CSPGs could lead to major advancements in therapies that promote functional recovery after CNS injury. In this SBIR project an innovative panel of cell permeant peptidomimetics will be developed that manipulate the activity of cytoskeletal proteins implicated in the axon growth cone responses to CSPGs. In Phase I the efficacy of this approach will be tested by developing technologies that manipulate the activity of cofilin an important cytoskeletal protein in CSPG-activated signaling pathways. Fluorescence microscopy assays will be used to select an optimal peptide transport system for neurons. In vitro biochemical assays will be used to screen cofilin-related peptides (CRPs) designed to manipulate cofilin protein activities. Growth cone motility assays will be used to assess the efficacy of the selected peptide transport system and CRP peptides for altering cofilin activity in a manner that promotes axon growth across CSPG containing borders. In Phase II the methods and technologies developed in Phase I will be used to create a panel of cell-permeant peptidomimetics that can regulate the activity of a variety of cytoskeletal proteins implicated in the growth cone responses to CSPGs. These peptidomimetics will be commercialized by ECM Biosciences in two ways as novel protein-manipulating research tools and as new therapeutic strategies for promoting functional recovery from CNS injuries. Project Relevance Currently there are limited therapeutic strategies for promoting recovery from central nervous system (CNS) injuries. A major factor limiting the development of therapies that promote recovery from CNS injuries is the difficulty promoting axon regeneration in the injured region. Advancements in the molecular tools used to study axon growth and regeneration is critical for new discoveries of the mechanisms involved with repair of the injured CNS. This SBIR proposal will facilitate the development of novel peptidomimetic technologies that can be used to manipulate protein function in neurons in vivo. These technologies will target proteins critical for axon outgrowth in an attempt to produce unique tools for studying axon regeneration. More importantly these research tools may lead to the development of agents that can promote axon regeneration in the injured CNS. Thus successful development of peptidomimetic technologies in this SBIR proposal will significantly advance axon regeneration research and could lead to the discovery of novel therapeutic strategies for promoting recovery from CNS injuries.

project_terms:
actin binding protein;axon;cytoskeletal proteins;growth cones;injury;neurons;peptides;proteins;regeneration;scars


application_id: 7152854
project_number: 5R01DE014605-06
project_title: Intra-and interspecies communication in oral bacteria
administering_ic: NIDCR
award_notice_date: 2006-12-13
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2008-09-29
study_section: Special Emphasis Panel[ZRG1-OBM-1(01)Q]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-12-01
project_abstract:
DESCRIPTION (provided by applicant): Periodontal disease is caused by bacterial pathogens that thrive in a complex microbial community which forms in the gingival pocket. The initiation and growth of this bacterial biofilm likely requires sophisticated molecular communication among the bacterial various species in this community. A chemical signal produced by the LuxS gene has recently been suggested to represent a broadly distributed mechanism for interspecies communication.  We have shown that LuxS is present in periodontal pathogens (A. actinomycetemomitans and P. gingivalis) and that the LuxS-dependent signal directs specific interspecies responses in these organisms. In this application we will determine the range and specificity of LuxS-dependent communication among various oral and non-oral organisms the mechanism by which this signaling pathway modulates iron acquisition by Aa and Pg and the role that signaling plays in the virulence of these organisms. We will complement LuxS-deficient strains of Aa and Pg with signals and/or/luxS genes from other oral and non-oral organisms. We will also determine if Aa or Pg respond differently to cognate and heterologous signals. Next we will examine the growth of signal deficient strains in various iron sources and determine the role that LuxS dependent signaling plays in controlling genes involved in the uptake of iron by Pg and Aa.  We have also shown that signaling regulates the expression of virulence-associated genes thus the contribution of signaling to virulence will be determined in vivo using a mouse model. Finally we will determine how signal information is transmitted within the bacterial cell to generate a specific response. Potential candidate proteins that may function in signal transduction have been identified; their genes will be inactivated and the resulting bacterial strains will be tested for their response to signal. These studies will provide some of the first evidence showing that LuxS-dependent signaling mediates intra- and interspecies communication among periodontal pathogens. This in turn may lead to the development of new therapeutics that may control growth and development of complex bacterial communities by blocking their communication pathways.

project_terms:
Actinobacillus actinomycetemcomitans;Address;Bacteria;Cell Communication;Cells;Chemicals;Communication;Communities;Compatible;Complement;Complex;Condition;Data;Dental Plaque;Development;Environment;Gene Expression;Genes;Genome;Gingiva;Gingival Pocket;Growth;Growth and Development function;Hemin;Infection;Iron;Lead;Mediating;Microbial Biofilms;Molecular;Monitor;Nutrient;Nutritional;Oral;Organism;Pathway interactions;Periodontal Diseases;Personal Satisfaction;Phosphotransferases;Play;Population Density;Porphyromonas gingivalis;Proteins;Range;Regulation;Role;Salmonella typhimurium;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Source;Specificity;Stimulus;Streptococcus pyogenes;System;Testing;Transferrin;Virulence;in vivo;luminescence;microbial community;mouse model;novel therapeutics;oral bacteria;pathogen;quorum sensing;response;sensor;uptake


application_id: 7151841
project_number: 1R01MH078228-01
project_title: Neuroimaging Studies of Depression in Parkinson's Disease
administering_ic: NIMH
award_notice_date: 2006-06-09
opportunity_number: RFA-MH-06-003
application_type: 1
activity_code: R01
ic: MH
serial_number: 078228
program_official: MEINECKE, DOUGLAS L
project_start_date: 2006-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZMH1 ERB-H (03)]
contact_pi_person_id: 8273960
contact_pi: BLONDER, LEE XENAKIS
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Parkinson&apos;s disease;amygdala;antiparkinson drugs;behavioral /social science research tag;bioimaging /biomedical imaging;brain disorder chemotherapy;brain mapping;brain morphology;caudate nucleus;cingulate gyrus;clinical research;cognition;depression;dopamine agonists;emotions;face expression;frontal lobe /cortex;human middle age (35-64);human old age (65+);human subject;neuroimaging;neuropathology;neuropharmacology;patient oriented research


application_id: 7151284
project_number: 7R01DE015254-03
project_title: Pattern Recognition of P. gingivalis Virulence Factors
administering_ic: NIDCR
award_notice_date: 2006-01-24
application_type: 7
activity_code: R01
ic: DE
serial_number: 015254
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-07-01
project_end_date: 2008-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-10-01
project_abstract:
DESCRIPTION: Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) form functional receptor complexes that recognize pathogen-associated molecular patterns (PAMPs). Activation of the TLR signaling pathway by PAMPs leads to induction of immune and inflammatory responses. Porphyromonas gingivalis is an important pathogen in human periodontitis. A major cell surface component of this oral pathogen is the fimbriae which function as an adhesin. Strikingly fimbriae activate transcription factor NF-KappaB and induce production of proinflammatory cytokines through interactions with several PRRs. Understanding the molecular basis of how the host recognizes and responds to P. gingivalis fimbriae is essential for developing molecular approaches to control periodontal inflammation. Therefore the objective of this grant is to elucidate the proinflammatory interactions of fimbriae with PRRs. The application proposes that fimbriae function as a PAMP and interact in a regulated mode and through discrete epitopes with different binding PRRs resulting in the activation of proinflammatory TLR signaling. Fimbrial epitopes involved in cellular binding and/or activation will be identified using fimbrial peptides and mutant fimbriae. Importantly epitopes involved in binding but not activation may find application as antagonists of fimbria-induced inflammation. Experiments in our laboratory have shown that TLR2 and TLR4 mediate fimbria-induced signaling but initial recognition of fimbriae is mediated by a cooperation between CD14 and CD11 b/CD18 which thus appear to serve as TLR co-receptors. It is posited that fimbriae initially bind to CD14 and the fimbriae/CD14 complex induces TLR2-mediated "inside-out" signaling that leads to activation of the ligand-binding capacity of CD11b/CD18. PRR-fimbriae interactions will be examined in human monocytes and mouse macrophages derived from normal and PRR-deficient mice. Elucidation of the mechanisms whereby PRRs recognize and respond to fimbriae and identification of fimbrial antagonists may facilitate the design of novel approaches to therapeutic intervention in both periodontitis and atherosclerosis where P. gingivalis has also been implicated.

project_terms:
Bacteroides gingivalis;CD antigens;CD14 molecule;SDS polyacrylamide gel electrophoresis;bacteria infection mechanism;bacterial proteins;biological signal transduction;cell adhesion molecules;clinical research;flow cytometry;host organism interaction;human subject;ion exchange chromatography;laboratory mouse;molecular shape;periodontitis;pilus;receptor binding;tissue /cell culture;toll like receptor;virulence


application_id: 7151082
project_number: 2R01AG020941-04
project_title: Changes in myogenic progenitor potential with age
administering_ic: NIA
award_notice_date: 2006-09-14
opportunity_number: RFA-AG-06-003
application_type: 2
activity_code: R01
ic: AG
serial_number: 020941
program_official: WILLIAMS, JOHN
project_start_date: 2002-06-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-2 (M1)]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Wnt gene /protein;adipocytes;age difference;aging;atrophy;biological signal transduction;body composition;bone marrow;cell differentiation;cell transplantation;clinical research;connective tissue cells;fats;gene expression;human subject;hypertrophy;laboratory mouse;lipids;mesenchyme;microarray technology;muscle;muscle cells;musculoskeletal system;myogenesis;stem cells;transfection


application_id: 7150922
project_number: 2R01DC002736-09A1
project_title: Functional Domains and Expression of Olfactory Receptors
administering_ic: NIDCD
award_notice_date: 2006-07-01
application_type: 2
activity_code: R01
ic: DC
serial_number: 002736
suffix: A1
program_official: DAVIS, BARRY
project_start_date: 1995-08-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1 IFCN-K (03)]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
G protein coupled receptor kinase;biological signal transduction;cell membrane;chemoreceptors;chimeric proteins;high throughput technology;immunocytochemistry;intracellular transport;laboratory rat;molecular chaperones;mutant;olfactions;olfactory stimulus;protein structure function;protein transport;receptor binding;receptor expression;receptor sensitivity;site directed mutagenesis;tissue /cell culture;western blottings;yeast two hybrid system


application_id: 7150191
project_number: 1R01AG026147-01A2
project_title: LDLR Genetics Splicing and AD Risk
administering_ic: NIA
award_notice_date: 2006-08-08
opportunity_number: PAS-03-128
application_type: 1
activity_code: R01
ic: AG
serial_number: 026147
suffix: A2
program_official: MILLER, MARILYN
project_start_date: 2006-08-15
project_end_date: 2010-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Alzheimer&apos;s disease;RNA splicing;aging;brain;cholesterol;clinical research;disease /disorder proneness /risk;family genetics;genotype;human genetic material tag;human tissue;immunoprecipitation;lipid metabolism;liver;low density lipoprotein receptor;molecular genetics;protein isoforms;protein localization;protein structure function;receptor expression;single nucleotide polymorphism;tissue /cell culture;transfection


application_id: 7150089
project_number: 1R01AG027219-01A1
project_title: SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT
administering_ic: NIA
award_notice_date: 2006-07-28
application_type: 1
activity_code: R01
ic: AG
serial_number: 027219
suffix: A1
program_official: SUNEJA, SANOJ
project_start_date: 2006-08-01
project_end_date: 2011-04-30
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alzheimer&apos;s disease;amyloid proteins;bioenergetics;biomarker;clinical research;cognition disorders;disease /disorder proneness /risk;human tissue;membrane proteins;memory disorders;mitochondria;neocortex;neural degeneration;neural growth associated protein;neuropathology;oxidative stress;pathologic process;postmortem;protein protein interaction;sensory cortex;synapses;transmission electron microscopy


application_id: 7149992
project_number: 5R01NS045131-06
project_title: Pathology of traumatic injury to CNS axons
administering_ic: NINDS
award_notice_date: 2007-01-18
application_type: 5
activity_code: R01
ic: NS
serial_number: 045131
program_official: HICKS, RAMONA R
project_start_date: 2002-12-15
project_end_date: 2008-11-30
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-12-01
project_abstract:
Traumatic brain injury afflicts 2 million people each year in the United States many of whom suffer persistentneurological disability as a result of diffuse axonal injury. Shearing or stretching of axons during traumaticbrain injury initiates progressive axonal damage ultimately leading to axotomy and neuronal death. Becausetraumatic injury most often causes delayed rather than immediate axotomy the opportunity exists tointervene therapeutically prior to axotomy. To elucidate the cellular mechanisms underlying traumatic axonalinjury and identify therapeutic targets we will perform dynamic optic nerve stretch injury in mice accuratelyreplicating the biomechanics of injury experienced by axons in the human brain during traumatic injury. Wepropose to use this established model of central nervous system axonal injury to test our working hypothesisthat activation of calpains after traumatic axonal injury causes microtubule damage and impairment of axonaltransport which unless reversed will lead to axotomy and neuronal apoptosis. In Aim 1 we will evaluateanterograde and retrograde fast axonal transport as a function of injury severity and establish the timecourse of transport impairment relative to axotomy. In Aim 2 we will establish a mechanistic link betweencalpain activation and interruption of axonal transport via degradation of microtubule-related proteins. In Aim3 we will test our hypothesis that prolonged disruption of axonal transport in optic nerve axons leads toapoptosis of retinal ganglion cells (RGCs). In Aim 4 we will use IGF-1 overexpressing mice and exogenousIGF-1 treatment to determine whether elevation of IGF-1 levels can reverse transport impairment afteraxonal injury by delaying RGC apoptosis and upregulating cytoskeletal protein synthesis. Becauseregeneration of central nervous system axons remains an elusive goal it is vital to intervene in thepathologic cascade of traumatic axonal injury before axotomy occurs. The optic nerve stretch injury modelallows correlations between axonal pathology and either mechanical injury parameters or the cell bodyresponse that are not currently possible in whole-brain axonal injury models. By exploiting these uniqueadvantages we hope to identify key mediators in axonal pathology and novel therapeutic strategies toeffectively sustain the vulnerable neuron and repair axonal damage prior to axotomy.

project_terms:
Acute;American;Apoptosis;Axon;Axonal Transport;Axotomy;Beds;Biomechanics;Brain;Calpain;Cell Death;Cessation of life;Craniocerebral Trauma;Cytoskeletal Proteins;Cytoskeleton;Data;Development;Diffuse Axonal Injury;Disruption;Dynein ATPase;Elevation;Event;Genes;Goals;Growth;Human;Immunoblotting;Impairment;Injury;Injury of central nervous system;Insulin-Like Growth Factor I;Interruption;Kinesin;Label;Lead;Left;Link;Localized;Measures;Mechanics;Mediator of activation protein;Microtubule Proteins;Microtubules;Modeling;Mus;Natural regeneration;Nature;Neuraxis;Neurologic;Neurons;Optic Nerve;Optic Nerve Injuries;Pathologic;Pathology;Protein Biosynthesis;Protein Overexpression;Proteins;Proteolysis;RNA Messenger;Recovery;Relative (related person);Research Personnel;Retinal Ganglion Cells;Role;Severities;Somatomedins;Stretching;Testing;Therapeutic;Therapeutic Intervention;Time;Tracer;Traumatic Brain Injury;Tubulin;United States;Wallerian Degeneration;Work;calpain inhibitor;caspase-3;cell body (neuron);day;design;disability;experience;fast axonal transport;inhibitor/antagonist;injured;insight;neuron apoptosis;novel therapeutics;programs;protein degradation;repaired;research study;response;retrograde transport;tau Proteins;therapeutic target


application_id: 7147730
project_number: 3R01ES008088-09S1
project_title: Convergence of TCDD Gene Activation with Other Pathways
administering_ic: NIEHS
award_notice_date: 2005-12-06
application_type: 3
activity_code: R01
ic: ES
serial_number: 008088
suffix: S1
program_official: BALSHAW, DAVID M
project_start_date: 1996-08-01
project_end_date: 2007-03-31
study_section: Special Emphasis Panel[ZRG1]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goals of this proposal are       to dissect the molecular mechanism(s) by which environmental contaminants          primarily 2 3 7 8 tetrachlorodibenzo-p-dioxin (TCDD) act as tumor              promoters. Many of the adverse biological effects of TCDD are thought to occur      following its activation of the aryl hydrocarbon receptor (AHR) dimerization       of the AHR with its DNA binding partner the aryl hydrocarbon receptor nuclear      translocator (ARNT) and gene activation by the AHR/ARNT heterodimer. Here we       suggest the existence of an additional mechanism; that TCDD induces nuclear         localization of the AHR and its heterodimerization with ARNT that disrupts ARNT     from its role in other signaling pathways i.e. that of the Myc/Max                heterodimer. Myc/Max is a well-described regulator of cell proliferation           apoptosis and differentiation that acts in part by upregulation of genes         such as p53. We found that 10 ARNT synergistically enhances the ability of Myc      to upregulate the p53 promoter 2) the synergistic actions of ARNT on Myc           transactivation occurs via the HLH domain of ARNT 3) TCDD decreases the mRNA       levels of p53 and the ability of Myo to upregulated the p53 promoter. These         results and that of others form the basis of our hypothesis that ARNT acts        synergistically with the Myc/Max heterodimer to upregulate the expression           levels of p53. Further we hypothesize that the addition of TCDD and                heterodimerization of ARNT with AHR removes ARNT form this role decreases the     ability of Myc to regulate the expression levels of p53 and hence decreases        the ability of Myc to induce apoptosis and differentiation. To test this idea      we will determine whether altered expression levels of ARNT significantly           impact the ability of Myc to upregulate p53 (Aim 1) and potentiate apoptosis       and induce differentiation (Aim 2) in the presence or absence of TCDD (Aim 3).      We will then determine whether ARNT is present within DNA binding complexes at      the p53 promoter (Aim 4) and identify the protein(s) that interact with ARNT to     elicit its synergistic effect on Myc transactivation (Aim 5).

project_terms:
DNA binding protein;apoptosis;aromatic hydrocarbon receptor;biological signal transduction;biotransformation;cell differentiation;dimer;dioxins;environmental exposure;gene expression;nucleic acid sequence;p53 gene /protein;protein binding;protein protein interaction;tissue /cell culture;toxicology;transcription factor;transfection;tumor promoters


application_id: 7147670
project_number: 1R01AG025771-01A2
project_title: Dietary restriction aging and the proteasome
administering_ic: NIA
award_notice_date: 2007-07-19
application_type: 1
activity_code: R01
ic: AG
serial_number: 025771
suffix: A2
program_official: VELAZQUEZ, JOSE M
project_start_date: 2007-08-01
project_end_date: 2007-12-24
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
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): The proteasome is an intracellular protease that is responsible for a significant amount of proteolysis including the degradation of oxidized proteins and a large number of established short-lived proteins lacking oxidative modifications. Increasing evidence suggests that inhibition of the proteasome-proteolytic pathway occurs as a part of normal aging with inhibition of proteasome function likely contributing to numerous age-related alterations in the proteome including age-related increases in oxidized protein. However the lack of a rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) is the only known manipulation to consistently and reliably increase average and maximal lifespan in mammals. Numerous studies have demonstrated that DR can ameliorate age-related increases in oxidized protein and suppress a variety of age-related alterations to the proteome. Data from our laboratory demonstrates that DR ameliorates age-related impairments in proteasome function with the preservation of proteasome function possibly contributing to the beneficial effects of DR on the proteome. The focus of this proposal is to utilize rigorous proteomic and biochemical analysis to test the hypothesis that DR ameliorates age-related impairments in proteasome function as the result of its direct effects on the proteasome complex with the preservation of proteasome activity contributing to DR-induced effects on the proteome (oxidized and non-oxidized proteins) during normal aging. The specific aims for testing this hypothesis are as follows: (1) To determine the effects of DR on proteasome subunit expression proteasome biogenesis proteasome composition and proteasome oxidation; (2) To determine the effects of DR on the individual peptidase activities and protein degrading capabilities of the proteasome; (3) To determine the cell-type specific effects of impaired proteasome function on the proteome including protein oxidation in primary CNS cell cultures in vitro; (4) To determine if proteins which exhibit altered expression or increased oxidation following proteasome inhibition in vitro exhibit similar changes during aging in vivo; (5) To determine if DR ameliorates alterations in the proteome including increases in oxidized protein observed during aging in vivo and following proteasome inhibition in vitro.

project_terms:
Age;Aging;Biochemical;Biogenesis;Complex;Cultured Cells;Data;Endopeptidases;Exhibits;Impairment;In Vitro;Individual;Laboratories;Life;Longevity;Mammals;Modification;Numbers;Pathway interactions;Peptide Hydrolases;Preservation Biological;Proteasome Inhibition;Proteins;Proteolysis;Proteome;Proteomics;Testing;age related;cell type;dietary restriction;in vivo;multicatalytic endopeptidase complex;normal aging;oxidation


application_id: 7146958
project_number: 1R01HL083320-01A1
project_title: Metabolic Mechanisms of Cardiac Injury and Protection
administering_ic: NHLBI
award_notice_date: 2006-07-15
application_type: 1
activity_code: R01
ic: HL
serial_number: 083320
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 2006-07-15
project_end_date: 2011-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
N acetylglucosamine;cardiac myocytes;cardiovascular disorder prevention;cardiovascular injury;cardiovascular pharmacology;cytoprotection;gene expression;glucose metabolism;heat shock proteins;ischemic preconditioning;laboratory mouse;laboratory rat;mitochondria;myocardial infarction;myocardial ischemia /hypoxia;newborn animals;posttranslational modifications;potassium channel;reperfusion;serine threonine protein kinase;tissue /cell culture;transfection /expression vector


application_id: 7146307
project_number: 1R01DA018822-01A2
project_title: Gated Carbon Nanotube Membrane Transdermal Drug Delivery
administering_ic: NIDA
award_notice_date: 2006-09-22
application_type: 1
activity_code: R01
ic: DA
serial_number: 018822
suffix: A2
program_official: AIGNER, THOMAS G
project_start_date: 2006-09-30
project_end_date: 2011-06-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 7929219
contact_pi: HINDS, BRUCE JACKSON
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
bias;birth;carbon;clonidine;dosage;drug delivery systems;fentanyl;nicotine;transdermal drug delivery


application_id: 7146200
project_number: 2R01DA013930-04
project_title: Redesign of Butyrylcholinesterase for Cocaine Metabolism
administering_ic: NIDA
award_notice_date: 2006-09-08
application_type: 2
activity_code: R01
ic: DA
serial_number: 013930
program_official: SHIH, MING L
project_start_date: 2003-08-20
project_end_date: 2011-05-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-10
project_terms:
bioenergetics;biotechnology;chemical kinetics;cholinesterases;cocaine;computer simulation;drug design /synthesis /production;drug metabolism;enzyme activity;enzyme substrate complex;hydrolysis;molecular dynamics;mutant;protein engineering;quantum chemistry;site directed mutagenesis


application_id: 7146012
project_number: 5R01AI053101-05
project_title: Borrelia burgdorferi LuxS-mediated quorum sensing
administering_ic: NIAID
award_notice_date: 2006-11-28
application_type: 5
activity_code: R01
ic: AI
serial_number: 053101
program_official: BREEN, JOSEPH J
project_start_date: 2003-06-15
project_end_date: 2008-11-30
study_section: Special Emphasis Panel[ZRG1-BM-1(01)Q]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-12-01
project_abstract:
The spirochete Borrelia burgdorferi the causative agent of Lyme disease is transmitted to humans andother warm blooded animals through the bite of infected Ixodes spp. ticks. The establishment of B.burgdorferi infection involves numerous interactions between the bacteria and a variety of vertebrate hostand arthropod vector tissues. Different bacterial proteins are required at specific points of this infectiouscycle and precise regulation of the synthesis of such proteins is essential for successful infection to occur.We have discovered that these spirochetes utilize a regulatory mechanism to control protein expressionpatterns that involves a chemical signal known as autoinducer-2 (AI-2). This molecule is produced by theB. burgdorferi LuxS protein which we have demonstrated to be a functional enzyme. Our preliminarystudies suggest that B. burgdorferi can regulate LuxS synthesis. Addition of AI-2 to cultured B. burgdorferidramatically alters the expression of more than 50 different proteins increasing expression levels of someproteins while decreasing expression of others. Through this mechanism a population of Lyme diseasespirochetes may synchronize production of proteins needed for infection processes. We hypothesize thatB. burgdorferi uses AI-2 as an important signaling molecule to control expression of proteins during thenatural infectious cycle of the Lyme disease spirochetes. The proposed studies will characterize theexpression of LuxS during bacterial infection the mechanisms by which B. burgdorferi controls synthesis ofAI-2 and functions of AI-2-regulated proteins. Results from these studies will enhance our understandingof the complex interactions between B. burgdorferi and its hosts as well as identifying potential bacterialtargets for improved therapies to prevent and treat Lyme disease.

project_terms:
Address;Animals;Arthropod Vectors;Bacteria;Bacterial Infections;Bacterial Proteins;Bite;Blood;Borrelia burgdorferi;Chemicals;Complex;Condition;DNA Sequence;Enzymes;Facility Construction Funding Category;Gene Expression;Gene Expression Regulation;Gene Fusion;Gene Proteins;Genes;Genomics;Histocompatibility Testing;Human;In Vitro;Infection;Ixodes (genus);Lyme Disease;Mammals;Mediating;Numbers;Operon;Order Spirochaetales;Pathogenesis;Pattern;Phenotype;Population;Process;Production;Promotor (Genetics);Proteins;Proteomics;RNA Messenger;Regulation;Signal Transduction;Signaling Molecule;Testing;Ticks;Tissues;VAI-2;base;improved;in vivo;numb protein;prevent;protein expression;quorum sensing;transmission process;vector


application_id: 7145081
project_number: 1R01AG027297-01A1
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2006-08-31
application_type: 1
activity_code: R01
ic: AG
serial_number: 027297
suffix: A1
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2006-09-01
project_end_date: 2011-06-30
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alzheimer&apos;s disease;aging;amyloidosis;astrocytes;biological signal transduction;brain metabolism;calcineurin;calcium channel;disease /disorder model;gene expression;genetically modified animals;in situ hybridization;inflammation;laboratory mouse;laboratory rat;leukocyte activation /transformation;nervous system disorder epidemiology;polymerase chain reaction;protein metabolism;protein protein interaction;protein structure function;tissue /cell culture;transcription factor;voltage gated channel;western blottings


application_id: 7144906
project_number: 1K23HD050581-01A1
project_title: Cervical (Neck) Auscultation and Developmental Outcomes
administering_ic: NICHD
award_notice_date: 2006-09-25
opportunity_number: PA-00-004
application_type: 1
activity_code: K23
ic: HD
serial_number: 050581
suffix: A1
program_official: RAJU, TONSE N
project_start_date: 2006-09-27
project_end_date: 2011-08-31
study_section: Pediatrics Study Section[CHHD-A]
contact_pi_person_id: 7584915
contact_pi: REYNOLDS, ERIC W
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
behavior test;bronchopulmonary dysplasia;clinical research;data collection methodology /evaluation;developmental neurobiology;disease /disorder proneness /risk;early /brief intervention /therapy;growth /development;human subject;human therapy evaluation;infant human (0-1 year);longitudinal human study;neck;oral behavior;outcomes research;premature infant human;prognosis;reflex;respiration regulatory center;swallowing;ultrasonography


application_id: 7144768
project_number: 1R21AA015611-01A2
project_title: Matrix Metalloproteinases in Alcoholic Liver Injury
administering_ic: NIAAA
award_notice_date: 2006-07-31
opportunity_number: PA-03-107
application_type: 1
activity_code: R21
ic: AA
serial_number: 015611
suffix: A2
program_official: RADAEVA, SVETLANA
project_start_date: 2006-08-01
project_end_date: 2008-05-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1861697
contact_pi: DEACIUC, ION
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
project_abstract:
DESCRIPTION (provided by applicant):  Years of research on alcoholic liver disease (ALD) have clearly demonstrated the multifactorial nature of this disease and to date the list of factors that have been implicated as causative in the disease is still growing.  This is of no surprise because alcohol (ethanol) is a cytotoxic agent and as such is expected to affect many facets of liver cells' function. Therefore there is an ongoing necessity to search for novel aspects related to the mechanisms underlying ALD. This project's long-term objective is investigation into what may constitute yet another aspect of the disease mechanism(s): a potential role of matrix metalloproteinases (MMPs) in the development and progression of ALD. We postulate that MMPs play an important pathogenic role in the earlier phases of the disease by both mediating the transmigration of extrahepatic cells into the liver which in turn produce liver injury and by disturbing the liver structural architecture. If confirmed by experimental work this postulate may unravel a novel aspect of the disease mechanisms and bring into light a novel target for therapeutic interventions in ALD: the MMPs. This project has two specific aims:  1)To investigate the kinetics of expression of MMPs and their natural inhibitors tissue inhibitors of metalloproteinases (TIMP) in the liver of laboratory animals (mice treated with alcohol) from the onset of the disease and during its progression toward more advanced phases and 2) To investigate the effects of several synthetic inhibitors of MMPs on the occurrence and progression of ALD. These experiments will be performed on mice chronically fed alcohol to develop alcoholic liver injury resembling the ALD in humans. The data obtained will provide an enhanced insight into the mechanisms of ALD and may provide insights into novel therapeutic approaches of ALD.

project_terms:
RNase protection assay;alcoholic beverage consumption;alcoholic liver cirrhosis;alcoholism /alcohol abuse;cell migration;chemical kinetics;disease /disorder onset;enzyme activity;gene expression;genetic regulation;laboratory mouse;liver function;messenger RNA;metalloendopeptidases;pathologic process;protein structure function;tissue inhibitor of metalloproteinases


application_id: 7143838
project_number: 1R03AG026530-01A1
project_title: Natural Killer Subset Senescence and Clonality in Aging
administering_ic: NIA
award_notice_date: 2006-09-12
opportunity_number: PA-03-108
application_type: 1
activity_code: R03
ic: AG
serial_number: 026530
suffix: A1
program_official: FLORES, ROBERTO L
project_start_date: 2006-09-15
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 III-F (01)]
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
project_abstract:
DESCRIPTION (provided by applicant): Natural killer (NK) cells use KIR and CD94/NKG2A receptors to detect infected cells and cancer cells that have downregulated MHC class I molecules. Declining NK cell function is associated with infection and poor health in the elderly but little is know about NK receptor expression or population dynamics in the elderly. OUR LONG-RANGE GOAL is to manipulate NK cells to promote healthy aging. Our CURRENT OBJECTIVE is to study human NK population dynamics and turnover in aging especially as they relate to age related shifts in NK receptor expression. Supported by our novel preliminary data our CENTRAL HYPOTHESIS is that an age related change in NK receptor expression is caused by a change in NK development and this in turn alters NK function and turnover. A feature of this shifting balance is the accumulation of NK cells with restricted receptor repertoire. The RATIONALE of the proposed research is that a better understanding of NK population dynamics and shifting NK receptor expression may allow us manipulate innate immunity in healthy and unhealthy aging. Our SPECIFIC AIM is to investigate human NK population dynamics as they relate to KIR and CD94/NKG2 receptor expression and other defined NK subsets. We will 1. test the replication potential and expression of senescence markers in NK subsets with aging 2. measure turnover rates in KIR+ and NKG2A+ NK cells from young and elderly adult subjects 3. evaluate the incidence of NK subpopulations with restricted receptor repertoire in young and elderly subjects and will rigorously test whether the NK subpopulations are polyclonal or monoclonal. Our approach is INNOVATIVE. We have documented a reciprocal relationship between NK receptors in aging and we have demonstrated for the first time that NK subpopulations with restricted receptor repertoire are found in healthy elderly people. It is our EXPECTATION that the proposed study will rigorously test our hypotheses and lead to definitive future studies on NK subset development function proliferation and senescence.

project_terms:
MHC class I antigen;aging;bone marrow;cell differentiation;cell population study;cell proliferation;cell senescence;clinical research;developmental immunology;flow cytometry;human old age (65+);human subject;immunologic receptors;immunosenescence;natural killer cells;receptor expression;stromal cells;tissue /cell culture;young adult human (21-34)


application_id: 7143490
project_number: 1R01HL082791-01A1
project_title: Vascular Smooth Muscle Hyper-contractility/Hypertension
administering_ic: NHLBI
award_notice_date: 2006-05-05
application_type: 1
activity_code: R01
ic: HL
serial_number: 082791
suffix: A1
program_official: RABADAN-DIEHL, CRISTINA
project_start_date: 2006-06-01
project_end_date: 2011-05-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
biological signal transduction;calcium flux;dietary lipid;disease /disorder model;enzyme activity;enzyme inhibitors;genetically modified animals;guanine nucleotide binding protein;hypertension;kinase inhibitor;laboratory mouse;noninsulin dependent diabetes mellitus;phosphoprotein phosphatase;phosphoproteins;phosphorylation;protein kinase C;protein structure function;serine threonine protein kinase;telemetry;tissue /cell culture;vascular smooth muscle;vasomotion


application_id: 7140678
project_number: 5R21DK074161-02
project_title: N-acetylcysteine pharmacokinetics--hemodialysis patients
administering_ic: NIDDK
award_notice_date: 2006-08-23
opportunity_number: PAR-04-065
application_type: 5
activity_code: R21
ic: DK
serial_number: 074161
program_official: KUSEK, JOHN W
project_start_date: 2005-09-30
project_end_date: 2008-03-31
study_section: ZDK1-GRB-7(O3)S
contact_pi_person_id: 3123643
contact_pi: WARD, RICHARD A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients and it has proven refractory to therapies such as lipid-lowering agents that lessen the severity of the disease in the normal population. Oxidant stress has been identified as a non-traditional risk factor for cardiovascular disease in hemodialysis patients. Oxidant stress in hemodialysis patients arises from an increase in production of reactive oxygen species and a consequent depletion of anti-oxidant defenses. One result of this imbalance is depletion of plasma protein thiols and low molecular weight thiols such as glutathione. Plasma protein thiols form the major extracellular anti-oxidant and their depletion leads to an increase in oxidized lipids and proteins that play a role in cardiovascular disease. Depletion of glutathione activates redox-regulated signaling pathways in endothelial and vascular smooth muscle cells which promote atherogenic plaque formation. Our hypothesis is that repletion of thiol stores will correct the redox state thereby reducing lipid and protein oxidation and turning off the pro-atherogenic signals. N-acetylcysteine (NAC) is an aminothiol which acts as a source of cysteine for glutathione synthesis. In addition to glutathione formation NAC directly scavenges reactive oxygen species and hypochlorous acid. NAC has been used as a source of thiols in patients with normal renal function; however there is little information on the disposition of NAC in hemodialysis patients. This research program addresses this gap in knowledge. The specific objectives are: 1. To determine the pharmacokinetics and pharmacodynamics of NAC in hemodialysis patients; 2. To examine the ability of NAC to provide a sustained reduction in protein and lipid oxidation in hemodialysis patients; and 3. To examine the safety profile and tolerability of NAC in hemodialysis patients. The pharmacokinetic and pharmacodynamic studies to be performed in the first year of the project will establish the optimal dose for thiol repletion in hemodialysis patients of an oral sustained release form of NAC. In the second year of the project this optimal dose will be used in a pilot study to investigate the ability and practicability of NAC to provide a sustained increase in reduced thiols and a concomitant reduction in protein and lipid oxidation in hemodialysis patients. The information gained from these studies will allow the design of a large clinical trial in hemodialysis patients to examine the effectiveness of N-acetylcysteine in reducing oxidant stress and cardiovascular disease the leading cause of death in these patients.

project_terms:
acetylcysteine;antioxidants;blood flow measurement;blood tests;cardiovascular disorder prevention;chemoprevention;clinical research;clinical trials;drug screening /evaluation;free radical oxygen;free radical scavengers;glutathione;hemodialysis;human subject;human therapy evaluation;lipid peroxides;medical complication;oxidative stress;patient oriented research;pharmacokinetics;thiols;vascular endothelium


application_id: 7140559
project_number: 5R21DA018372-02
project_title: Nicotinic Receptor Regulation of Dopamine Transporter
administering_ic: NIDA
award_notice_date: 2006-08-31
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: DA
serial_number: 018372
program_official: PILOTTE, NANCY S
project_start_date: 2005-09-30
project_end_date: 2009-08-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tobacco use is the number one preventable cause of death in the US. The reinforcing efficacy of nicotine (NIC) the most abundant alkaloid in tobacco plays a major role in the maintenance of tobacco smoking. Furthermore tobacco use and depressive disorders are highly comorbid and NIC maybe be used in part to alleviate depression in this clinical population. Research on the neurobiology of reward and drug addiction has focused on mesocorticolimbic and nigrostriatal dopamine (DA) pathways. NIC activates nicotinic receptors which increases extracellular DA concentrations at both terminal and cell body regions of these pathways. Extracellular DA concentration is the net result of neurotransmitter release from the presynaptic terminal and neurotransmitter clearance from the extracellular space. DA clearance is mediated primarily by the plasma membrane dopamine transporter (DAT). Although there is a wealth of information on NIC stimulated DA release the ability of NIC to modulate DAT function and the underlying mechanisms responsible for this effect have not been studied in detail. Preliminary data show that in prefrontal cortex acute NIC increases DA uptake into synaptosomes DA clearance in in vivo voltammetry studies and DAT trafficking to the cell surface. Thus NIC augmentation of DAT function appears to sharpen the kinetics of the NIC-induced increase in extracelluar DA concentration in prefrontal cortex. The proposed study will begin to elucidate the underlying mechansims responsible for the NIC-induced enhancement of DAT function. The hypothesis to be tested in the current application is that NIC via nicotinic receptor activation mediates the trafficking of DAT. This hypothesis will be tested using the rat as the animal model and will determine (1) the dose-related effects of acute in vivo administration of NIC on DAT trafficking in striatum nucleus accumbens prefrontal cortex and amygdala; (2) if nicotinic receptors mediate the effect of NIC on DAT trafficking; and (3) the effect of intermittent and continuous NIC administration on DAT trafficking. Results of these experiments will begin to elucidate the cellular mechanisms by which NIC and nicotinic receptors modulate DAT function and thereby contribute to the regulation of extracellular DA concentration. Thus insight will be provided with respect to the effect of NIC on DA neurotransmission in brain regions associated with drug abuse.

project_terms:
amygdala;biological models;corpus striatum;dopamine transporter;dosage;drug receptors;laboratory rat;neuropharmacology;neurotransmitter transport;nicotine;nicotinic receptors;nucleus accumbens;prefrontal lobe /cortex;protein structure function;psychopharmacology;receptor expression;reinforcer;smoking;tobacco abuse


application_id: 7140472
project_number: 5R21AI062826-02
project_title: Proteomic analysis of the T. gondii vacuolar membrane
administering_ic: NIAID
award_notice_date: 2006-05-24
opportunity_number: PA-03-080
application_type: 5
activity_code: R21
ic: AI
serial_number: 062826
program_official: ROGERS, MARTIN J
project_start_date: 2005-07-15
project_end_date: 2007-06-30
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant): Successful parasitism by the obligate intracellular Toxoplasma gondii is critically dependent on efficient nutrient scavenging and subversion of diverse host functions. Access to nutrients and cellular functions within the host cytoplasm is restricted by the parasitophorous vacuole membrane (PVM) a parasite modified structure that serves as the boundary defining the replication permissive niche. Activities at the PVM are critical in nutrient acquisition structural integrity and the manipulation of host signaling cascades including potentially the immune response to the parasite. While the PVM is involved in many facets of infection the molecular basis for these activities remains elusive. The inability to purify the PVM has prevented detailed biochemical analyses of these activities. In this proposal we aim to characterize the proteome of the T. gondii PVM using mass spectroscopic approaches coupled with novel polyclonal antisera as affinity reagents. In addition to conventional mass spectroscopic techniques we will apply multi-dimensional protein identification technology (MudPit) which permits the analysis of complex protein mixtures. These approaches to define the PVM proteome are made feasible by recent advances in the mass spectrometric identification of proteins open access to the T. gondii genome databases and bioinformatic algorithms to analyze the data. The culmination of this approach is to establish the foundation for the characterization of activities in the PVM by defining its protein composition. These approaches will likely lead to the identification of potentially novel chemotherapeutic targets for Toxoplasma and other apicomplexan including Cryptosporidium parvum and hepatic stages of Plasmodia.

project_terms:
Toxoplasma gondii;bioinformatics;biotechnology;cell membrane;host organism interaction;immunoprecipitation;intracellular parasitism;mass spectrometry;membrane activity;molecular cloning;parasite infection mechanism;protein protein interaction;protein quantitation /detection;proteomics;vesicle /vacuole


application_id: 7140236
project_number: 5R21AI065631-02
project_title: Identification of Anaplasma phagocytophilum adhesins
administering_ic: NIAID
award_notice_date: 2006-06-23
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AI
serial_number: 065631
program_official: PERDUE, SAMUEL S
project_start_date: 2005-07-15
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-IDM-A(90)S]
contact_pi_person_id: 6434147
contact_pi: CARLYON, JASON A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Human granulocytic anaplasmosis (HGA; formerly human granulocytic ehrlichiosis) is an emerging and potentially deadly disease. It is the second most common tick-borne infection in endemic areas of the United States. HGA is caused by Anaplasma phagocytophilum an obligate intracellular bacterium that colonizes a most unusual host cell - the neutrophil. Neutrophils normally play beneficial roles in microbial clearance and inflammation in response to injury or infection. Neutrophil dysfunction as associated with inflammatory disorders can have considerably damaging effects. A. phagocytophilum cellular adhesion to and invasion of human neutrophils are dependent on bacterial recognition of P-selectin glycoprotein ligand-1 (PSGL-1) and sialylated and fucosylated glycans on neutrophil surfaces. Using a novel assay we further defined the A. phagocytophilum cytoadherence mechanism by identifying 2 key molecular features of PSGL-1 to which the organism binds: (i) a primary amino acid sequence found in the N-terminus of human PSGL-1 and (ii) sialyl Lewis x (sLex) a sialylated and fucosylated tetrasaccharide that modifies PSGL-1 and other selectin ligands. The bacterial protein(s) that mediate these interactions are unknown which represents a considerable gap in our knowledge. We hypothesize that A. phagocytophilum adherence to neutrophils is dependent on 1 or more adhesins that target PSGL-1 N-terminal peptide and sLex. Identifying the cognate adhesins will be integral to developing strategies for disrupting the interaction of A. phagocytophilum with the surface of its host cell. The objectives of this proposal are to identify and characterize the A. phagocytophilum adhesin(s) that mediate cytoadhesion to human neutrophils. The specific aims are: (1) to isolate putative adhesins based on their affinities for PSGL-1 and sLex and identify them using proteomic and molecular methods (2) to functionally characterize the adhesin candidates using glycoconjugate and cellular binding assays. Achieving these aims will provide the initial framework for a comprehensive assessment of the adhesin(s)' contributions to A. phagocytophilum infection. Additionally it will fill significant voids in our understanding of A. phagocytophilum pathogenesis and bacterial adhesion strategies. Furthermore it will identify novel targets for preventing and treating HGA and may pave the way for development of pharmacologic inhibitors of cellular adhesion events associated with disease.

project_terms:
CHO cells;Rickettsiales;adhesin;arthropod borne communicable disease;bacteria infection mechanism;clinical research;ehrlichiosis;emerging infectious disease;glycoproteins;gram negative bacteria;host organism interaction;human subject;laboratory mouse;neutrophil;protein binding;protein purification;proteomics;selectins


application_id: 7139462
project_number: 1R01AG028925-01A1
project_title: INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION
administering_ic: NIA
award_notice_date: 2006-09-06
opportunity_number: PA-03-147
application_type: 1
activity_code: R01
ic: AG
serial_number: 028925
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2006-09-15
project_end_date: 2011-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
age difference;aging;apoptosis;atrophy;biological signal transduction;bone;bone disuse atrophy;bone morphogenetic proteins;cell differentiation;cell population study;cell proliferation;hematopoietic stem cells;immobilization of body part;insulinlike growth factor;laboratory rat;male;muscle;musculoskeletal regeneration;myoblasts;protein structure function;restraint;restricted physical activity;sarcopenia;stem cells


application_id: 7136890
project_number: 1R36HS016347-01
project_title: The Development of Cancer Beliefs in Older Rural Appalachian Women
administering_ic: AHRQ
award_notice_date: 2006-06-09
opportunity_number: PAR-04-039
application_type: 1
activity_code: R36
ic: HS
serial_number: 016347
program_official: HARDING, BRENDA
project_start_date: 2006-07-01
project_end_date: 2007-11-30
study_section: Healthcare Research Training [HCRT]
contact_pi_person_id: 8586943
contact_pi: LEACH, CORINNE R
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant): Despite tremendous improvements in the early detection of breast cancer and related long-term survival certain groups of women including rural Appalachian women continue to experience a disproportionate burden of disease. This dissertation seeks to understand how older rural women from an underserved area of Appalachian Kentucky develop knowledge and beliefs about cancer in general and in particular breast cancer over the life course and how beliefs shape the use of cancer screening services. Since existing literature demonstrates that health beliefs influence the uptake of health services it is essential that we improve our understanding of the development and nature of cancer health beliefs. Previous quantitative studies have not been able to capture the experience or thoroughly explain why certain women do not receive cancer screenings. Use of qualitative methods grounded theory in particular will allow the researcher to explore underlying beliefs and meanings in an in-depth and contextualized manner. Using theoretical sampling approximately 20 women ages 55 and older without a history of cancer diagnosis will participate in the study. Each woman will be interviewed approximately three times each due to the in-depth nature of the interview guide. While grounded theory will shape the project we draw on the Health Belief Model the Common Sense Model of Illness and Anderson's (1995) Health Behavior Model to focus the research questions. Questions assess the perceived availability of health resources health and cancer beliefs knowledge of cancer and breast cancer screenings and mammography self-breast exam and clinical breast exam thoughts and behaviors. After transcription each interview will undergo coding and thematic analysis using NVivo 7 qualitative analysis software. Results from this study will be used to initiate a long-term focus on underserved rural populations and challenges to health service utilization. This research project seeks to enhance access to cancer services through learning more about the barriers older women in an underserved area experience a goal consistent with the priorities of AHRQ. Indeed the selected county falls under the Appalachian Regional Commission's "distressed" status due to the high poverty rates low per capita income and high rates of unemployment in the county. In addition the sample included in the study represents identified "priority populations": elderly rural low-income and women. Finally the study begins work toward eliminating cancer disparities and reducing cancer illness and death the two Healthy People 2010 goals by identifying beliefs meanings and screening barriers among this underserved and disproportionately affected population of women.

project_terms:
behavioral /social science research tag;belief;breast neoplasms;clinical research;female;health behavior;health care service availability;health disparity;human old age (65+);human subject;interview;low socioeconomic status;medically underserved population;model design /development;rural health;social model;women&apos;s health


application_id: 7134806
project_number: 1R03DA021821-01
project_title: Emotional and attentional biases to drug and trauma cues in addiction with PTSD
administering_ic: NIDA
award_notice_date: 2006-09-26
opportunity_number: PAR-03-146
application_type: 1
activity_code: R03
ic: DA
serial_number: 021821
program_official: SCHNUR, PAUL
project_start_date: 2006-09-30
project_end_date: 2007-09-29
study_section: Special Emphasis Panel[ZDA1 MXS-M (10)]
contact_pi_person_id: 8136073
contact_pi: SOKHADZE, ESTATE M
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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 goal of this project is to utilize ERP autonomic variables and behavioral measures of performance on mental tasks to study the role of attentional biases in responses to drug- and traumatic stress-related cues in individuals with substance use disorder (SUD) with comorbid posttraumatic stress disorder (PTSD). Dense-array ERPs heart rate and skin conductance responses will be assessed during exposure to a battery of cognitive tasks containing emotional drug- and traumatic stress-relevant cues. Specific aim I am to investigate physiological patterns of emotional reactivity in a gender category judgment task by contrasting ERP and autonomic responses to images of facial expression of affect and neutral faces in four groups of subjects (SUD-PTSD SUD-only PTSD-only and controls). We will use images of facial expressions of fear and happiness to elicit emotional interference during task. We predict enhanced ERP and autonomic reactivity to expression of fear in a group of dual and PTSD patients as compared to SUD and control groups. We predict that this process will be reflected in an automatic orienting to fearful face images. The aim II is to examine ERPs to drug- and trauma-associated stimuli and investigate how heightened orienting to these motivationally salient distracters will interfere with cognitive functions during performance on a three-category oddball task with verbal and pictorial stimuli. We predict that dual patients will show enhanced reactivity to the task-irrelevant drug- and threat-related cues which negatively affects processing of task-relevant stimuli. Specific aim III is to investigate the effects of cocaine abuse on prefrontal executive top-down control and assess response inhibition in a continuous performance task (Go-NoGo) in four groups of subjects. We predict decreased response inhibition in dual and SUD groups vs. controls which will be expressed in a higher number of commissions and a lower amplitude of the anterior NoGo-N2 and NoGo- P3 ERP components. The abnormality in information processing in a SUD-PTSD comorbidity in our model is linked with attentional and emotional bias in responses to both threat and drug cues. We propose that SUD and PTSD are functionally related through information-processing biases which are a function of automatic processes due to a conditioned sensitization to both threat and drug-related stimuli. Decreased frontal topdown control further contributes to inability to override these automatic responses and addictive behaviors.

project_terms:
behavior;bias;clinical research;cocaine;cues;diagnosis;emotions;face;face expression;fear;performance;stress;trauma


application_id: 7131082
project_number: 1R01ES014849-01
project_title: AHR-Protac a novel aryl hydrocarbon receptor antagonist
administering_ic: NIEHS
award_notice_date: 2006-08-07
application_type: 1
activity_code: R01
ic: ES
serial_number: 014849
program_official: COLLINS, JENNIFER B
project_start_date: 2006-08-15
project_end_date: 2011-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-15
project_terms:
affinity chromatography;apoptosis;aromatic hydrocarbon receptor;biological signal transduction;biotherapeutic agent;cancer prevention;carcinogenesis;cardiovascular disorder prevention;cell cycle;cell senescence;chemoprevention;diabetes mellitus therapy;dioxins;drug design /synthesis /production;drug screening /evaluation;environment related neoplasm /cancer;environmental exposure;genetic transcription;inhibitor /antagonist;pathologic process;protein degradation;protein protein interaction;receptor binding;receptor expression;small interfering RNA;tissue /cell culture


application_id: 7128395
project_number: 1R15HD051622-01A1
project_title: Pavlovian Conditioning of Sexual Behavior and Fertility
administering_ic: NICHD
award_notice_date: 2006-09-26
opportunity_number: PA-03-053
application_type: 1
activity_code: R15
ic: HD
serial_number: 051622
suffix: A1
program_official: LAMAR, CHARISEE A
project_start_date: 2006-09-27
project_end_date: 2010-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 2185033
contact_pi: CUSATO, BRIAN M
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 077867604
primary_uei: DDJFJ6UEBEF5
duns_number: 077867604
uei: DDJFJ6UEBEF5
fips: US
organization_id: 1295801
organization_name: CENTRE COLLEGE
organization_city: DANVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 404221309
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Sexual conditioning has been demonstrated in a variety of species but it has been most extensively investigated in male Japanese quail. The majority of these studies have used arbitrary conditioned stimuli (CSs) but recent experiments have demonstrated that using ecologically relevant female cues as CSs results in significantly improved male sexual conditioning. The proposed experiments are designed to investigate the extent to which ecologically relevant male cues facilitate the sexual conditioning of females. This ecological approach also is extended to non-traditional ways of measuring conditioned responding. In addition to assessing the effects of sexual conditioning by measuring changes in an animal's CS-directed responding a more functional approach will measure increases in the efficiency of a subject's interactions with a copulation partner. The ultimate standard of ecological validity by which sexual conditioning studies may be measured is facilitated reproductive success. Sexual conditioning has been shown to improve fertility but the specific conditioning mechanisms that underlie the effect have not yet been identified. The present experiments are designed to investigate the conditioning parameters that regulate the conditioned fertility effect the relationship between conditioned sexual behavior and increases in reproductive success and the extent to which sexual conditioning can compensate for fertility deficits. Unlike most conventional animal learning investigations that lack ecological validity the present experiments incorporate species typical cues directly into the experimental designs. This ecological approach to investigate ways to accentuate an animal's reproductive success facilitates the application of the experimental findings to situations outside the laboratory that animals may experience in their natural environment.

project_terms:
Japanese;animal ecology;behavior test;conditioning;cues;fertility;fertilization;quail;sex behavior;sex partner;stimulus /response


application_id: 7128185
project_number: 5R01AA015970-02
project_title: S-adenosylhomocysteine and S-adenosylmethionine in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2006-06-23
application_type: 5
activity_code: R01
ic: AA
serial_number: 015970
program_official: PUROHIT, VISHNU
project_start_date: 2005-09-30
project_end_date: 2010-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_terms:
S adenosylmethionine;adenosine;alcoholic liver cirrhosis;apoptosis;biopsy;clinical research;clinical trials;cytokine;disease /disorder etiology;ethanol;hepatotoxin;homocysteine;human subject;human therapy evaluation;liver cells;liver disorder chemotherapy;metabolism disorder;mitochondrial disease /disorder;patient oriented research;sulfur;therapy design /development;transmethylation;tumor necrosis factor alpha


application_id: 7127983
project_number: 1R21DK075473-01
project_title: Proteomic identification of diabetes biomarkers
administering_ic: NIDDK
award_notice_date: 2006-06-29
opportunity_number: PA-04-081
application_type: 1
activity_code: R21
ic: DK
serial_number: 075473
program_official: SECHI, SALVATORE
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1 EMNR-K (90)]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The central hypothesis to be tested in this proposal is that the development of Type 2 diabetes induces alterations in the protein composition of lipid rafts in monocytes and in lipoproteins. Furthermore we hypothesize that these changes will serve as biomarkers for both the development of diabetes (pre-diabetic to diabetic transition) and serve as biomarkers for the development of subsequent cardiovascular complications. The goal of this proposal is to elucidate proteins that are altered in monocyte lipid rafts and lipoproteins in patients with impaired glucose tolerance and newly diagnosed type 2 diabetics compared to patients with normal glucose tolerance. A unique aspect of this proposal is the use of pediatric patients. Type 2 diabetes has historically been an adult disease but unfortunately a large and growing number of children have type 2 diabetes. Although the mechanisms and progression of the disease appear similar in adults and children a major difference between adult and pediatric patients is that the pediatric patients do not have as extensive co-morbidities such as atherosclerosis renal failure and neuropathy. A major problem in identifying biomarkers for type 2 diabetes are confounds created by patients having multiple diseases and taking multiple medications. For the most part these confound is not a major problem in pediatric patients. For these reasons we have chosen to use pediatric patients. Three Specific Aims are proposed. Aim 1: To elucidate the complete proteome of lipid rafts in monocytes and in isolated lipoproteins (LDL and HDL) isolated from patients with normal glucose tolerance. Aim 2: To identify a subset of proteins that associate or disassociate with lipid rafts in monocytes and in lipoproteins (LDL and HDL) isolated from patients with impaired glucose tolerance. Aim 3: To characterize the proteome of lipid rafts in monocytes and in lipoproteins (LDL and HDL) isolated from newly diagnosed Type 2 diabetics.

project_terms:
adolescence (12-20);biomarker;biotechnology;blood lipoprotein metabolism;cardiovascular disorder risk;child (0-11);clinical research;diabetes risk;glucose tolerance;glucose tolerance test;high density lipoproteins;human subject;lipid raft;low density lipoprotein;monocyte;noninsulin dependent diabetes mellitus;obesity;prediabetic state;proteomics


application_id: 7127684
project_number: 5UC1HS014897-03
project_title: ED Information Systems-Kentucky & Indiana Hospitals
administering_ic: AHRQ
award_notice_date: 2006-09-26
opportunity_number: RFA-HS-04-011
application_type: 5
activity_code: UC1
ic: HS
serial_number: 014897
program_official: BASU, JOY
project_start_date: 2004-09-30
project_end_date: 2007-09-29
study_section: ZHS1-HSR-W(01)
contact_pi_person_id: 8736914
contact_pi: MCKNIGHT, JACOB
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 130401078
duns_number: 130401078
fips: US
organization_id: 10004239
organization_name: JEWISH HOSPITAL/ST MARY'S HEALTHCARE INC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 402022877
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-30
budget_end_date: 2007-09-29
project_abstract:
DESCRIPTION (provided by the applicant):  The Emergency Department (ED) is the front door to a hospital and can account for 50 percent of inpatient admissions.  One way to improve patient safety and quality of care and contain costs is to track and document ED patient treatment in a complete electronic medical record that ensures comprehensive patient evaluation and continuity of care.  The objective is to successfully implement and formally evaluate a contemporary web-browser-based electronic record system called the Ibex PulseCheck(r) emergency department information system at two small county-owned community hospitals and one medium-sized community hospital in southern Indiana one rural hospital in central Kentucky and three private primary care physician practices in Indiana.  The lead partner Jewish Hospital is a tertiary-care urban hospital in Louisville Kentucky to which the smaller hospitals refer patients.  The Jewish Hospital ED has already implemented the Ibex ED information system and has the institutional experience to diffuse this technology to the small community hospitals to create a network for ED data sharing.  The four specific aims are to: 1) implement the Ibex ED information systems and train users at four hospitals and three physician groups during three years 2) evaluate the reduction in medical errors (improper discharges) and waiting time in the EDs 3) evaluate the reduction in costs through improved diagnostic coding and billing and fewer repeat tests and 4) evaluate patient and physician satisfaction.  Data gathering will be sequential to ensure a large sample size before (paper) and after (paperless) Ibex implementation.  The lead partner the four unconnected paper-based emergency departments and the three physician offices will no longer be islands of information but will be connected into an integrated eight-facility bi-state urban-rural data- sharing ED health information network.

project_terms:
Internet;automated medical record system;clinical research;computer assisted patient care;computer program /software;computer system design /evaluation;emergency health services;health services research tag;hospital organization /administration;human subject;patient safety /medical error;physicians;training


application_id: 7127265
project_number: 5F31AA015863-02
project_title: Alcohol and a Model of Ischemic Brain Damage
administering_ic: NIAAA
award_notice_date: 2006-08-17
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: AA
serial_number: 015863
program_official: BROWN, RICARDO A
project_start_date: 2005-09-11
project_end_date: 2007-09-10
study_section: ZAA1-HH(30)
contact_pi_person_id: 8201805
contact_pi: STEPANYAN, TRACY D
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Oxygen-glucose deprivation (OGD) has never before been considered as a potential factor in alcohol related neurological damage. Studies suggest that chronic ethanol exposure prior to OGD-induced toxicity will likely exacerbate OGD-induced neurotoxicity via pathological excitation of NMDARs. The objective of this proposal is to examine agents which inhibit the effects of polyamines on NMDARs. These agents will likely be neuroprotective in vitro and in vivo against OGD-induced toxicity in particular following prior ethanol exposure. I will first look at these agents against OGD alone within the hippocampal slice culture model. Next cultures will be exposed chronically to ethanol and then following removal of ethanol the cultures will be exposed to OGD (~1.5hr). Toxicity will be assessed using the non-vital fluorescent dye propidium iodide. These in vitro studies will be followed by in vivo studies that will evaluate if the agents that were effective in vitro reduce the behavioral deficits associated with alcohol exposure in vivo. The studies proposed both investigate the mechanism for potential interactions between OGD and alcohol and also act as a model for the evaluation of potential pharmacological treatments.

project_terms:
NMDA receptors;cerebral ischemia /hypoxia;drug discovery /isolation;drug screening /evaluation;ethanol;fluorescent dye /probe;inhibitor /antagonist;laboratory rat;neuroprotectants;neurotoxicology;polyamines;predoctoral investigator;receptor expression;tissue /cell culture


application_id: 7127156
project_number: 5R01DA012964-07
project_title: Novelty Dopamine and Response to Amphetamine
administering_ic: NIDA
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: DA
serial_number: 012964
program_official: LYNCH, MINDA
project_start_date: 2000-03-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-4(05)M]
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
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Evidence indicates that repeated early life exposure to an enriched environment produces changes in response to novelty and response to drugs of abuse later in life. The overall working hypothesis of this proposal is that exposure to novel environmental stimulation during development decreases responding for nondrug and drug reinforcers during adulthood and that this behavioral change is due at least in part to enhanced basal DA activity in the mesocorticolimbic reward system. The specific aims of the proposed experiments are to determine if environmental enrichment alters: (1) extinction or reinstatement of amphetamine seeking behavior; (2) the ability of nondrug reinforcers to decrease amphetamine self-administration; (3) neuronal processing in the nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) in response to nondrug reinforcers; and (4) activity of the DA transporter (DAT) and vesicular monoamine transporter (VMAT2) in mPFC.      In the proposed experiments rats will be raised from 21 days of age in either an enriched condition (EC) social condition (SC) or imporverished condition (IC). At 50 days of age rats from each condition will be trained to self-administer amphetamine at one of various doses. Extinction and reinstatement of responding for amphetamine will be examined and the ability of a concurrent alternative nondrug reinforcer (sweet solution or visual novelty) to reduce amphetamine self-administration will be examined in EC SC and IC rats. To identify the critical neural mechanisms that underlie these enrichment-induced behavioral changes separate groups of EC and IC rats will be examined for single-unit neuronal activity in the mPFC Nacc core and Nacc shell while having access to sweet solution or novelty. Other experiments will use in vivo voltammetry or in vitro binding/uptake to access potential changes in DAT or VMAT2 in EC and IC rats.     To the extent that both novelty and drugs of abuse activate the same mesocorticolimbic DA circuitry this would suggest that novel stimulation might substitute for drug reward. Novelty-induced reductions in amphetamine self-administration would provide the impetus for examining the effectiveness of presenting enriching stimulation in drug abuse prevention interventions in humans prone to abuse drugs. The long-term objective of our work is to design biologically relevant behavioral treatment and prevention strategies that can be evaluated in a controlled human study.

project_terms:
amphetamines;behavioral /social science research tag;craving;dopamine;early experience;electrophysiology;environmental exposure;laboratory rat;limbic system;neurochemistry;nucleus accumbens;reinforcer;self medication;stimulus /response;substance abuse related behavior


application_id: 7126936
project_number: 5R01DA013519-06
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2006-08-31
application_type: 5
activity_code: R01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2010-08-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_terms:
analog;binding sites;chemical synthesis;computer simulation;conformation;dopamine;drug abuse;drug addiction antagonist;drug design /synthesis /production;drug screening /evaluation;high throughput technology;laboratory rat;membrane transport proteins;methamphetamine;neurotransmitter transport;nicotinic receptors;protein protein interaction;synaptic vesicles


application_id: 7126886
project_number: 5R01DA018633-02
project_title: Mechanisms of Opiate Drug-HIV-Induced Neurodegeneration
administering_ic: NIDA
award_notice_date: 2006-08-01
application_type: 5
activity_code: R01
ic: DA
serial_number: 018633
program_official: LAWRENCE, DIANE M
project_start_date: 2005-09-30
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-A(05)M]
contact_pi_person_id: 8536116
contact_pi: HAUSER, KURT F
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): The opioid system plays a fundamental role in the pathogenesis of AIDS. Brain regions expressing a high number/density of opioid receptors such as the striatum and hippocampus display increased viral load and are preferentially decimated by HIV infection. The progression to AIDS dementia in HIV-positive individuals may also be markedly accelerated in opiate drug abusers. Although the virus itself propagates in microglia and astroglia HIV-1 proteins such as gp120 and Tat are subsequently released and cause degeneration in neighboring neurons. "Opiates" (substances derived from the opium poppy such as heroin) or analogues (e. g. OxyContin) are popular drugs of abuse. Although many aspects of HIV are caused indirectly by infected macrophages/microglial cells direct toxic effects of the viral proteins themselves can be seen in isolated neurons. This direct neurotoxicity is exacerbated by mu opiate drugs. This proposal focuses on the interactions between mu opioids and HIV-1 proteins that result in direct synergistic neurotoxicity. Morphine synergistically increases Tat neurotoxicity via a pathway that is mediated in part by caspase-3. Our hypothesis is that opiates exacerbate neurodegenerative effects of HIV-1 by disrupting cellular homeostasis and increasing the probability of pro-apoptotic intracellular events. Disruptions in premitochondrial pathways involving PI3K Akt PTEN calcium calcineurin and GSKSbeta will be examined for effects on both caspase- 3 dependent and independent (endonuclease-G) cell death using pharmacological transfection (silencing/ overexpression vectors) and genetic strategies [caspase-3(-/-) and PTEN(-) mice]. Complementary in vivo/ in vitro approaches will identify the mechanisms by which mu opiates affect the survival of gp120/Tat- compromised striatal neurons. Aim 1 will explore the mechanisms by which opiate drugs exacerbate gp120/ Tat-induced neuronal death in vitro. Aim 2 will identify the effects of opiates on gp12Q7Tat-induced neurotoxicity in vivo using conditional Tat and gp120 expressing transgenic mice and caspase-3 knockout and PTEN-deficient mice injected intrastriatally with Tat/gp120. Our long-term goal is to define the mechanisms by which opiate drug abuse contributes to neurodegeneration accompanying HIVE in the CNS and to identify the underlying signaling pathways that could be targeted for therapeutic intervention.

project_terms:
AIDS;AIDS dementia complex;HIV envelope protein gp120;HIV infections;drug abuse;drug adverse effect;drug interactions;genetically modified animals;immunocytochemistry;laboratory mouse;nerve /myelin protein;neural degeneration;neurotoxicology;opiate alkaloid;pathologic process;protein protein interaction;small interfering RNA;terminal nick end labeling;tissue /cell culture;virus load;western blottings


application_id: 7126506
project_number: 5R01DA020429-02
project_title: Preventing Cocaine Relapse: Developing Pharmacotherapies
administering_ic: NIDA
award_notice_date: 2006-07-25
opportunity_number: RFA-DA-05-004
application_type: 5
activity_code: R01
ic: DA
serial_number: 020429
program_official: BISWAS, JAMIE
project_start_date: 2005-09-27
project_end_date: 2009-07-31
study_section: ZDA1-RXL-E(15)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cocaine abuse continues to be a significant public health concern. Relapse rates to cocaine use after treatment remain discouragingly high even with the advent of sophisticated behavioral and cognitive relapse prevention therapies. Identifying an effective pharmacological adjunct will likely be necessary to further reduce cocaine relapse rates. The specific aim of this proposal is to demonstrate that aripiprazole is an effective "anti-relapse" medication for cocaine and possibly determine the behavioral mechanism by which it exerts this effect (i.e. aripiprazole attenuates the discriminative effects of priming doses of cocaine thereby reducing subsequent drug self-administration). To accomplish this aim we will first determine the safety and tolerability of cocaine-aripiprazole combinations by administering ascending doses of oral and intranasal cocaine doses during aripiprazole maintenance and monitoring physiological and behavioral responses (Exp. 1). We will then demonstrate that chronic aripiprazole treatment attenuates the discriminative-stimulus effects of cocaine (Exp. 2). The discriminative-stimulus effects of drugs may be involved in relapse to drug taking behavior in that the initial or priming dose (i.e. a lapse) functions as a discriminative stimulus that signals the availability of more cocaine. Finally Exp. 3 will demonstrate that a priming dose of cocaine (i.e. a lapse) increases subsequent cocaine taking using a novel self-administration procedure designed to model relapse and that aripiprazole attenuates this effect. Aripiprazole was chosen for study because it is a potent partial agonist at the dopamine (DA) D2 and serotonin (5-HT) 5-HT1A receptors. Cocaine is thought to exert its effects by blocking monoamine transporters (e.g. DA and 5-HT). Partial agonists may represent a novel and effective means to prevent relapse to cocaine use because theoretically they should have the therapeutic advantages of both an agonist and an antagonist. Consistent with this notion the results of a recent experiment conducted in our laboratory suggest that acutely administered aripiprazole significantly attenuates the discriminative-stimulus and subjective effects of d-amphetamine in humans. We are unaware of any published reports in which the effects of cocaine were assessed in humans following pretreatment with aripiprazole. The proposed research will provide the initial clinical information regarding the efficacy of aripiprazole as a putative "anti-relapse" medication for cocaine dependence. The conduct of the proposed controlled laboratory studies will provide important information (e.g. appropriate doses) that will guide the design of a subsequent clinical trial. Reducing relapse to drug use is important because intravenous abuse of cocaine may be associated with increased risk of acquired immunodeficiency syndrome (A.I.D.S.).

project_terms:
behavior test;chemoprevention;clinical research;cocaine;drug abuse chemotherapy;drug abuse prevention;drug addiction antagonist;drug interactions;drug screening /evaluation;human subject;inhalation drug administration;oral administration;patient oriented research;psychopharmacology;questionnaires;relapse /recurrence;urinalysis


application_id: 7126474
project_number: 5R01CA082159-05
project_title: Regulation of breast cancer growth by activation peptide
administering_ic: NCI
award_notice_date: 2006-08-08
application_type: 5
activity_code: R01
ic: CA
serial_number: 082159
program_official: FORRY, SUZANNE L
project_start_date: 2002-09-01
project_end_date: 2008-08-31
study_section: Experimental Therapeutics Subcommittee 1[ET-1]
contact_pi_person_id: 1865667
contact_pi: VETVICKA, VACLAV
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
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: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant):  The long-term objective is to develop a new treatment for breast cancer based on blockade of the autocrine growth factor activity of procathepsin D. Breast cancer cells secrete procathepsin D the zymogen from which the aspartic proteinase cathepsin D is generated by removal of an activation peptide (APpCD). Procathepsin D has been identified as an independent prognostic factor in breast cancer. In preliminary experiments procathepsin D was found to act as a specific autocrine growth factor for breast cancer-derived cells but not for any other cell type tested. These effects were mediated through a new previously unknown specific receptor moiety expressed on breast cancer cell lines. The region of procathepsin D responsible for its mitogenic activity was localized in position 36-44 of the APpCD sequence. No growth factor activity could be shown with the mature enzyme cathepsin D. The proposed specific aims are based on the central hypothesis that procathepsin D is involved in breast cancer via a specific receptor that mediates autocrine activation for increased metastatic growth. For Aim lit is hypothesized that the overproduction of procathepsin D results in an increase in the metastatic potential of breast tumor cells. A low metastatic human breast cancer cell line will be transfected with human procathepsin D cDNA such that the cells will secrete constitutively varying amounts of procathepsin D. The metastatic potential of each transfected cell line will be evaluated both in vitro and in vivo in relationship to the amount of procathepsin D secretion. In addition the synthesis of pCD will be inhibited using specifically constructed ribozymes. Attempts will be made to determine the exact site in procathepsin D responsible for breast cancer cell growth factor activity. Synthetic peptides representing fragments of APpCD will be prepared. Amino acid substitutions in the most active peptide fragment will be used to map the essential amino acid contact sites for the receptor. For Aim 2 attempts will be made to identify the membrane receptor for procathepsin D. A synthetic peptide representing the binding site domain of procathepsin D will be used to isolate candidate receptor molecules. For Aim 3 it is hypothesized that inhibition of the APpCD interaction with its receptor will result in inhibition of cancer cell growth. Peptide analogs or complementary peptides will be prepared with D-amino acids to block the growth and malignancy of cancer cells both in vitro and in vivo. The overall goal is to generate a pharmacological agent for breast cancer based on blockage of the autocrine growth factor activity of pCD.

project_terms:
affinity chromatography;aspartic endopeptidases;athymic mouse;biological signal transduction;breast neoplasms;cathepsin D;cell growth regulation;complementary DNA;enzyme biosynthesis;enzyme mechanism;growth factor;growth factor receptors;metastasis;mitogens;neoplasm /cancer chemotherapy;neoplasm /cancer pharmacology;nucleotides;prognosis;ribozymes;synthetic peptide;tissue /cell culture;transfection;yeast two hybrid system;zymogens


application_id: 7126430
project_number: 5R43CA109866-02
project_title: Chimeric CD80-SA as a Novel Cancer Vaccine
administering_ic: NCI
award_notice_date: 2006-08-04
application_type: 5
activity_code: R43
ic: CA
serial_number: 109866
program_official: MUSZYNSKI, KAREN
project_start_date: 2005-09-27
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-G(10)B]
contact_pi_person_id: 7246525
contact_pi: HUSEBY, ROLF M
other_pis: Not Applicable
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: 2006-09-01
budget_end_date: 2007-08-31
assistance_listing_number: 93.395
project_abstract:
DESCRIPTION (provided by applicant): Cancer is one of the major causes of death in the U.S. and many developed countries with an estimated economic burden of over 100 billion dollars in direct and indirect costs in the U.S. alone. Although surgery  chemotherapy and radiotherapy are commonly used treatment modalities these therapies not only fail to effectively manage cancer but also are associated with adverse side effects due to their lack of specificity against cancer cells. Therefore there is an acute need for the development of more effective and tumor-specific therapies for the treatment and prevention of cancer.  Immunotherapy has recently gained impetus as a cancer treatment modality due to its specificity safety and its ability to generate immunological memory that can safeguard against recurrences. Tumor cells genetically modified to express costimulatory molecules such as CD80 have been shown to be effective in preventing tumor development and eradicating existing tumors when used as a vaccine in preclinical studies. This approach has been the subject of several recent Phase l/ll clinical trials with encouraging results. However the expression of costimulatory molecules via gene therapy is elaborate inefficient expensive and associated with several safety concerns. To circumvent these problems Apolmmune Inc. is developing vaccines based on a novel proprietary technology designated as ProtEx(tm) that allows for the display of exogenous proteins on the surface of tumor cells in a rapid (<2 hrs) and efficient (100% of the targeted cells) manner without the costs or safety issues inherent to gene therapy. ProtEx involves the generation of chimeric proteins with core streptavidin biotinylation of the cell surface and decoration with chimeric proteins. Most importantly since the chimeric proteins exist as oligomers they can effectively crosslink their counter receptors on relevant immune cells for the delivery of potent signals thereby generating effective anti-cancer immune responses. Proof-of-principle for a proprietary vaccine (ApoVax(tm)) based on the use of tumor cells  decorated" with a chimeric human CD80 molecule (CD80-SA) has been generated in a preclinical tumor model and ex vivo clinical studies. This application is intended to support the development of ApoVax(tm)as a lead vaccine product that will eventually be used in Phase I clinical trials which will be the subject of a Phase II SBIR application. It specifically focuses on i) high yield production purification and characterization of the CD80-SA protein ii) developing a final stable formulation for the protein and ApoVax(tm) vaccine iii) determining the most effective treatment regimens in preclinical studies vi) performing toxicological studies and v) producing pilot cancer vaccine materials under current GMP conditons. The long term success of this project may allow for the development of ApoVax(tm) as a multi-million dollar cancer vaccine product and improvement in the longevity and quality of life for millions of cancer patients.

project_terms:
B cell lymphoma;CD28 molecule;T lymphocyte;affinity chromatography;binding proteins;biotechnology;biotin;cell line;cell surface receptors;chimeric proteins;disease /disorder model;drug adverse effect;glycoproteins;laboratory mouse;leukocyte activation /transformation;lung neoplasms;neoplasm /cancer immunotherapy;neoplasm /cancer vaccine;nonhuman therapy evaluation;protein engineering;protein purification;vaccine development;vaccine evaluation


application_id: 7126393
project_number: 5R01MH063705-06
project_title: Targeting Mass Media Campaigns for HIV STD and Pregnancy Prevention
administering_ic: NIMH
award_notice_date: 2006-09-07
application_type: 5
activity_code: R01
ic: MH
serial_number: 063705
program_official: SCOTT-SHELDON, LORI ANN JENNIFER
project_start_date: 2001-06-28
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-G(02)M]
contact_pi_person_id: 1963601
contact_pi: ZIMMERMAN, RICK S.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-07
project_terms:
AIDS education /prevention;African American;adolescence (12-20);behavioral /social science research tag;caucasian American;child psychology;clinical research;communicable disease control;decision making;education evaluation /planning;family planning;gender difference;health education;high risk behavior /lifestyle;human subject;impulsive behavior;interview;mass information media;personality;public health;safe sex /sex abstinence;sex behavior;sexually transmitted diseases;social psychology;television


application_id: 7126064
project_number: 5R03CA119295-02
project_title: Effects of chemopreventive agents on DNA damage response
administering_ic: NCI
award_notice_date: 2006-08-17
opportunity_number: PAR-04-147
application_type: 5
activity_code: R03
ic: CA
serial_number: 119295
program_official: SEIFRIED, HAROLD E
project_start_date: 2005-09-27
project_end_date: 2008-08-31
study_section: ZCA1-SRRB-Q(O1)
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Benzo[a]pyrene (B[a]P) is a prototypical polycyclic aromatic hydrocarbon produced by incomplete combustion and is a major carcinogen present in cigarette smoke and charred foods. PAH such as B[a]P are major environmental pollutants and exposure is widespread. The highly reactive and mutagenic B[a]P metabolite (+)-7R8S-dihydroxy-9S10R-epoxy-78910-tetrahydrobenzo[a]pyrene (BPDE) is believed to play a significant role in human lung carcinogenesis. Chemoprevention is a relatively new and promising strategy to prevent cancer. Chemopreventive agents such as genistein curcumin and resveratrol have a number of molecular targets impact several signalling pathways and have strong antiproliferation effects on lung breast prostate and colon cancers. These three constituents have received a great deal of attention recently as cancer chemoprotective agents. Little work has been done to investigate the chemoprevention effects of genistein resveratrol and curcumin with respect to PAH-induced DNA damage and repair responses. The global genomic repair component of nucleotide excision repair is regulated by p53 induction in response to DNA damage. P53 is induced in a dose and time-dependent manner after DNA damage. Low dose BPDE which is known to be mutagenic fails to induce the p53 mediated response to DNA damage. Our preliminary results suggest that pretreatment with a combination of resveratrol and curcumin enables p53 induction by low dose BPDE exposure. We hypothesize that chemopreventive agents may "sensitize" the cell to respond to low dose genotoxicant induced DNA damage through induction of p53 which activates global genomic DNA repair process allowing more efficient DNA repair. This study aims to investigate the effects of chemoprevention agents on cellular responses to BPDE-induced DNA damage in human lung cells. We aim to determine mechanism and effects of chemopreventive agents (singly and in combination) on p53 mediated regulation of (1) cell cycle progression and (2) DNA repair induction. Experimental approaches will include western blot to measure p53 and regulated signaling proteins in human lung cells and measure BPDE-induced DNA adduct formation and repair rate by 32P-post-labeling analyses. The results will likely illuminate a chemoprevention mechanism and also provide a deeper understanding of the mechanism of DNA damage and repair under a more physiologically relevant environmental exposure dose.

project_terms:
DNA damage;DNA repair;adduct;benzopyrenes;cancer prevention;cell cycle;chemoprevention;chemosensitizing agent;combination chemotherapy;environmental exposure;gene expression;lung neoplasms;p53 gene /protein;pharmacokinetics;respiratory epithelium;western blottings


application_id: 7125182
project_number: 5P20CA097942-05
project_title: James Graham Brown P20 Application
administering_ic: NCI
award_notice_date: 2006-07-13
opportunity_number: PAR-00-011
application_type: 5
activity_code: P20
ic: CA
serial_number: 097942
program_official: BHORJEE, JASWANT
project_start_date: 2002-08-02
project_end_date: 2008-07-31
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: (Applicant's Description) The James Graham Brown Cancer Centeris the Cancer Program of the University of Louisville. The overall goal ofthis P20 application is to obtain support for the planning activitiesnecessary to achieve NCI designation as a Comprehensive Cancer Center withinthe next five years. The University of Louisville has made designation of theBrown Cancer Center as a Comprehensive Cancer Center its highest objective inthe Challenge for Excellence program over the next decade. The UniversityPresident and Vice-President for Health Affairs have recognized the difficultyof this task by making a substantial financial and space commitment to theCancer Center. The resources required to support the necessary growth for thedevelopment of a Comprehensive Cancer Center have been committed. In fact theJGBCC fundraising campaign has generated firm commitments for $55 million ofthe $100 million goal in the past year. This commitment has resulted in therecruitment of an experienced Director and thirty new faculty during the pasttwo years. A Strategic Plan which builds on pre-existing strengths of theBrown Cancer Center and narrowly focused new recruitment will allow theaccomplishment of this goal. This plan relies heavily on the advice of anExternal Advisory Committee comprised of Cancer Center Directors andscientific leaders from around the country. In addition an Internal AdvisoryCommittee will provide counsel on the integration of the Brown Cancer Centerprograms into the University of Louisville research infrastructure. TheStrategic Plan includes the development of four scientific programs and onedevelopmental program. The four scientific programs are: Molecular Targets;Chemokine and Growth Factors; Developmental Therapeutics; and CancerPrevention and Control. The developmental Stem Cell Biology Program(currently in the Chemokine & Growth Factors Program) will evolve into anindependent scientific program. Additionally establishment of theBrown/Norton Cancer Hospital will provide much of the clinical growth whichwill be necessary to support growing clinical research programs.

project_terms:
cancer prevention;comprehensive medical planning;experimental designs;health care service planning;health science research;health science research support;health services research tag;interdisciplinary collaboration;neoplasm /cancer diagnosis;neoplasm /cancer education;neoplasm /cancer therapy


application_id: 7125039
project_number: 5K12DA014040-07
project_title: BUILDING INTERDISCIPLINARY RESEARCH CAREERS
administering_ic: NIDA
award_notice_date: 2006-08-29
opportunity_number: RFA-OD-05-002
application_type: 5
activity_code: K12
ic: DA
serial_number: 014040
program_official: FRANKENHEIM, JERRY
project_start_date: 2000-09-30
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-J(50)R]
contact_pi_person_id: 7875362
contact_pi: FERGUSON, JAMES E.
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
career;drug abuse;endocrinology;gender difference;health science profession;health science research potential;hormone regulation /control mechanism;mentoring /mentor;oral health;pregnancy;training;women&apos;s health


application_id: 7125036
project_number: 5R01DA016718-03
project_title: Licit & Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2006-08-07
opportunity_number: PA-01-048
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: WETHERINGTON, CORA LEE
project_start_date: 2004-07-10
project_end_date: 2009-06-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: 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): Epidemiological studies report increasing non-medical use and diversion of prescription opioid analgesics. Oxycodone is marketed in an array of formulations and used for the treatment of acute and chronic pain. Oxycontin(r) is a sustained-release formulation which is marketed in higher dosage formulations compared to immediate release products; both formulations have received substantial negative publicity due to reports of increased frequency of unintentional addiction fatal overdose and criminal diversion. Hydrocodone a related semi-synthetic opioid is the most widely prescribed opioid analgesic in the United States and the most frequently mentioned prescription opioid in emergency room admissions. Despite their widespread clinical use few studies have evaluated the abuse liability and clinical pharmacology of these commonly used opioids. This project will employ controlled laboratory procedures to evaluate and characterize the effects of oxycodone and hydrocodone in volunteers with histories of opioid abuse under an array of conditions. Each of the studies will use randomized placebo-controlled double blind within-subject designs. Dose rising pilot evaluations will precede randomized testing for safety purposes. Experiment 1 will compare the effects of oral oxycodone and hydrocodone to those of hydromorphone a mud opioid agonist with known high abuse potential and placebo over a broad range of doses. Experiment 2 will focus on the sustained-release Oxycontin(r) product and will compare its pharmacokinetic and pharmacodynamic properties when administered intact or after tampering (pulverizing to by-pass the sustained release features) to immediate release oxycodone and placebo; pharmacokinetic analyses will yield bioavailability data in this study. Experiment 3 will evaluate the pharmacodynamic effects of IVoxycodone and hydrocodone compared to morphine heroin and placebo. In all studies data will be collected across multiple domains. Physiological and subjective measures will be collected to assess safety and abuse liability respectively and a battery of psychomotor and cognitive tasks will assess the impairing effects of these agents. These studies will contribute substantial new knowledge about the relative abuse potential and safety of these widely available agents at therapeutic and supratherapeutic doses in a population of subjects who are likely to abuse them. Information relevant to the public health will include the relative potency and tolerability of these compounds the consequences of tampering with marketed formulations and empirical information relevant to safety scheduling and marketing of these agents.

project_terms:
analgesics;behavioral /social science research tag;clinical research;cognition;disease /disorder proneness /risk;drug abuse;drug administration rate /duration;drug adverse effect;drug delivery systems;drug tolerance;heroin;human subject;morphine;opiate alkaloid;patient oriented research;performance;pharmacokinetics;psychological tests;psychometrics;psychomotor function;psychopharmacology;relapse /recurrence;residential care facility;self medication;stimulant /agonist;substance abuse epidemiology;substance abuse related behavior


application_id: 7125034
project_number: 5R21CA115345-02
project_title: Telehealth Symptom Management in Head and Neck Cancer
administering_ic: NCI
award_notice_date: 2006-08-17
opportunity_number: RFA-CA-05-013
application_type: 5
activity_code: R21
ic: CA
serial_number: 115345
program_official: O'MARA, ANN M
project_start_date: 2005-09-23
project_end_date: 2008-11-30
study_section: ZCA1-SRRB-3(M1)
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This study will design and evaluate a telehealth intervention to improve symptom management and palliation for patients undergoing treatment for head and neck cancers.  Using a telehealth monitoring system the study will address and attempt to overcome communication barriers common to this patient population in an effort to bridge the gap between established symptom management science and the actual application of validated measures to ameliorate symptom distress.  The study will consist of two phases.  In Phase One best practices and participatory action research with patients caregivers and clinicians will be employed in developing a telehealth algorithm based on symptoms and issues commonly experienced by head and neck cancer patients.  This algorithm will be integrated into a telehealth device system that involves patients in daily symptom assessment addressing their comprehensive interdisciplinary care needs.  The device is inexpensive and simple for patients to use.  In Phase Two a randomized controlled trial will evaluate the efficacy efficiency acceptability and feasibility of the intervention.  The primary outcome evaluated will be symptom distress.  Both experimental and usual care groups will complete evaluation instruments measuring symptom distress symptom prevalence symptom severity quality of life self-efficacy to address symptoms and satisfaction with symptom management.  The long-term goal of this study is to design a telehealth methodology to improve symptom management that is generalizable to the broader cancer community.

project_terms:
behavioral /social science research tag;cancer rehabilitation /care;clinical research;focus groups;head /neck neoplasm;health services research tag;human subject;patient care management;patient oriented research;telemedicine


application_id: 7124441
project_number: 1R21AG028816-01
project_title: A screen for small molecule inhibitors of soluble Abeta oligomer assembly
administering_ic: NIA
award_notice_date: 2006-08-09
opportunity_number: PAR-05-056
application_type: 1
activity_code: R21
ic: AG
serial_number: 028816
program_official: SUNEJA, SANOJ
project_start_date: 2006-09-01
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 BST-L (50)]
contact_pi_person_id: 2421413
contact_pi: LEVINE, HARRY
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): Soluble oligomeric forms of the Alzheimer's beta-peptide (Abeta(1-42)) are receiving increasing attention as potential mediators of the neurotoxic activity of Abeta and as a possible causative agent for Alzheimer's disease. The search for potentially therapeutic anti-oligomer compounds has been hampered by the lack of a high-throughput screening assay and artifactual interactions of compounds with antibodies. This exploratory proposal applies a novel inexpensive assay format to screen for compounds that inhibit the formation of soluble Abeta oligomers or destabilize their structure facilitating biological clearance. A small library of pharmaceutical agents will be screened to establish performance parameters followed by evaluation of a more extensive pharmacophore library to identify structures of potential interest. Specific Aim 1. To develop a high-throughput assay system to identify compounds to inhibit Abeta oligomer formation. Preventing Abeta(1-42) oligomer assembly at an early stage will prevent stable toxic species from being formed. Oligomeric species of synthetic N-terminally biotinylated Abeta(1-42) will be quantified with a novel biotin-avidin single site binding assay. This method is preferable for primary screening over even oligomer-specific antibodies because it avoids a significant number of false positives inactive compounds that interfere with antibody epitopes and antibodies. The procedure will be implemented on a Tecan Genesis LiHa/TeMo robotics system at UK. Specific Aim 2. To develop a high-throughput assay system to identify compounds to destabilize Abeta oligomer structure. Abeta oligomers are highly protease-resistant and thus poorly cleared from the brain. Compounds that destabilize oligomers allowing degradation by Abeta-metabolizing proteases would be useful in reducing oligomer levels and be of potential therapeutic value. Synthetic Abeta oligomers formed in the presence of compound or preformed and then treated with compound will be screened with trypsin and if positive digested with insulin-degrading enzyme and neprilysin proteases believed to degrade Abeta peptides in vivo. Selected positive compounds will be also tested for their effect on the protease sensitivity of soluble Abeta oligomers extracted from AD brain employing a new highly sensitive single site immunoassay configured for the Luminex-100(r) Beadlyte(tm) system. This method shows promise for the detection of oligomeric Abeta in biological fluids including animal models and clinical specimens to determine the effectiveness of anti-oligomer therapeutics. Specific Aim 3. To determine the performance of the assays developed in Specific Aims 1 and 2 on screening the LOPAC compound library and a targeted screen of the more extensive Hit-Finder(tm) pharmacophore collection. The LOPAC library will be used to troubleshoot the protocols optimized in Specific Aims 1 and 2 applied in a screening format. Results from this screen will be used to predict which compounds in the 16000 compound Maybridge Hit-Finder(tm) collection may be active in blocking oligomer formation. Although the intent of this exploratory/developmental proposal is primarily to validate the assays active compounds will provide tools that will be useful in probing the biological effects of Abeta oligomers since the pharmaceutical agents that make up LOPAC are compatible with cellular systems. Anti-oligomer compounds could potentially block the cognitive impairment symptoms that oligomers elicit in animal models and interfere with the progression of Alzheimer's disease.

project_terms:
amyloid proteins;biotinylation;chemical registry /resource;chemical synthesis;clearance rate;combinatorial chemistry;drug screening /evaluation;endopeptidases;high throughput technology;human tissue;inhibitor /antagonist;nanotechnology;neuropharmacology;pharmacokinetics;postmortem;protein biosynthesis;protein degradation;protein structure;small molecule;technology /technique development


application_id: 7124340
project_number: 5R01HL071865-05
project_title: Mechanisms of E-C Coupling in Atrial Cells
administering_ic: NHLBI
award_notice_date: 2006-07-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 071865
program_official: PRZYWARA, DENNIS
project_start_date: 2003-08-01
project_end_date: 2008-07-31
study_section: Cardiovascular and Pulmonary Research A Study Section[CVA]
contact_pi_person_id: 1901564
contact_pi: BALKE, C WILLIAM
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: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): Normal excitation-contraction (EC) coupling in mammalian cardiac cells requires the coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR). In mammalian ventricular cells the extensive transverse-tubular (t-tubular) system conducts electrical depolarization rapidly to the cell interior that triggers a near synchronous release of C2+ from the SR and subsequent activation of the myofibrils throughout the cell. Because atrial cells lack an extensive t-tubular network the coordination of SR Ca2+-release and contraction in atrial cells must depend on an entirely different cellular process. The aim of the proposed research is to answer the question "What is (are) the cellular mechanism(s) responsible for the transduction of membrane depolarization to subsequent contraction in cardiac atrial cells?" The overall hypotheses of this proposed project are (1) that the mechanism of coupling Ca2+-entry through L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings of atrial cells is the same as that which occurs at the t-tubular-junctional SR region in ventricular cells and (2) that because of the absence of a well-organized t-tubular system in atrial cells the normal physiological mechanisms of SR Ca2+-release away from the peripheral couplings are entirely different. Specific aim 1 tests the hypothesis that the relationship between Ca2+-entry via L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings in atrial cells is identical to that in the t-tubular-junctional SR region of ventricular cells. Specific aim 2 tests the hypothesis that both propagated and non-propagated Ca2+-release occur in atrial cells and that the type of Ca2+-release is determined by SR Ca2+-load ryanodine receptor (RyR) Ca2+-sensitivity and the magnitude and duration of the Ca2+-entry through L-type Ca2+ channels. Specific aim 3 tests the hypothesis that the magnitude and velocity of contraction depends on the type of Ca2+-release (non-propagating or propagating) and the "diffusional" size of the cell. We hypothesize that an increase in the cell circumference triggers a switch between non-propagating and propagating Ca2+-release thereby providing a means for maintaining the speed and magnitude of contraction despite differences in cell size. Specifically we test (1) that non-propagating Ca2+-release can elicit rapid and large contractions in atrial cells with small circumference. (2) Propagating Ca2+-waves are needed to cause rapid and large contractions in atrial cells with a large circumference. (3) The transverse axial tubular system (TATS) by reducing diffusional distances allows non-propagating Ca2+-release to cause rapid and large contractions in large atrial cells. This proposal uniquely combines mathematical modeling cellular electrophysiology and Ca2+ imaging and will provide a quantitative understanding of Ca2+ homeostasis in cardiac atrial cells.

project_terms:
atrium;biological signal transduction;calcium channel;calcium ion;cardiac myocytes;cell membrane;cell morphology;cellular polarity;charge coupled device camera;confocal scanning microscopy;electrophysiology;heart contraction;laboratory rat;mathematical model;myofibrils;sarcoplasmic reticulum;voltage /patch clamp


application_id: 7124222
project_number: 5UC1HS015182-03
project_title: Connecting Healthcare in Central Appalachia
administering_ic: AHRQ
award_notice_date: 2006-09-01
opportunity_number: RFA-HS-04-011
application_type: 5
activity_code: UC1
ic: HS
serial_number: 015182
program_official: WHITE, JON
project_start_date: 2004-09-30
project_end_date: 2008-08-31
study_section: ZHS1-HSR-W(01)
contact_pi_person_id: 7839487
contact_pi: BENTLEY, POLLY M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 058685439
primary_uei: MXUKTEJZLNL4
duns_number: 058685439
uei: MXUKTEJZLNL4
fips: US
organization_id: 5326001
organization_name: APPALACHIAN REGIONAL HEALTHCARE, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405054808
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant):  Appalachian Regional Healthcare Inc. is an integrated rural health care delivery system serving approximately 20 counties throughout eastern Kentucky and southern West Virginia.  With hospitals clinics home health agencies and home care stores the rural location and wide range of services offered by this system require an intense focus on building connectivity via technology.  
  
With this proposal the various facilities that make up the ARM system will launch the implementation of a major component of its clinical information initiative.  The implementation of the initial stages of electronic medical records will increase the timeliness and accuracy of care provided to patients improve workflow throughout the system and across the continuum of care and ultimately improve the overall quality of care provided to patients.  The rollout of ARH's electronic medical records will begin in the system's Whitesburg ARM Hospital and Hazard ARH Regional Medical Center locations.  
  
Funding requested with this proposal will provide essential hardware components to initiate this kick-off training for project core team members and hospital medical records staff and the personnel costs associated with the adaptation of the electronic medical records system to accommodate ARH's needs and the standardization of forms to complement the system.

project_terms:
automated medical record system;behavioral /social science research tag;computer assisted patient care;cooperative study;health care quality;health services research tag;interdisciplinary collaboration;patient safety /medical error;rural area


application_id: 7124219
project_number: 5R01CA106281-02
project_title: The CXCR4-SDF-1 Axis in Metastatic Rhabdomyosarcoma
administering_ic: NCI
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 106281
program_official: TRICOLI, JAMES
project_start_date: 2005-09-20
project_end_date: 2010-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_terms:
antineoplastics;athymic mouse;cell line;chemokine receptor;chemotaxis;cytokine;host neoplasm interaction;human tissue;laboratory mouse;metastasis;neoplasm /cancer transplantation;neoplastic cell;neoplastic growth;rhabdomyosarcoma;xenotransplantation


application_id: 7124211
project_number: 5R01MH072567-02
project_title: Tat amyloid beta and brain endothelial barrier function
administering_ic: NIMH
award_notice_date: 2006-08-01
opportunity_number: PAS-04-072
application_type: 5
activity_code: R01
ic: MH
serial_number: 072567
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2005-09-20
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-A(05)M]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
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): One (1) of the emerging problems in HIV/AIDS is an increase in an older population affected by HIV infection. This phenomenon is of significant concern because aging is a predictor of rate of progression of HIV infection. Elderly patients develop AIDS more rapidly and have higher morbidity and mortality rates. Older patients are also more likely to develop AIDS-associated dementia. The present research application is focused on the mechanisms that may contribute to the development of dementia in elderly HIV-infected patients. Specifically we propose to study the mechanisms related to the injury to the vascular endothelium and dysfunction of the blood brain barrier (BBB). Our research has concentrated on the hypothesis that the viral gene product HIV Tat protein can be responsible for brain microvascular endothelial cells (BMEC) injury and impaired normal function of the BBB. Furthermore aging is associated with increased deposits of amyloid P-peptide (AP) which also can induce dysfunction of BMEC. Therefore it is striking to notice that AB and HIV Tat protein may work in concert in older HIV patients to induce impaired function of the brain vascular endothelium and contribute to the development of neuroAIDS. In the present grant application we hypothesize that AB and Tat can cross-amplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus a combined exposure to Ap and Tat can lead to accelerated entry of HIV-1 into the CNS. To study these hypotheses this research proposal is focused on the pathways related to AP and/or Tat-induced cellular oxidative stress monocyte transendothelial passage disruption of expression of cell junction proteins and decreased barrier function of the BBB. The main in vitro experimental system will consist of the unique and innovative co-cultures of human BMEC with astrocytes which endogenously produce and release Tat. Part of our studies will also employ an animal model of amyloid angiopathy exposed to Tat. The long term goals of the current proposal are to determine mechanisms which may prevent Ap and Tat-induced injury to BMEC. Data arising from this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV-1 infection associated with aging. In a broader aspect this proposal will contribute to better knowledge of how aging can contribute to the development of neurological complications of HIV/AIDS.

project_terms:
AIDS /HIV neuropathy;HIV infections;aging;amyloid proteins;biological signal transduction;blood brain barrier;cell migration;cytotoxicity;gene expression;human immunodeficiency virus 1;human tissue;intercellular connection;laboratory mouse;monocyte;nervous system disorder epidemiology;oxidative stress;tissue /cell culture;virus infection mechanism;virus protein


application_id: 7123785
project_number: 5R01HL068733-04
project_title: CA Permeable Na Channels & Cardiac Cell Excitation
administering_ic: NHLBI
award_notice_date: 2006-08-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 068733
program_official: LATHROP, DAVID A
project_start_date: 2003-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-HEM-2(02)M]
contact_pi_person_id: 1901564
contact_pi: BALKE, C WILLIAM
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: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): ICa(TTX) is a sodium current component seen in a number of neural and cardiac preparations. In each case ICa(TTX) channels were found to express both different gating and different permeability properties from the main body of sodium current in that cell type. For rat ventricular cells we have shown that ICa(TTX) channels are encoded by a different gene from that encoding the classical cardiac sodium current. As expected from the very existence of a clear current component ICa(TTX) channels do affect the electrical behavior of ventricular cells and can even generate action potentials. ICa(TTX) activates over a more negative range of potentials than the classical cardiac sodium current. It should then act to amplify the depolarization delivered to a ventricular cell and so provide the immediate trigger for the cardiac action potential. Owing to this role ICa(TTX) could be of considerable importance in cardiac arrhythmias and in their control. It has been reported in both human atrial and ventricular cells. We have then a new channel encoded by a distinct gene that contributes to cardiac cell electrical behavior. The potential importance of this channel for both normal and pathological cardiac electrophysiology calls for its extensive study. We propose to: (i) Determine the slow inactivation properties of ICa(TTX) and compare them to those of the classical sodium current. The slow inactivation process is critical for determining the stationary state pool of available sodium channels. The expected role of ICa(TTX) as the immediate trigger for the cardiac action potential suggests that its slow inactivation properties (and defects in them) could have disproportionately strong effects on the generation and conduction of the cardiac action potentials. (ii) Quantitatively determine the selectivity sequence of ICa(TTX) channels to both mono- and divalent ions. The characteristics of a current component are determined by it selectivity as well as its gating properties. This will be the first determination of the alkali ion selectivity of a native sodium channel that expresses high calcium permeability and could be of importance for the emerging picture of the structural basis for ion selectivity in typical sodium channels. (iii) Start the molecular identification of ICa(TTX) channels by use of antisense oligonucleotides directed against the several sodium channel isoforms known to be expressed in cardiac cells. (iv) Compare the properties of ICa(TTX) in normal and failing human hearts to see if alterations in its properties correlate with pathological conditions.

project_terms:
action potentials;antisense nucleic acid;atrium;calcium channel;clinical research;electrophysiology;heart cell;heart conduction system;heart electrical activity;heart ventricle;human tissue;laboratory rat;mathematics;membrane permeability;protein isoforms;sodium channel


application_id: 7123703
project_number: 1R21AG028307-01
project_title: The impact of aging on the inflammatory response
administering_ic: NIA
award_notice_date: 2006-09-08
opportunity_number: RFA-AG-05-011
application_type: 1
activity_code: R21
ic: AG
serial_number: 028307
program_official: FLORES, ROBERTO L
project_start_date: 2006-09-15
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-5 (M1)]
contact_pi_person_id: 1969952
contact_pi: STOUT, ROBERT D
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Elderly Individuals are more suceptible to bacterial infection and these infections are a major cause of morbidity and mortality in hospitalized elderly patients. Research on the adaptive immune response has identified several age-associated defects in  lymphocytes. Research on the innate response has been more sparse focusing for the most part on the functional responsiveness of isolated resting macrophages and neutrophils to in vitro stimuli. The inflammatory response in young mice is a highly orchestrated sequence of events that entail sequential extravasation of neutrophils monocytes and lymphocytes. The activities displayed by the macrophages and neutrophils are inflammatory microbicidal and cytotoxic. Upon successful debridement of the wound neutrophils apoptose and are phagocytized by macrophages and the macrophages fibroblasts and endothelial cells collaborate in wound resolution. If Th1 cells entering the site become activated they will help sustain the inflammatory and cytotoxic activities of the macrophages. We hypothesize that age-associated deficiencies in inflammation may be associated with a loss of orchestration of these events rather than a loss of responsiveness of the cells of the innate immune system. To explore the validity of this hypothesis we propose to examine the inflammatory response in young and aged mice using a model of intra-abdominal inflammation elicited by alum-precipitated egg albumin. To include T cells in the model mice will receive intravenously activated Th1-polarized OT-II ovalbumin-reactive T cells. The rate and degree of infiltration of neutrophils macrophages and T cells will be monitored. Neutrophils will be analyzed ex vivo for expression of secretory vesicles and specific granules expression of inflammatory cytokine and chemokine mRNA and apoptosis and analyzed in vitro for  phagocytosis H2O2 production and chemotaxis. Macrophages will be analyzed for expression of inflammatory and anti-inflammatory cytokine and chemokine mRNA for expression of cell surface co-stimulatory molecules and effective interaction with infiltrating T cells. This project will provide critical data on how advanced age impacts the inflammatory response and provide avenues of future study on means of therapeutic targeting of the deficiencies. Even transient improvement in inflammatory response will not only enhance microbial clearance and wound healing but likely will also enhance the efficacy of vaccination against infectious disease.

project_terms:
B lymphocyte;T lymphocyte;aging;apoptosis;cell cell interaction;chemotaxis;genetically modified animals;immune response;immunoregulation;immunosenescence;inflammation;interferon gamma;laboratory mouse;leukocyte activation /transformation;macrophage;messenger RNA;neutrophil;nitric oxide synthase;ovalbumin;phagocytosis;polymerase chain reaction


application_id: 7123510
project_number: 5F31NR008979-03
project_title: Performance Actigraphy and Sleep in Long-Haul Truckers
administering_ic: NINR
award_notice_date: 2006-07-13
opportunity_number: PAR-02-019
application_type: 5
activity_code: F31
ic: NR
serial_number: 008979
program_official: MANN KOEPKE, KATHY M
project_start_date: 2004-08-04
project_end_date: 2007-08-03
study_section: Nursing Science Review Committee[NRRC(28)]
contact_pi_person_id: 7798432
contact_pi: HEATON, KAREN L
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this study is to determine the effect of performance actigraphy on attitude toward and perceived control of sleep and on quality and quantity of sleep in long-haul truck drivers. Truckers will be randomly assigned to a control group and two intervention groups. Measures of attitude toward sleep and perceived control of sleep will be obtained on day one from all participants. From days 1 - 20 the two intervention groups will be given sleep logs and non-performance actigraphs. On day 21 intervention group 2 will be switched to performance actigraphy; group 1 will continue with non-performance actigraphy. At day 40 measures of attitude and perceived control of sleep will be repeated for all 3 groups. Performance actigraphy may cue long-haul truckers to proactively engage in healthy sleep practices by planning and coordinating sleep behaviors and on-off duty activities. The aims of this study are in keeping with the research and health promotion initiatives of the National Institutes of Health (National Sleep Research Agenda); Healthy People 2010 (Injury Prevention); and the National Institute of Occupational Safety and Health (Traumatic Injury). Because the proposed study investigates a specific intervention that promotes self-management and decision making it also reflects the theme "Changing lifestyle behaviors for better health" outlined in the National Institute of Nursing Research's Research Themes for the Future (2003).

project_terms:
actigraphy;attitude;behavior therapy;behavioral /social science research tag;clinical research;cues;decision making;health behavior;human subject;injury prevention;occupational health /safety;performance;predoctoral investigator;sleep;transportation /recreation safety;wakefulness


application_id: 7123084
project_number: 5K01AA015344-02
project_title: Mechanisms of Sensitization to TNF hepatotoxicity in ALD
administering_ic: NIAAA
award_notice_date: 2006-08-21
opportunity_number: PAR-02-065
application_type: 5
activity_code: K01
ic: AA
serial_number: 015344
program_official: PUROHIT, VISHNU
project_start_date: 2005-09-15
project_end_date: 2010-08-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 7929995
contact_pi: SONG, ZHENYUAN
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):  Alcoholic liver disease (ALD) continues to be an important health problem in the United States. Abnormal hepatic methionine metabolism is an acquired metabolic abnormality in ALD and the effects of chronic alcohol intake on hepatic methionine metabolism are initially seemingly paradoxic. Whereas alcohol consumption causes hepatic deficiency of S-adenosylmethionie (SAMe) it elevates hepatic homocysteine levels a product of SAMe metabolism.   
  
Decreased SAMe levels and elevated homocysteine levels may contribute to alcohol induced liver injury. The effect of alcohol on S-adenosylhomocysteine (SAH) levels another metabolite in the methionine metabolism pathway has received little investigative attention. It is our working hypothesis that tumor necrosis factor (TNF) in conjunction with certain metabolic abnormalities observed in ALD such as altered intracellular methylation status due to abnormal methionine/SAMe/SAH metabolism play an etiologic role in the development of liver injury in ALD. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia generation of reactive oxygen intermediates activation of Kupffer cell NFkB with increased TNF production decreased hepatocyte MAT activity with subsequent SAMe deficiency increased S-adenosylhomocysteine (SAH) concentrations inhibition of transmethylation reactions decreased hepatic methylation status elevated expression/ activation/activity of proteins sensitive to intracellular methylation status such as caspase-8 mitochondrial dysfunction increased susceptibility to hepatic TNF cytotoxicity and subsequent liver injury. In this proposal we will evaluate inhibition of hepatic transmethylation reactions by chronic alcohol exposure as a mechanism for hepatic sensitization to TNF-induced cytotoxicity in a relevant model of ALD. The specific objectives of this project are as follows: 1. Evaluate the effects of inhibition of hepatic transmethylation reactions on "sensitization" to TNF hepatotoxicity; 2. Investigate possible mechanisms by which inhibition of transmethylation reactions sensitizes hepatocytes to TNF hepatotoxicity; and 3. Evaluate the effects of chronic alcohol consumption (+/- SAMe supplementation) on hepatic methylation status and sensitization to TNF-hepatotoxicity in rats intragastrically fed alcohol.   
  
This research will be performed with structured mentoring support and a detailed training program designed to maximize my opportunity to become an independent NIH-funded investigator.

project_terms:
S adenosylmethionine;alcoholic beverage consumption;alcoholic fatty liver;alcoholic liver cirrhosis;alcoholism /alcohol abuse;cysteine endopeptidases;enzyme activity;enzyme inhibitors;enzyme linked immunosorbent assay;gel mobility shift assay;hepatotoxin;laboratory rat;liver toxic disorder;methionine;polymerase chain reaction;terminal nick end labeling;tissue /cell culture;transmethylation;tumor necrosis factor alpha


application_id: 7122780
project_number: 5R01DK071765-02
project_title: Mechanisms of S-adenosylmethionine in NASH
administering_ic: NIDDK
award_notice_date: 2006-07-31
application_type: 5
activity_code: R01
ic: DK
serial_number: 071765
program_official: DOO, EDWARD
project_start_date: 2005-09-15
project_end_date: 2010-07-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_terms:
S adenosylmethionine;antidepressants;antioxidants;cell differentiation;clinical research;cytokine;depression;drug screening /evaluation;hepatitis;human subject;human therapy evaluation;liver cells;liver disorder chemotherapy;liver function;liver metabolism;liver pharmacology;metabolic syndrome;methylation;methyltransferase;obesity;oxidative stress;patient oriented research;pharmacokinetics;protein quantitation /detection;proteomics;quality of life;tumor necrosis factor alpha


application_id: 7122541
project_number: 5K23DK073750-02
project_title: Evaluation of the Effect of Green Tea Polyphenols on IBD
administering_ic: NIDDK
award_notice_date: 2006-09-04
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DK
serial_number: 073750
program_official: PODSKALNY, JUDITH M,
project_start_date: 2005-09-15
project_end_date: 2010-08-31
study_section: Clinical Research Review Committee[RIRG-G]
contact_pi_person_id: 7368605
contact_pi: DRYDEN, GERALD W
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
alternative medicine;antiinflammatory agents;antioxidants;clinical research;clinical trials;cytokine;drug screening /evaluation;flavonoids;gastrointestinal disorder chemotherapy;gene expression;human subject;human therapy evaluation;inflammatory bowel diseases;interleukin 1;interleukin 10;interleukin 8;monocyte;nuclear factor kappa beta;patient oriented research;pharmacokinetics;tea;tumor necrosis factor alpha;ulcerative colitis


application_id: 7122400
project_number: 5R34MH073071-02
project_title: Outcomes of Teacher Training on Autism
administering_ic: NIMH
award_notice_date: 2006-07-14
opportunity_number: PAR-03-078
application_type: 5
activity_code: R34
ic: MH
serial_number: 073071
program_official: MARRO, MARY ACRI
project_start_date: 2005-09-15
project_end_date: 2007-07-31
study_section: Services Research Review Committee[SRV]
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed project is pilot research aimed at developing "novel service delivery models designed to target children with complex comorbid and/or chronic conditions in school and community-based settings." It is timely and responds to the National Institute of Mental Health PA: PAR-03-078 "From intervention development to services: Exploratory research grants"1 and a concern of the lag between research and practice for children with autism. This gap is significant because of the increasing numbers of children with autism identified by public service agencies and a lack of trained community and school-based personnel. The proposed study will evaluate the effects of an innovative treatment approach for children with autism who participate in community-based public school programs. Guidelines of effective practice and recommendations for research generated by the National Research Council (NRC) in 2001 are incorporated. Caregiver teacher and school variables as well as child effects will be evaluated. The evaluation of this intervention is longitudinal and focuses on important child outcomes over a period of one school year as well as parent/caregiver and teacher outcomes. The aims of this proposal are: (1) To generate pilot data and effect size estimates of the impact of a child-specific consultation approach (COMPASS) vs. "usual" educational program development practice by prospectively following a random sample of 60 children whose teachers received COMPASS and whose teachers did not receive COMPASS and (2) to generate pilot data of additional factors (school organization teacher parent and child) that may account for variance in teacher child and family outcomes.

project_terms:
allied health education;autism;behavioral /social science research tag;caregivers;child behavior;child mental health service;child psychology;clinical research;community mental health services;data collection methodology /evaluation;education evaluation /planning;educational resource design /development;health care model;health care policy;health services research tag;human subject;longitudinal human study;mental health education;outcomes research;parent offspring interaction;psychological stressor;questionnaires;schools;teacher;training


application_id: 7121408
project_number: 3P50AG005144-21S4
project_title: ALZHEIMER'S DISEASE RESEARCH CENTER
project_terms: Alzheimer&apos;s disease
administering_ic: NIA
award_notice_date: 2005-09-12
opportunity_number: AG99-003
application_type: 3
activity_code: P50
ic: AG
serial_number: 005144
suffix: S4
program_official: LARKIN, JENNIE
project_start_date: 1985-09-30
project_end_date: 2006-07-14
study_section: ZAG1
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
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
project_abstract:
This application is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of Kentucky's Sanders-Brown Center on Aging. The UK ADRC has developed a multi-disciplinary program including basic and clinical research exemplary clinical care and neuropathological activities satellite clinics for rural and minority subjects and a broad spectrum of educational training programs all of which are responsive to investigators health care delivery professionals AD families and needs of the community state and region. The long-term objective is to a) build on our established broad based AD program b) enhance our understanding of the early clinical and neuropathological manifestations of AD through study of our unique community-based normal aged control group and c) study the pathogenetic mechanisms of neuron degeneration with the eventual goals goal of preventing the disease. The ADRC is house in a building in a building dedicated to aging and AD research which has had 20 new laboratories added this year. The application consists of five core and four projects. The Administrative Core organizes coordinates and supervises all ADRC activities. The Biostatistical and Data Management Cores maintain and manage data sets from the Cores and provides valuable assistance in experimental design and statistical analysis. The Clinical Core evaluates and longitudinally follows AD patients and our unique normal aged control group. It maintains satellite diagnostic and treatment clinics for underserved rural subjects in Appalachian eastern Kentucky and African-American subjects in conjunction with Meharry Medical School in Nashville TN. The Neuropathology Core provides a Rapid Autopsy Program that performs short postmortem interval autopsies on AD patients and normal control subjects and maintains a brain bank. The Education and autopsies on AD patients and normal control subjects and maintains a brain bank. The Education and Information Transfer Core provides training for investigators and disseminate information to health care professionals caregivers and the lay public. The research projects in this renewal request includes "Mechanisms of synapse degeneration" (Project 1 Dr. Mattson); "Recovery from Cytoskeletal Disruption" (Project 2 Dr. Geddes); "Novel Peptide Inhibitors of Abeta accumulation and action" (Project 3 Dr. Estus) and "Lipid peroxidation antioxidants in AD" (Project 4 D. Montine). Pilot studies will be determined annually.


application_id: 7121190
project_number: 5R01NS044157-04
project_title: Cox-2 deficient mice are resistant to MPTP neurotoxicity
administering_ic: NINDS
award_notice_date: 2006-07-13
application_type: 5
activity_code: R01
ic: NS
serial_number: 044157
program_official: REFOLO, LORENZO
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-4(01)S]
contact_pi_person_id: 7875115
contact_pi: BING, GUOYING
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc). Loss of SNpc dopaminergic neurons results in the depletion of striatal dopamine levels and produces symptoms such as tremor muscle rigidity and bradykinesia. The etiology of PD is unknown but chronic inflammatory processes microglial activation and oxidative stress are thought to play prominent roles in the degeneration of dopaminergic neurons in the SNpc. Microglia are thought to contribute to neurodegeneration by releasing cytotoxic agents such as pro-inflammatory cytokines and reactive oxygen species that increase inflammation and oxidative stress. N-Methyl-4-phenyl-1236-tetrahydropyridine (MPTP) is a neurotoxin found to mimic many of the features of PD in animal models including loss of dopaminergic neurons in SNpc and activation of microglia. Recent observations indicate that cyclooxygenase-2 (COX-2) deficiency in mice reduces the susceptibility of SNpc dopaminergic neurons to MPTP toxicity and diminishes MPTP-induced microglial activation. The purpose of this study is to test the hypothesis that COX-2-regulated inflammatory processes exacerbate MPTP neurotoxicity by activating microglia and increasing oxidative stress that contributes to the degeneration of dopaminergic neurons in the SNpc. To test this hypothesis mice deficient in the COX-2 gene will be treated with MPTP to determine the role of COX-2 in MPTP-induced neurodegeneration. Furthermore wild-type mice will be administered exogenous COX-2 inhibitors prior to MPTP treatment to evaluate the protective effects of COX-2 inhibitors against MPTP neurotoxicity. Following these experiments dopaminergic neuron survival microglial activation striatal dopamine levels and functional recovery will be assessed. In addition protein modification generation of reactive oxygen species expression of inflammatory cytokines and apoptosis-related genes and activation of specific signaling molecules will be evaluated to determine the molecular mechanisms by which COX-2 exacerbates MPTP neurotoxicity. The goals of this study are to elucidate the changes in inflammatory processing affected by COX-2 deficiency to explore the etiology and molecular mechanisms underlying Parkinsonian symptoms in the experimental MPTP model and to develop novel therapeutic treatments for PD and other neurodegenerative diseases.

project_terms:
Parkinson&apos;s disease;RNase protection assay;apoptosis;automated data processing;behavior test;biological signal transduction;cytokine;dopamine;enzyme activity;free radical oxygen;functional ability;high performance liquid chromatography;inflammation;laboratory mouse;methylphenyltetrahydropyridine;microglia;mitochondria;neural degeneration;neurons;neuropharmacology;neurotoxicology;oxidative stress;oxidoreductase inhibitor;prostaglandin endoperoxide synthase;substantia nigra;terminal nick end labeling


application_id: 7120510
project_number: 5R01CA102301-03
project_title: CSN5 Mediates HIF-alpha Stability and Tumor Growth
administering_ic: NCI
award_notice_date: 2006-06-02
application_type: 5
activity_code: R01
ic: CA
serial_number: 102301
program_official: KNOWLTON, JOHN R
project_start_date: 2004-09-01
project_end_date: 2008-06-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 1959966
contact_pi: ZUNDEL, WAYNE S
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Hypoxia-Inducible transcription factors (HIFs) are thought to regulate multiple facets of solid tumor progression. Using genetic and biochemical screens for proteins able to modify HIF-1alpha responses we have isolated the CSN5 subunit of the COP9 Signalosome (CSN). We have further found that CSN5 associated directly and constitutively with the pVHL tumor suppressor. This proposal seeks to define the precise mechanism(s) in which CSN5 regulates pVHL-mediated HIF-alpha stability. To accomplish this we propose to: 1) test if CSN5 regulates global or specific 26S-dependent protein degradation; 2) test if CSN5 binds HIF-1a or pVHL in association with the CSN holocomplex or as a component of another protein complex and which CSN5-associated complex (es) are able to prevent HIF-la ubiquitylation; 3) test if mutations in CSN components that influence CSN assembly or activity can alter HIF-la stability; and 4) examine the mechanism(s) by which CSN5 directly alters HIF-1a stabilization. Accomplishment of these specific aims will reveal novel pathways of HIF-1alpha and pVHL regulation and will suggest potential mechanisms by which these pathways could be manipulated for therapeutic benefit.

project_terms:
biological signal transduction;cell line;enzyme mechanism;gene mutation;gene targeting;hypoxia inducible factor 1;immunoprecipitation;metalloendopeptidases;molecular assembly /self assembly;neoplastic growth;protein binding;protein degradation;protein kinase;protein protein interaction;protein structure function;proteomics


application_id: 7120507
project_number: 5R01CA105266-02
project_title: Ethnicity Breast Cancer Recurrence & Long-Term QOL
administering_ic: NCI
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 105266
program_official: AZIZ, NOREEN M
project_start_date: 2005-09-09
project_end_date: 2010-06-30
study_section: Epidemiology of Cancer Study Section[EPIC]
contact_pi_person_id: 6652159
contact_pi: BAUMGARTNER, KATHY B
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
budget_start_date: 2006-07-01
project_terms:
Hispanic Americans;behavioral /social science research tag;breast neoplasms;caucasian American;clinical research;cognition;depression;fatigue;female;human mortality;human subject;lifestyle;longitudinal human study;neoplasm /cancer classification /staging;neoplasm /cancer epidemiology;neoplasm /cancer relapse /recurrence;prognosis;quality of life;questionnaires;racial /ethnic difference;telemedicine;women&apos;s health


application_id: 7120088
project_number: 5R25CA098220-03
project_title: Kentucky Cancer Prevention and Control Training Program (R25T)
administering_ic: NCI
award_notice_date: 2006-09-01
opportunity_number: PAR-00-064
application_type: 5
activity_code: R25
ic: CA
serial_number: 098220
program_official: MYRICK, DORKINA C
project_start_date: 2004-09-15
project_end_date: 2009-08-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application requests five years of support to develop implement and evaluate a new education and career development program at the University of Kentucky (UK) -- the Kentucky Cancer Prevention and Control Training Program (KCPCTP).  The program will be designed to provide a specialized curriculum of cancer prevention and control training focusing on rural low-income populations.  One predoctoral and one postdoctoral trainee will be recruited in year one and two predoctoral and two postdoctoral trainees will be recruited in years 2-5.  Predoctoral trainees will be supported for 3-4 years and postdoctoral trainees up to 2 years.  Trainees may be from many disciplines including public health behavioral science hematology/oncology (postdoctoral only) and nursing.  The program will focus on cancer epidemiology behavioral science and tobacco control and will include coursework structured interactions with mentors and supervised research experiences.  Coursework will include core didactic courses elective didactic courses and special program initiatives.  The core didactic courses will provide instruction in cancer epidemiology biostatistics behavioral science in cancer prevention and control grant writing and research ethics and elective didactic courses will be selected from a wide range of opportunities across the University.  The special program initiatives will include participation in the cancer prevention and control seminar series a journal club and opportunities with an Agricultural Extension Program and an Integrative Medicine Clinic.  In addition to the coursework each trainee in the KCPCTP will have the support of at least two mentors who will provide guidance in selection of elective didactic courses and supervised research experiences focusing on cancer prevention and control among low income rural populations.  Resources to support trainees will be provided through faculty in the Cancer Control Program of the Markey Cancer Center University of Kentucky Prevention Research Center Kentucky Cancer Registry Kentucky School of Public Health School of Nursing Department of Kinesiology and Health Promotion and Departments of Behavioral Science and Internal Medicine in the School of Medicine.  Evaluation will focus on all aspects of the KCPCTP including recruitment and retention of trainees and faculty quantitative assessment of trainee accomplishments tracking of their success following completion of the program and qualitative evaluation to collect information on factors that facilitate or impede trainee progress.

project_terms:
behavioral /social science;behavioral /social science research tag;cancer prevention;career;clinical research;curriculum;education evaluation /planning;ethics;experience;health science research potential;human subject;low socioeconomic status;neoplasm /cancer epidemiology;postdoctoral investigator;predoctoral investigator;role model;rural area;statistics /biometry;tobacco abuse prevention;training


application_id: 7119641
project_number: 5R01RR020357-03
project_title: Zebrafish Mutant Mapping Facility
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: PAR-02-142
application_type: 5
activity_code: R01
ic: RR
serial_number: 020357
program_official: O'NEILL, RAYMOND R
project_start_date: 2004-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-CDF-4(50)R]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
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): The objective of this proposal is to accelerate the identification of zebrafish genes discovered during mutagenesis screens. This proposal is in response to PAR-02-142 to develop "Tools for Genetic Studies in Zebrafish." A major focus of this PA is to use novel screens to identify mutants of interest. However an essential part of this effort is to identify the genes responsible for the novel phenotypes generated. While thousands of mutants already have been described only 167 genes are listed in the zebrafish database (ZFIN) for which mutations are known (although there are probably some not listed). The major reason for this is the time consuming nature of the positional cloning strategy that must be used. The major bottleneck in gene discovery by positional cloning is the need to do whole genome linkage mapping. This takes considerable resources and time as well as technical expertise. This goal of this proposal is to eliminate this bottleneck by setting up a high throughput mapping facility. The usual laborious task of screening sometimes hundreds of markers to find one that is linked to the mutation of interest will be accomplished in 2 days. This will be done using fluorescence sequencers to automate genotyping of SSLPs (short sequence length polymorphisms) that span the genome. The mapping will be done in two main stages. First an approximate location will be determined using bulk segregant analyses. Second once closely flanking markers are identified 500-1000 individual mutant embryos will be genotyped to identify the region containing the mutant gene. Third for a small number of mutants the genes will be identified. The core will map a minimum of 100 mutants per year and identify the gene in 5-10 although both these numbers are likely to increase dramatically once the genome sequence is completed. The service will be modular so that investigators can have the initial mapping phases done by the facility and then complete the mutant gene isolation in there own laboratories. This project will have considerable impact because it will greatly accelerate the discovery of genes that already have been shown to be models of human diseases. The facility is committed to full and open access and all data pertaining to mapping will be made available at publication. Given the importance of zebrafish as a model organism this facility will have an immediate impact on the rate at which mutant genes are discovered which will provide new insights into the genetic underpinnings of important biochemical pathways involved in disease.

project_terms:
alternatives to animals in research;animal colony;animal population genetics;fluorescent dye /probe;gene expression;genetic mapping;genetic markers;genetic recombination;genetic screening;genotype;high throughput technology;linkage mapping;molecular cloning;mutant;polymerase chain reaction;zebrafish


application_id: 7119410
project_number: 3R01HL070963-03S1
project_title: Role of Glutathione Reductase and Macrophage Oncosis
administering_ic: NHLBI
award_notice_date: 2005-09-26
application_type: 3
activity_code: R01
ic: HL
serial_number: 070963
suffix: S1
program_official: SRINIVAS, POTHUR R
project_start_date: 2002-08-01
project_end_date: 2005-07-18
study_section: Pathology A Study Section[PTHA]
contact_pi_person_id: 7875256
contact_pi: ASMIS, RETO H.R.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We hypothesize that increased glutathione reductase activity protects human macrophages from OxLDL-induced mitochondrial dysfunction and cell death thereby decreasing the severity of atherosclerosis. Macrophage and foam cell death by oncosis plays a crucial role in the development of atherosclerotic lesions. We propose to study the molecular mechanism of glutathione reductase-mediated protection of macrophages from oncosis.Specific Aim 1: To determine the effect of OxLDL on the thiol redox state of mitochondria. Our preliminary data demonstrate that OxLDL induces mitochondrial depolarization and loss of ATP synthesis. We will use human monocyte-derived macrophages to determine if OxLDL promotes oncosis by 1) altering the thiol redox status of mitochondria 2) inactivating mitochondrial glutathione reductase and 3) increasing mitochondrial inner membrane permeability.Specific Aim 2: To determine the role of mitochondrial and cytosolic glutathione reductase in preventing OxLDL-induced oncosis. Mitochondria do not synthesize glutathione (GSH) and therefore rely on GSH uptake and the reduction of GSSG to maintain the appropriate thiol redox state. We will use human monocyte-derived macrophages to determine 1) if adenovirus-mediated doxycycline-controlled expression of mitochondrial or cytosolic glutathione reductase (GR) prevents GSSG accumulation and protein thiol oxidation and 2) if increasing glutathione reductase activity restores mitochondrial function and protects macrophages from OxLDL-induced oncosis.Specific Aim 3: To determine whether increased macrophage glutathione reductase activity decreases the severity of atherosclerosis. Foam cell death promotes the formation of the necrotic core and the progression of atherosclerotic lesions. We will perform bone marrow transplantation studies to determine in vivo whether augmented expression of glutathione reductase (GR) in macrophages prevents foam cell death and lesion progression. GR-overexpressing bone marrow cells generated by retroviral gene transfer will be used to repopulate irradiated LDL receptor null mice and apoE null mice.  We will measure both lesion size and lesional cholesterol/cholesterol ester content.

project_terms:
atherosclerosis;bone marrow transplantation;cell death;cholesterol;cholesterol esters;clinical research;enzyme activity;fluorescence microscopy;gene expression;genetically modified animals;glutathione reductase;human tissue;immunofluorescence technique;laboratory mouse;low density lipoprotein;low density lipoprotein receptor;macrophage;mitochondrial disease /disorder;oxidative stress;plasma


application_id: 7118907
project_number: 5R01CA084036-07
project_title: Screening for Ovarian Cancer: Psychobehavioral Outcomes
administering_ic: NCI
award_notice_date: 2006-06-28
application_type: 5
activity_code: R01
ic: CA
serial_number: 084036
program_official: NELSON, WENDY
project_start_date: 2000-03-01
project_end_date: 2008-06-30
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1874012
contact_pi: ANDRYKOWSKI, MICHAEL A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Transvaginal sonography (TVS) can facilitate early detection of ovarian cancer (OC) however like all cancer screening tests TVS yields a proportion of "abnormal" findings. While the vast majority of abnormal TVS results are benign the impact of this potentially stressful screening experience upon affective cognitive and behavioral outcomes has not been adequately examined. The proposed research builds on our current study (R01 CA84036) of psychological and behavioral outcomes associated with routine TVS screening by focusing explicitly on the impact of an abnormal TVS result. Women (n=400) receiving an abnormal TVS result during routine screening (Abnormal Screening (AS) group) and returning for a repeat TVS test four-eight weeks later will be matched (age prior screening history) with women (n=400) receiving a normal TVS result during routine screening (Routine Screening (RS) group). All women will complete a baseline assessment prior to either routine (RS group) or repeat (AS group) TVS screening and follow-up assessments 14 and 18 months post-baseline. Some women (n=120) in the AS group will complete an additional "true" baseline assessment prior to the routine TVS test yielding their abnormal result. Measures of dispositional variables (optimism monitoring emotional approach coping) are obtained at baseline and affective (e.g. OC-specific distress) cognitive (e.g. OC risk perception TVS efficacy beliefs benefit finding) and behavioral (e.g. OC-specific monitoring behavior emotional approach coping participation in screening for breast/colon cancers) endpoints will be assessed longitudinally. Adherence with recommendations for routine TVS screening will be monitored by OC screening program records. Several contemporary theoretical models of response to stressful events (Cognitive-Social Health Information Processing Monitoring Process Social-Cognitive Processing) guide selection of study variables and provide specific hypotheses for testing. Three specific aims will be addressed: (1) characterize the impact of an abnormal TVS result with regard to the nature magnitude valence and trajectory of outcomes; (2) identify clinical demographic dispositional and psychosocial variables associated with magnitude and persistence of these outcomes; and (3) develop and pilot test an appropriate psycho educational intervention for minimizing negative outcomes after an abnormal TVS result. Results will enhance understanding of response to abnormal results in response to screening for OC and will also enhance understanding of response to abnormal screening results for other malignant and nonmalignant conditions.

project_terms:
behavior test;behavioral /social science research tag;cancer risk;clinical research;cognition;diagnostic tests;education evaluation /planning;emotions;human subject;interview;longitudinal human study;neoplasm /cancer diagnosis;neoplasm /cancer education;neuropsychological tests;ovary neoplasms;perception;psychological aspect of cancer;questionnaires;social psychology;stress;ultrasonography;vagina;women&apos;s health


application_id: 7118626
project_number: 5R01AR048700-04
project_title: Biomaterials with Rationally Immobilized Growth Factors
administering_ic: NIAMS
award_notice_date: 2006-05-19
opportunity_number: PA-02-011
application_type: 5
activity_code: R01
ic: AR
serial_number: 048700
program_official: PANAGIS, JAMES S
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-SSS-M(01)]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Ideally implants should be designed with the ability to promote specific biological responses. In the case of bone-contacting materials this would mean that immediately following implantation the devices would induce cells of the osteoblastic lineage to form bone on or in close proximity to the biomaterial. Stable fixation of the implant and better integration into the tissue would be the result. The overall goal of this research is to develop biomolecular surface modification strategies that induce specific cell and tissue responses. For example stimulation of tissue regeneration in which the implant becomes integrated into the tissue is more desirable than repair in which the implant is generally walled off with a fibrous capsule. It is postulated that bone-contacting materials possessing surfaces with osteotropic biomolecules in a specific presentation can control initial cellular events at the tissue-biomaterial interface. In Specific Aim 1 bis-hydrazide-derivatized poly(DL-lactide-co-glycolide) coatings microspheres and porous scaffolds will be developed for use in site-directed immobilization of osteotropic growth factors. Surfaces with different lengths and surface densities of bis-hydrazide molecules will be produced. In Specific Aim 2 rational schemes will be designed and implemented for site-directed immobilization of growth factors on the materials developed in Aim 1. Recombinant DNA techniques will be used to introduce modifications to the amino termini of insulin-like growth factor I and bone morphogenetic protein 2. These unique sites will allow the growth factors to be immobilized in an orientation that maximizes interaction with cell surface receptors. In Specific Aim 3 in vitro and in vivo biological activity of the rationally modified biomaterials will be determined. Cell cultures will also be used to assess activation of the appropriate cell surface receptors by the immobilized growth factors. It is hypothesized that site-directed immobilization of growth factors will yield higher specific bioactivity and therefore will result in greater cell and tissue responses (specifically bone formation) compared to randomly immobilized protein. The findings of these studies will impact the development of bone-contacting biomaterials having the ability to induce desired interracial responses.

project_terms:
X ray spectrometry;binding sites;bioassay;biomaterial development /preparation;biomaterial evaluation;biomaterial interface interaction;biotechnology;bone morphogenetic proteins;bone regeneration;carboxyl group;cell surface receptors;growth factor;laboratory mouse;laboratory rat;medical implant science;microcapsule;osteogenesis;polymers;receptor binding;recombinant DNA;scanning electron microscopy;surface coating;tissue /cell culture;tissue support frame


application_id: 7118497
project_number: 5F31MH069028-02
project_title: Victim Schema and Peer Victimization
administering_ic: NIMH
award_notice_date: 2006-06-23
application_type: 5
activity_code: F31
ic: MH
serial_number: 069028
program_official: FERRELL, COURTNEY
project_start_date: 2005-07-01
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-F11(20)L]
contact_pi_person_id: 7549997
contact_pi: ROSEN, PAUL J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Peer victimization is a serious problem of childhood that has been shown to lead to internalizing and externalizing difficulties. It has been proposed that chronic peer victims have an easily accessible "victim schema" that lead them to engage in behaviors that lead to victimization. Children with easily accessible victim schemas are likely to associate themselves implicitly as victims experience dyscontrolled emotional arousal in response to threats make hostile attributions and respond with inappropriately submissive or reactive behaviors. The aim of the present study is to test whether the presence of an easily accessible victim schema predicts future peer victimization. The present study will use a longitudinal multi-cohort design to assess the relation of victim schema to peer victimization. Children from the community will be assessed at baseline and one-year follow-up. Participants will be administered implicit cognitive measures to assess the accessibility of their victim schema and explicit questionnaires regarding their histories of peer victimization experiences. The primary hypothesis is that the presence of an easily accessible victimization will influence both concurrent and future peer victimization status.

project_terms:
behavior prediction;behavioral /social science research tag;child (0-11);child behavior;child psychology;child rearing;clinical research;human subject;longitudinal human study;parent offspring interaction;peer group;predoctoral investigator;psychological tests;questionnaires;social perception


application_id: 7118185
project_number: 5R01NR009280-02
project_title: BMI Nutrition Inflammation and Heart Failure Outcomes
administering_ic: NINR
award_notice_date: 2006-04-27
opportunity_number: PA-01-109
application_type: 5
activity_code: R01
ic: NR
serial_number: 009280
program_official: HUSS, KAREN
project_start_date: 2005-09-01
project_end_date: 2008-05-31
study_section: Nursing Science: Adults and Older Adults Study Section[NSAA]
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cardiac cachexia is an independent risk factor for morbidity and mortality in patients with heart failure (HF). In contrast obesity was recently reported to be associated with decreased risk of morbidity and mortality.  The finding that overweight and obese patients with HF have surprisingly better outcomes is in contrast to our current understanding of the relationships between obesity and HF and conflicts with the recommendation that these individuals should lose weight.  The biobehavioral mechanisms underlying the differences in outcomes between these groups of patients are not well understood.  Nutritional intake is a major contributor to body weight and may also play a crucial role in influencing HF outcomes.  Proinflammatory cytokines released as part of the systemic inflammatory response to both obesity and HF affect appetite food intake body composition myocardial function vascular epithelium and are predictors of patient outcomes.  The purpose of the proposed research is to examine the relationships among body fat content nutritional intake inflammation and patient outcomes in 300 patients with HF of ischemic origin that are equally distributed among four groups: underweight normal weight overweight and obese.  The primary aim of this prospective study is to determine the relationship between body fat mass and twelve-month patient outcomes (composite end-point of rehospitalization of death). Secondary aims are to examine how differences in body fat mass and distribution alter the effect nutritional deficiencies (four-day food diaries) and proinflammatory cytokine activity (tumor necrosis factor-alpha [TNFalpha] soluble TNF-alpha receptors interleukin-6 interleukin-1 receptor antagonist and interleukin-10) on patient outcomes.  Examination of the interactions among body fat content nutritional intake and proinflammatory cytokine activity will provide an understanding of the biobehavioral mechanisms underlying the improved patient outcomes observed in overweight and obese patients with HF.  This will assist with developing new nutrition and body weight guidelines for patients with HF who are overweight and obese.  An understanding of the underlying mechanisms may also allow application of these findings to underweight patients resulting in improved outcomes for these patients.

project_terms:
body composition;body weight;clinical research;cytokine receptors;dietary sodium;endotoxins;heart failure;human subject;inflammation;interleukin 1;interleukin 6;lipoprotein lipase;longitudinal human study;nutrition;obesity;patient oriented research;psychobiology;questionnaires;statistics /biometry;tumor necrosis factor alpha


application_id: 7118032
project_number: 5R01AG025403-03
project_title: Mitochondrial Proteome Changes in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2006-08-07
opportunity_number: RFA-AG-04-006
application_type: 5
activity_code: R01
ic: AG
serial_number: 025403
program_official: SUNEJA, SANOJ
project_start_date: 2004-09-30
project_end_date: 2009-08-31
study_section: ZAG1-ZIJ-5(O1)
contact_pi_person_id: 7947546
contact_pi: LYNN, BERT C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The major barrier to treating or preventing Alzheimer's disease (AD) is its unknown etiology/pathogenesis. However increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD. Most information on mitochondrial dysfunction has been obtained one protein at a time. It is the hypothesis of this proposal that changes in the mitochonrial proteome are an early event in the pathogenesis of neuron degeneration in AD and that these changes may be evaluated using quantitative proteomics. In preliminary studies we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC/MS/MS) and the isotope coded affinity tag (ICAT) method to identify and quantify protein levels in mitochondria isolated from early AD late stage AD and age-matched control subjects. 2D-HPLC/MS/MS analysis of ICAT-labeled mitochondrial samples identified and quantified 22 unique proteins. Our results show that for early AD subjects ATP synthase and pyruvate kinase (essential for ATP production) and VDAC (part of the permeability transition pore) are significantly depleted. In late stage AD subjects our results show that most proteins involved in ATP production are significantly depleted along with VDAC while uracil DNA glycosylase (base excision repair) and guanine nucleotide-binding protein (extra-matrix signal modulation) are significantly increased. To test the hypothesis that changes in mitochondrial proteome are an early event in the pathogenesis of neuron degeneration in AD we will a) quantitatively evaluate mitochondrial protein expression in the hippocampus temporal pole superior and middle temporal gyrus and cerebellum of control early AD and late-stage AD subjects b) immunohistochemically examine tissue sections from the same subjects to determine if proteins with altered expression correlate with neuropathologic features and c) quantitatively evaluate changes in mitochondrial protein expression in primary rat cortical neuron cultures resulting from AD relevant insults including AB iron/hydrogen peroxide glucose deprivation and glutamate.

project_terms:
Alzheimer&apos;s disease;amyloid proteins;biotechnology;cerebellum;clinical research;glucose;glutamates;high performance liquid chromatography;hippocampus;human tissue;hydrogen peroxide;immunocytochemistry;laboratory rat;mitochondrial disease /disorder;neurons;neuropathology;oxidative stress;postmortem;protein localization;protein quantitation /detection;proteomics;temporal lobe /cortex;tissue /cell culture


application_id: 7117786
project_number: 5R01HL071896-04
project_title: Alpha1-Adrenoceptor Subtype Signaling in Preconditioning
administering_ic: NHLBI
award_notice_date: 2006-08-24
application_type: 5
activity_code: R01
ic: HL
serial_number: 071896
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-01
project_end_date: 2008-08-31
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 7033203
contact_pi: ROKOSH, GREGG
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: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): Myocardial preconditioning (PC) protects the heart from the consequences of ischemic heart disease and ischemia - reperfusion injury.  Catecholamines released during ischemia induce myocardial PC by activating alpha1-adrenoceptors(AR) in the heart.  Two alpha1-AR subtypes are expressed in the heart.  Recently in alpha1-AR subtype knockout (KO) mice each alpha1-AR subtype was found to activate different:signaling pathways.  The broad objective of this project is to define the subtype(s) that are responsible for catecholamine induced PC the mechanisms by which PC is induced and ultimately whether therapeutics can be utilized to capitalize on subtype specific signaling to benefit cardiac health.  The alpha1-AR subtype(s) responsible for catecholamine induced early and late PC will be determined using alpha1-AR subtype KO mice in loss of function studies.  An in vivo mouse model of ischemic PC will be used to study the effect of alpha1-AR- and ischemia- induced PC on infarct size.  An in vitro mouse Langendorf heart model will be used to study the effect of alpha1-AR- and ischemia- induced PC on myocardial stunning.  Subtype specific signaling cascade studies will focus on antiapoptotic signaling via PI3K/AKT reactive oxygen species protein kinase C mitogen activated protein kinases and tyrosine kinase activation during preconditioning protocols.  Signaling complexes formed at each subtype that can account for differences in subtype signaling will be studied using tagged alpha1A and alpha1B subtypes in immunoprecipitation experiments.  Late PC requires gene transcription.  We have identified several candidate genes that may participate in late PC.  The regulation of gene expression and how these gene products contribute to PC will be studied.  The ability to precondition the heart for prolonged periods would be an important contribution to many clinical applications where:the heart is exposed to or at risk during prolonged ischemic heart disease or with ischemia - reperfusion injury.  The benefits of overexpressing and enhancing alpha1-AR subtype-specific signaling responsible for PC will be tested using a gene therapy approach.  The subtype will be expressed in the heart acutely using an adenovirus vector.

project_terms:
alpha adrenergic receptor;apoptosis;biological signal transduction;cytoprotection;epidermal growth factor;gene therapy;genetic transcription;genetically modified animals;heat shock proteins;immunoprecipitation;laboratory mouse;mitogen activated protein kinase;myocardial ischemia /hypoxia;phosphatidylinositol 3 kinase;protein isoforms;protein kinase C;protein tyrosine kinase;reperfusion;serine threonine protein kinase;thioredoxin;transfection /expression vector


application_id: 7117691
project_number: 5R01NS039774-05
project_title: Sympathetic Function in Diabetes
administering_ic: NINDS
award_notice_date: 2006-08-05
application_type: 5
activity_code: R01
ic: NS
serial_number: 039774
program_official: MITLER, MERRILL
project_start_date: 1999-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-CICS(01)Q]
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_terms:
blood pressure;central nervous system;clinical research;diabetic neuropathy;heart rate;implant;laboratory rat;medical implant science;neuroregulation;nutrition related tag;parasympathetic nervous system;sympathetic nervous system;telemetry;tocopherols;vascular smooth muscle nervous control


application_id: 7117682
project_number: 5R01GM070662-04
project_title: COOPERATIVE INTERACTIONS IN DNA REPAIR
administering_ic: NIGMS
award_notice_date: 2006-08-30
application_type: 5
activity_code: R01
ic: GM
serial_number: 070662
program_official: LEWIS, CATHERINE D
project_start_date: 2004-04-01
project_end_date: 2009-08-31
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 8344857
contact_pi: FRIED, MICHAEL G.
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
budget_start_date: 2006-09-01
project_terms:
DNA repair;crosslink;enzyme activity;enzyme mechanism;methylguanine DNA methyltransferase;molecular genetics;nucleic acid structure;nucleosomes;point mutation;protein binding;protein protein interaction;stoichiometry


application_id: 7117656
project_number: 5R01GM062866-05
project_title: STRUCTURAL BASIS OF RNA-CATALYZED AMINOACYLATION OF RNA
administering_ic: NIGMS
award_notice_date: 2006-09-01
application_type: 5
activity_code: R01
ic: GM
serial_number: 062866
program_official: LEWIS, CATHERINE D
project_start_date: 2002-09-15
project_end_date: 2008-08-31
study_section: Biophysics and Biophysical Chemistry B Study Section[BBCB]
contact_pi_person_id: 1923548
contact_pi: ARNEZ, JOHN G
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
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
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): Attachment of amino acids to adapter RNA molecules is a key reaction in protein biosynthesis. The aminoacylation reaction is catalyzed in the cell by aminoacyl-tRNA synthetases. Recently three classes of catalytic RNAs (ribozymes) that recapitulate this activity by transferring the aminoacyl moiety from a pre-formed adenylate to their own 3'-termini have been obtained through in vitro selection. The first class contains RNAs that accept any aminoacyl moiety whereas members of the second class are specific for phenylalanine and tyrosine. Ribozymes of the third class also catalyze the formation of dipeptides a reaction analogous to that catalyzed by a large ribozyme the ribosome. In this proposal the three-dimensional structures of self-aminoacylating RNAs of the three classes will be determined by x-ray crystallography. The ribozymes will be analyzed in complex with substrate and product analogs. The structural information obtained in this study will reveal the configuration of the active site of these ribozymes organization of the amino acid-specific binding pocket and the mechanism of catalysis. It will help clarify the issue of whether the aminoacyl transfer to a peptide or an RNA involves entropic catalysis (i.e. precise positioning of the substrates) or it requires special catalytic groups on the enzyme such as an acid or base; hence it will add to our understanding of the reactions catalyzed by the larger biological systems such as the aminoacyl-tRNA synthetases and the ribosome.

project_terms:
RNA;X ray crystallography;active sites;acylation;aminoacid;apoenzymes;electrospray ionization mass spectrometry;enzyme mechanism;gel electrophoresis;nuclear magnetic resonance spectroscopy;nucleotides;protein biosynthesis;ribosomes;ribozymes;structural biology


application_id: 7116458
project_number: 5U01DA016205-05
project_title: Central States Criminal Justice Drug Abuse Center
administering_ic: NIDA
award_notice_date: 2006-09-12
opportunity_number: RFA-DA-02-011
application_type: 5
activity_code: U01
ic: DA
serial_number: 016205
program_official: CHANDLER, REDONNA
project_start_date: 2002-09-30
project_end_date: 2008-08-31
study_section: ZDA1-MXS-M(10)
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):   The U.S. criminal justice system is awash with drug abusers. However few approaches have been developed which focus on criminal justice involved drug abusers as they transition from prison to community treatment. This is alarming because it is estimated that 500000 prisoners will return to the community each year for the next several years and 83 percent of those returning are estimated to be drug abusers. This application is presented to focus on examining community transitions by establishing the Central States Criminal Justice Drug Abuse Treatment Research System (CJ-DATS) Center. The overall aim of the Central States CJ-DATS Center is to develop information to improve transition interventions for criminal justice involved drug abusers which reduce recidivism reduce drug abuse and reduce related crime. The established experience of the University of Kentucky Center on Drug and Alcohol Research is described to continue to carry out rural/urban theoretically grounded criminal justice studies which build upon current research. These studies include two on-going NIDA trials which are examining an enhanced Probationer HIV intervention and an enhanced Drug Court employment intervention as well as a project which is examining prison and community health services utilization among drug abusing prisoners in 5 prisons with 12 month follow-up from prison to the community. This application also describes four Central States Center Committees that will be established to (1) Plan (2) Implement (3) Collect/Analyze Data and (4) Develop Publications in concert with the Principal Investigator the Center Steering Committee and the Center Advisory Board. Letters of commitment from a State Corrections Commissioner a State Substance Abuse Director 6 criminal justice agencies and 8 community treatment agencies present rural and urban subject availability of 15709 criminal justice participants and 13087 community treatment participants for the first year and subsequent years. In addition two study protocols are presented as multi-site trials across CJ-DATS Centers to enhance prison/community transitions: (1) An enhanced employment intervention focused on obtaining maintaining and upgrading employment and (2) A case management/criminal thinking error enhanced intervention.

project_terms:
AIDS education /prevention;HIV infections;behavior therapy;behavioral /social science research tag;clinical research;cooperative study;correctional institutions;criminal behavior;drug abuse information system;drug abuse prevention;employment /unemployment;health care service utilization;human subject;questionnaires;substance abuse related behavior


application_id: 7115462
project_number: 3R01AA012178-06S1
project_title: FAMILY AND GROUP THERAPIES FOR ADOLESCENT ALCOHOL ABUSE
administering_ic: NIAAA
award_notice_date: 2005-08-29
opportunity_number: AA98-003
application_type: 3
activity_code: R01
ic: AA
serial_number: 012178
suffix: S1
program_official: LOWMAN, CHERRY
project_start_date: 1998-09-30
project_end_date: 2006-02-28
study_section: ZAA1
contact_pi_person_id: 6382863
contact_pi: STANTON, MORRIS D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
fips: US
organization_id: 4214801
organization_name: MORTON CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 402041667
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
budget_end_date: 2006-02-28
assistance_listing_number: 93.273
project_abstract:
APPLICANT'S ABSTRACT:  Despite well-founded societal concerns over use of       illicit drugs by youth alcohol use has persisted for decades as the number     one adolescent substance abuse problem in the U.S. Further research has        shown that the earlier the onset of alcohol use the more likely a person is    to develop alcohol dependence later during the life course.  Consequently      the need is clear for interventions that will arrest this process at the        earliest point possible.  Hence interventions that mobilize a youth's          social systems to help that young person deal with the problem i.e. the       family and peer systems would make sense from a number of standpoints.                                                                                         The first objective of the research proposed here is to compare the             effectiveness of two different modalities.  One of these is a                   state-of-the-art family therapy approach Transitional Family Therapy (TFT)    which integrates nuclear family here-and-now interventions with               multigenerational issues.  The other is a standardized version of the           established modality of Adolescent Group Therapy (AGT) which includes both     psycoeducational and therapeutic components.  Both approaches have been         developed expressly to target adolescent alcohol problems.  Participants        will be 140 males and females ages 13-17 with diagnoses of alcohol abuse      or dependence.  Following random assignment to conditions treatment in         either condition will take four months in addition to two months of             aftercare (six months total).  Outcomes will be compared at treatment           termination one year post-treatment and two years post-treatment.                                                                                             The second objective is to establish a standard as to the outcomes that can     be achieved with AGT for this population.  Even though group therapy is         probably the most widely used treatment modality for such problems there       presently appear to be no clinical trails defining its parameters and           expectation with adolescent alcohol abusers.

project_terms:
adolescence (12-20);alcoholism /alcohol abuse;alcoholism /alcohol abuse therapy;behavioral /social science research tag;clinical research;early experience;family therapy;group therapy;human subject;human therapy evaluation;longitudinal human study;outcomes research


application_id: 7115368
project_number: 5F31AI064120-02
project_title: Minority predoctoral fellowship program
administering_ic: NIAID
award_notice_date: 2006-08-14
application_type: 5
activity_code: F31
ic: AI
serial_number: 064120
program_official: HERNANDEZ, MILTON J
project_start_date: 2005-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-P(29)L]
contact_pi_person_id: 8002596
contact_pi: MANIRARORA, JEAN N
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant):  CD4+CD25+ regulatory T cells play a major role in the control of immunity as the lack of this T cell population results in the activation of autoreactive T cells and the development of autoimmune diseases. It has been reported that the level of CD4+CD25+ regulatory T cells is lower in autoimmune-prone mice such as NZBxNZWFI (BWF1) and NOD mice. The central hypothesis of this proposal is that autoimmune-prone mice may have a defect in CD4+CD25+ regulatory T cell function which may play a role in the pathogenesis of autoimmune diseases. Our preliminary studies suggest that NOD antigen presenting cells (APC) play a crucial role in the defect of CD4+CD25+ regulatory T cell function but that activation of NOD APC restores normal regulation in vivo. The objective of this proposal is therefore to develop novel strategies using TLRs to restore optimal regulation in NOD mice and to characterize the mechanisms of this regulation. Moreover we will investigate whether APC from diabetic patients have also a defect in activating regulatory T cells and whether enhancement of their APC function can ameliorate regulation as well as whether regulatory T cells from diabetic patients can be activated directly via TLRs.

project_terms:
NOD mouse;T cell receptor;T lymphocyte;antigen presenting cell;autoimmune disorder;clinical research;helper T lymphocyte;human subject;immune response;insulin dependent diabetes mellitus;leukocyte activation /transformation;leukocyte activation disorder;predoctoral investigator


application_id: 7115299
project_number: 5R01NR008379-05
project_title: Improving School Learning Environments in HIV Prevention
administering_ic: NINR
award_notice_date: 2006-07-17
opportunity_number: RFA-MH-02-007
application_type: 5
activity_code: R01
ic: NR
serial_number: 008379
program_official: HARE, MARTHA L
project_start_date: 2002-09-30
project_end_date: 2008-06-30
study_section: ZMH1-NRB-W(02)
contact_pi_person_id: 7952401
contact_pi: CUPP, PAMELA KAY
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: OTHER SPECIALIZED SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  While a number of HIV prevention programs have been evaluated in school settings much of the focus of this research has been the content of the curriculum; as a result we still know little about the specific facets of the classroom environment that may yield the strongest effects of an effective school-based FHV other STD and pregnancy prevention curriculum.  In the proposed research we plan to bring together expertise from our research in health communications and our research in classroom instruction combining Donohew's individual differences model of information exposure with Eccles' stage-environment fit theory to assess the impact of curricular teacher instructional and student individual difference variables on HIV-related mediating and outcome variables while developing an effective prevention program. 

Specific aims of the project are within a randomized control trial in high school health classrooms to (1) adapt a modified version of a skills-based MV other STD and pregnancy-prevention curriculum to be more appropriate for the needs of impulsive decision makers in order to bring about desired behavior change in sexual decision-making; (2) assess the impact of characteristics of the instructional environment in health classrooms (i.e. teacher efficacy teacher immediacy value orientation and teacher identity) in order to identify effective instructional methods and teacher characteristics; (3) implement reinforcement and relevance of the curriculum across other classes and content areas in order to foster more effective learning of the material; and 4) Evaluate the interaction among the student the teacher and the curriculum to determine optimal learning environments that lead to sustained behavior change. 

The proposed study including over 5000 students and 10-12 schools will be conducted over a period of five years.  During the first three years six separate intervention implementation studies will occur (two consecutive interventions per year) with the design for five of the six intervention studies as experimental with randomization occurring by school.  In Years 4 and 5 we will also examine the effects of a combined "best practices" classroom based intervention by comparing two groups of students randomized by schools: a comparison condition with a skills-based HIV/pregnancy prevention curriculum or the optimal version that contains the most successful elements tested in the three preceding years.  The analytic design will include individual classroom teacher and school levels to be assessed through hierarchical linear modeling or other tests of differences.

project_terms:
AIDS education /prevention;adolescence (12-20);age at pregnancy;behavior modification;behavioral /social science research tag;clinical research;clinical trials;curriculum;decision making;education evaluation /planning;human subject;impulsive behavior;interpersonal relations;longitudinal human study;secondary schools;sex behavior;sex education;sexually transmitted diseases;teacher


application_id: 7114485
project_number: 5R01AA011691-08
project_title: Individual Differences in Alcohol-Related Aggression
administering_ic: NIAAA
award_notice_date: 2006-08-30
application_type: 5
activity_code: R01
ic: AA
serial_number: 011691
program_official: EGLI, MARK
project_start_date: 1998-09-15
project_end_date: 2009-08-31
study_section: Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]
contact_pi_person_id: 7876958
contact_pi: GIANCOLA, PETER 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this revised application is to support an ongoing program of research aimed at determining in whom and in what contexts acute alcohol consumption facilitates aggressive behavior. The overarching aim of this 2-study laboratory project is to elucidate the influence of 3 individual difference variables [1) beliefs about aggression 2) beliefs about alcohol and 3) dispositional empathy] and 2 contextual variables [1) induced empathy and 2) provocation] on the alcohol-aggression relation in men-and women. STUDY 1 will examine the impact of 3 individual difference variables (i.e. beliefs about aggression beliefs about alcohol and dispositional empathy) on intoxicated aggression under varying levels of contextual provocation (low and high). Subjects will be 230 adult male and female social drinkers randomly assigned to either an Alcohol or a Placebo group. Beliefs about aggression beliefs about alcohol and dispositional empathy will be measured using a battery of validated self-report inventories. Aggression will be measured using a modified version of the well-established Taylor Aggression Paradigm (TAP; Taylor 1967) in which subjects administer and receive mild electric shocks to/from a fictitious opponent (actually a computer program) under the guise of a competitive reaction-time task. Aggression is operationalized as the intensity of shock administered by the subject to the fictitious opponent. STUDY 2 will examine the impact of dispositional (individual difference) and induced (contextual) empathy on the alcohol-aggression relation under varying levels of provocation (low and high). Subjects will be 320 adult male and female social drinkers randomly assigned to 1 of 4 groups" 1) Alcohol/Empathy-Induction 2) Alcohol/No Empathy-Induction 3) Placebo/Empathy-Induction or 4) Placebo/No Empathy- Induction. Empathy will be induced using well-validated empathy-induction techniques. Aggression will be measured using the TAP.

project_terms:
aggression;alcoholic beverage consumption;alcoholism /alcohol abuse;behavior prediction;behavior test;behavioral /social science research tag;belief;clinical research;clinical trials;computer data analysis;electrostimulus;empathy;expectancy;human subject;interview;operant conditionings;personality;questionnaires;self concept;substance abuse related behavior;toxicant interaction


application_id: 7114359
project_number: 5R01CA116428-02
project_title: Targeting of 6-Phosphofructo-2 kinase in Cancer
administering_ic: NCI
award_notice_date: 2006-08-14
application_type: 5
activity_code: R01
ic: CA
serial_number: 116428
program_official: FORRY, SUZANNE L
project_start_date: 2005-08-19
project_end_date: 2009-04-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-14
project_abstract:
DESCRIPTION (provided by applicant): The ability of neoplastic cells to survive and grow in a hypoxic environment requires a global shift that involves large increases in the use of glucose not only for energetic but also for anabolic activities.  Glycolytic flux in neoplastic cells is activated by Hypoxia Inducible Factor 1 (HIF-1) and the oncogenic proteins c-myc and ras. HIF-1 and ras independently induce the synthesis of fructose-26-bisphosphate (F26BP) a potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1) the rate-limiting enzyme of glycolysis. The steady-state concentration of F26BP depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2) which is expressed in several tissue-specific isoforms (PFKFB1-4). The only isoform expressed in epithelial cells inducible PFK-2 (iPFK-2; PFKFB3) also has been found to be: (I) over-expressed by human solid tumors in situ (ii) induced by hypoxic exposure via HIF-1a; and (iii) required for K562 leukemia tumor growth in vivo. The long-term objectives of this application are to validate iPFK-2 as a molecular target for the development of anti-neoplastic agents. We developed a computational model of the tertiary structure of iPFK-2 based on the crystal structures of two homologous PFK-2 isozymes and screened virtual combinatorial libraries for pharmacophore fits of the fructose-6-phosphate (F6P) binding site of iPFK-2. We examined 81 highly scored compounds for cytotoxic activity against Jurkat T cell leukemia cells and identified a lead compound designated F6P33 that suppresses glycolytic flux to lactate and induces apoptosis selectively in transformed cells (100 nM-1M). We now propose to both silence and  
ectopically enhance iPFK-2 in transformed cells in vitro and in vivo and examine the consequences on the anti-neoplastic effects of F6P33. We expect that these studies will support the role of iPFK-2 as the molecular target of F6P33 and thus validate the development of small molecule inhibitors of iPFK-2 as antineoplastic agents.

project_terms:
6 phosphofructokinase;adenocarcinoma;antineoplastics;apoptosis;disease /disorder model;drug design /synthesis /production;enzyme inhibitors;gene expression;genetically modified animals;glycolysis;human tissue;hypoxia;laboratory mouse;lung neoplasms;neoplasm /cancer chemotherapy;neoplasm /cancer pharmacology;neoplastic cell;small interfering RNA;small molecule


application_id: 7114317
project_number: 5R01HL063763-06
project_title: SR-BI and SR-BII recycling and selective lipid uptake
administering_ic: NHLBI
award_notice_date: 2006-07-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 063763
program_official: SRINIVAS, POTHUR R
project_start_date: 1999-12-01
project_end_date: 2009-07-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
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: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): HDL levels are inversely related to coronary artery disease. The HDL receptor SR-BI plays a key role in HDL metabolism. SR-BI binds HDL and mediates the process known as selective lipid uptake the mechanism of which is not understood. Various studies have indicated that selective uptake by SR-BI in certain cells occurs at the cell surface by a non-endocytic process. However recent studies have reported that in hepatocytes SR-BI mediates the internalization of intact HDL particles and suggest that selective lipid uptake involves HDL internalization and recycling in cells. We have shown that SR-BII a variant of SR-BI differs markedly from SR-BI in its cellular trafficking and endocytosis of HDL. The central hypothesis of this proposal is that the functions of SR-BI and SR-BII in intracellular cholesterol trafficking are coupled to receptor/ligand recycling in cells and that SR-BI and SR-BII follow different internalization and recycling routes and differentially affect cellular cholesterol trafficking and regulation. The specific aims are: 1) determine the contribution of HDL internalization and intracellular recycling to the selective lipid uptake process mediated by SR-BI and SR-BII. HDL recycling by each of the two receptors will be quantified in hepatocytes and other cells 2) elucidate the mechanisms responsible for HDL internalization and recycling by SR-BI and SR-BII. Endocytic and recycling pathway(s) used by SR-BI and SR-BII will be studied and protein motifs in the C-terminal tails of SR-BI and SR-BII that are responsible for receptor targeting will be identified 3) determine how differences in the intracellular targeting of HDL by SR-BI and SR-BII influence cellular cholesterol regulation and trafficking. We will determine the effects of selective lipid uptake via SR-BI and SR-BII on the pool of regulatory sterols in cells and on cholesterol efflux and 4) assess the roles of SR-BI and SR-BII in HDL metabolism and atherogenesis in vivo using isoform-specific knock-in mice. Isoform-specific knock-in mice will be generated and the effects of each receptor on plasma lipoproteins HDL metabolism and atherogenesis studied.

project_terms:
apolipoproteins;atherosclerosis;blood lipoprotein metabolism;blood lipoprotein transport;cholesterol;cholesterol esters;clinical research;fluorescence microscopy;gel mobility shift assay;high density lipoproteins;high performance liquid chromatography;human subject;intracellular transport;laboratory mouse;lipid metabolism;polymerase chain reaction;receptor expression;tissue /cell culture


application_id: 7114113
project_number: 1F31AA016265-01
project_title: Longitudinal & experimental analysis of positive urgency
administering_ic: NIAAA
award_notice_date: 2006-05-09
opportunity_number: PA-04-032
application_type: 1
activity_code: F31
ic: AA
serial_number: 016265
program_official: ARROYO, JUDITH A
project_start_date: 2006-07-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZAA1 HH (52)]
contact_pi_person_id: 8410180
contact_pi: CYDERS, MELISSA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The goal of the proposed program of research is to further examine the role of positive urgency in college alcohol use and risky behavior. Positive urgency can be defined as the tendency to act rashly and maladaptively while in a very positive mood state; it may be an important predictor of college drinking and risk taking which tend to be celebratory in nature. In a recent series of studies I developed and validated self-report and interview measures of positive urgency: the measures related to drinking quantity/frequency problem drinking and certain kinds of risky behavior. With this award I propose to first test whether positive urgency measured at the beginning of the freshman year in college predicts problem drinking and drinking while in a positive mood over the course of that first year. Second I propose to conduct three laboratory experiments. Those experiments will show that (a) individuals high in positive urgency become more disinhibited when in a very positive mood than when not; (b) they become more disinhibited when in a positive mood than do individuals low in positive urgency; and (c) they drink more alcohol when in a very positive mood than do others.

project_terms:
alcoholic beverage consumption;alcoholism /alcohol abuse;behavior prediction;behavioral /social science research tag;child psychology;clinical research;craving;data collection methodology /evaluation;disease /disorder proneness /risk;emotions;high risk behavior /lifestyle;human subject;impulsive behavior;longitudinal human study;mathematical model;predoctoral investigator;questionnaires;substance abuse epidemiology;substance abuse related behavior;university student


application_id: 7113228
project_number: 5R01DK069766-02
project_title: Tolerance Induction to Islet Transplants
administering_ic: NIDDK
award_notice_date: 2006-08-21
application_type: 5
activity_code: R01
ic: DK
serial_number: 069766
program_official: APPEL, MICHAEL C
project_start_date: 2005-09-01
project_end_date: 2010-08-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_terms:
NOD mouse;apoptosis;cell population study;dendritic cells;hematopoietic growth factor;hematopoietic stem cells;hematopoietic tissue transplantation;homologous transplantation;immune tolerance /unresponsiveness;immunopathology;pancreatic islet transplantation;pathologic process;tissue mosaicism;transplantation immunology


application_id: 7113192
project_number: 5R01AG022859-04
project_title: Species comparison of stem cell aging
administering_ic: NIA
award_notice_date: 2006-08-08
opportunity_number: RFA-AG-03-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 022859
program_official: WILLIAMS, JOHN
project_start_date: 2003-09-30
project_end_date: 2008-08-31
study_section: ZAG1-ZIJ-5(O1)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The replenishment of spent cells is a common theme in a newly appreciated and growing number of mammalian organs. In most cases stem cells fuel this process over a lifetime. Recent evidence suggests that an animal's absolute number of hematopoietic stem cells is conserved and is irrespective of body size and lifespan. What mechanistic strategies and adaptations allow the same-sized population of stem cells to replenish mature cell populations that in the human are several thousand-fold larger than those in the mouse over a lifespan that is forty-fold longer in humans than in mice? The first aim of this proposal will determine the changes in stem cell number cell cycle status responsiveness to cytokines and apoptosis rate from young to old age in both species. Human umbilical cord blood stem cells from newborns will be compared to bone marrow stem cells from humans greater than 75 years old. A parallel comparison will be made between bone marrow stem cells of 2 month old and 24 month old mice. Inter-species similarities and differences in these parameters during aging will provide insight to the physiological mechanisms employed at the cellular level. The second aim will determine the similar and contrasting inter-specific strategies employed at the molecular level. Hematopoietic stem cells from both humans and mice at young and old age will be purified by cell sorting. The repertoire of expressed genes in each stem cell population will be determined by extracting RNA from the purified populations and hybridizing it to gene sets of human and mouse respectively on microarrays. Comparative species analysis of gene expression during aging of stem cells is expected to reveal several patterns of special interest. Those genes whose expression is turned on increased or maintained during aging in human but not in the mouse suggest candidates that might account for maintenance of stem cell function over a long lifespan in humans. Those whose expression changes in a parallel pattern in both species suggests conserved genes fundamentally important for dealing with the rigors of aging. Those whose expression declines with age in the mouse but not the human suggests candidates that are responsible for the maintenance of the longevity of stem cell function. Patterns of gene expression in stem cells during aging will reveal molecular pathways important in defining longevity and may suggest molecular targets of intervention in the treatment of age-related disorders including cancer.

project_terms:
age difference;apoptosis;cell age;cell cycle;cell proliferation;clinical research;cord blood;cytokine;flow cytometry;gene expression;hematopoietic stem cells;human subject;human tissue;laboratory mouse;microarray technology;nucleic acid hybridization;nucleic acid purification;species difference;stem cells;telomere


application_id: 7112911
project_number: 5R01NS049126-03
project_title: Proteomic and Functional Studies of Mitochondria in ALS
administering_ic: NINDS
award_notice_date: 2006-08-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 049126
program_official: REFOLO, LORENZO
project_start_date: 2004-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-CDIN(01)Q]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
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
budget_start_date: 2006-09-01
project_terms:
RNA interference;amyotrophic lateral sclerosis;apoptosis;cell line;fluorescent dye /probe;gene mutation;genetically modified animals;glia;laboratory mouse;mass spectrometry;membrane proteins;mitochondrial disease /disorder;molecular pathology;motor neurons;neuropathology;neurotoxicology;phosphorylation;posttranslational modifications;protein structure function;proteomics;spinal cord;superoxide dismutase;two dimensional gel electrophoresis


application_id: 7112271
project_number: 5R01AG013418-10
project_title: Neural Mechanisms Resetting The Aged Circadian Pacemaker
administering_ic: NIA
award_notice_date: 2006-08-14
application_type: 5
activity_code: R01
ic: AG
serial_number: 013418
program_official: SUNEJA, SANOJ
project_start_date: 1996-07-17
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-3(01)S]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): Aging induces deficits in circadian rhythms in rest-activity hormone secretion and other functions. The normal expression of circadian rhythms depends upon the ability of the circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) to respond to timing signals conveyed by several afferent pathways including serotonergic neurons. During aging the pacemaker loses its ability to respond appropriately to several timing signals including serotonergic drugs such as 8-OH-DPAT. Our findings from the previous funding period have shown that this age-related loss of sensitivity is associated with a large loss of specific serotonin7 (5-HT7) receptor binding sites in the dorsal raphe nucleus (DRN). The DRN is a target site for 8-OH-DPAT induction of circadian phase shifts and a source of innervation of two other circadian substrates the median raphe nucleus (MRN) and the intergeniculate leaflet (IGL) which both communicate with the SCN. The proposed project will test the following working hypothesis: Age-related reduction in 5-HT7 receptors in the DRN attenuates 8-OH-DPAT modulation of neurotransmission within the MRN and IGL. Reduced communication with the MRN and IGL leads to age-related deficits in phase resetting of the circadian pacemaker in the SCN. The specific aims are: 1) To determine the significance of the age-related reduction in 5-HT7 receptors in the DRN for circadian phase shifts 2) To identify the neurochemical phenotype of 5-HT7 receptor-containing cells in the DRN 3) To elucidate the role of the IGL and MRN in mediating the phase-shifting effects of 8-OH-DPAT microinjections in the DRN and 4) To determine the factors responsible for the age-related loss of 5-HT7 receptors in the DRN. These proposed studies focus on the DRN as an important locus of aging of the circadian timing system. The DRN not only communicates with circadian substrates but also with brain structures such as the hippocampus and pedunculopontine tegmental nucleus regulating memory and sleep respectively. These processes also exhibit deficits with aging which may reflect age-related changes in the function of the DRN. The proposed project will elucidate whether the 5-HT7 receptors in the DRN are an important target for new pharmacotherapeutic approaches to ameliorate the disrupted circadian rhythms especially sleep-wake cycles that disturb the elderly as well as jet travelers and shift workers. Deterioration of circadian rhythms compromises an individual's health by causing chronic fatigue lowering resistance to disease impairing cognition and memory and reducing longevity.

project_terms:
age difference;aging;binding sites;biological clocks;central neural pathway /tract;circadian rhythms;dorsal raphe nucleus;hamsters;microinjections;neural information processing;neurochemistry;neuropharmacology;neurotransmitter transport;receptor expression;serotonin;serotonin receptor;suprachiasmatic nucleus;tissue /cell culture


application_id: 7111848
project_number: 5R01GM036065-20
project_title: Regulation of Protein N-Glycosylation in the CNS
administering_ic: NIGMS
award_notice_date: 2006-08-29
application_type: 5
activity_code: R01
ic: GM
serial_number: 036065
program_official: MARINO, PAMELA
project_start_date: 1981-06-01
project_end_date: 2009-08-31
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
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
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant):  The co-translational N-glycosylation of many important cell surface receptors ion channels and lysosomal enzymes is essential for their correct folding intracellular routing and function in the CNS and other mammalian cells. The vital importance of protein N-glycosylation in humans is emphasized by the clinical consequences of a series of inherited genetic defects in this pathway classified as Congenital Disorders of Glycosylation (CDG). While the enzymology and topology of the biosynthesis of Glc3Man9GlcNAc2-P-P-Dol the oligosaccharyl donor in the endoplasmic reticulum (ER) have been studied extensively many gaps remain in the understanding of how the enzymes in this pathway are organized and regulated. This proposal describes further studies to learn more about the role of ER-associated proteins in the regulation of dolichyl phosphate (Dol-P) biosynthesis and recycling and the transbilayer movement of Man-P-Dol.      
  
Three Specific Aims are planned using biochemical genetic and immunochemical approaches designed: 1) To utilize a recently cloned cDNA to learn more about the long-chain c/s-isoprenyltransferase (c/s-IPTase) catalyzing the elongation stage in Dol-P biosynthesis by investigating its regulation and the nature of its association with potential binding partners in the ER; 2) To utilize cloned cDNAs encoding dolichol kinase (DK) and Dol-P-P phosphatase an ER enzyme with a lumenally-oriented active site in in vivo and in vitro experiments aimed at elucidating their precise roles in the ote novo synthesis of Dol-P and the recycling of the glycosyl carrier lipid and 3) To purify identify and characterize the ER protein(s) mediating the transverse diffusion of Man-P-Dol in mammalian cells ("flippase"). The information gained on the structure of the Man-P-Dol flippase will be relevant to related membrane proteins mediating the transbilayer movement of other dolichyl-P-(P)-saccharide intermediates in protein O- C- and N-glycosylation glycerophospholipids glucosylceramide and glycosylphosphatidylinositol (GPI) anchor precursors and potential defects in patients with Congenital Disorders of Glycosylation (CDG).

project_terms:
active sites;brain metabolism;central nervous system;complementary DNA;dolichol;embryo /fetus tissue /cell culture;endoplasmic reticulum;enzyme activity;glycoprotein biosynthesis;glycosylation;membrane proteins;posttranslational modifications;protein binding;protein purification;protein transport;site directed mutagenesis;temperature sensitive mutant


application_id: 7111679
project_number: 5R25CA044789-14
project_title: 'Cancer Education Grant Program'
administering_ic: NCI
award_notice_date: 2006-07-20
opportunity_number: PAR-00-033
application_type: 5
activity_code: R25
ic: CA
serial_number: 044789
program_official: GORELIC, LESTER S
project_start_date: 2002-08-01
project_end_date: 2009-01-31
study_section: ZCA1-GRB-R(M3)
contact_pi_person_id: 1969100
contact_pi: BURZYNSKI, NORBERT J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The objective of the present application is to continue the long-standing highly successful short-term research program in Cancer Biology at the University of Louisville.  The current program has been the recipient of over twenty years of near-continuous NIH support.  Throughout the tenure of this program the highest priority has been given to disseminating to health professional students an appreciation for issues in cancer biology as they relate to diagnosis prevention and treatment of the disease from a clinical and research perspective.  The current program provides a unique venue for student - faculty interaction and provides highly motivated and qualified students with the opportunity to gain exposure to cancer biology and enhance their knowledge in this area through weekly Tumor Board conferences Program Workconferences special programmatic seminars a "Cancer Careers Minisymposium" laboratory research and presentations at local/national meetings.  The present application has been revised substantially with regard to training faculty outcomes assessment procedures and special initiatives to increase student awareness of career opportunities in cancer health care and research.  A new Health Science Center-wide training venture has been initiated which benefits from the participation of eighteen core faculty all of whom are funded extensively through federal/foundation sources and have a demonstrated commitment to biomedical research and education.  This multidisciplinary group represents a forging of research and training partnerships spanning seven University departments and incorporating the University of Louisville Schools of Dentistry and Medicine J. Graham Brown Cancer Center Birth Defects Center Center for Genetics and Molecular Medicine and Kosair Children's Hospital Research Institute.  Seventeen of the program Core Faculty are participating members of the J. Graham Brown Cancer Center.  All have committed to provide trainees with exposure to and involvement in contemporary research programs in varied aspects of cancer biology and molecular mechanisms of cellular growth control.  A noted cancer epidemiologist from the MD Anderson Cancer Center has been enlisted as a consultant to develop and execute a systematic strategy for program evaluation and trainee tracking and to function as an educational advisor for the program.  In summary it is the objective of our program to provide a unique and contemporary educational venue in cancer biology designed to train the next generation of academic clinical scientists.  These individuals will be poised to enter the fields of cancer health care and research and have a long-term impact on reducing cancer incidence mortality and morbidity....the foremost theme of cancer prevention through cancer biology!

project_terms:
clinical research;curriculum;education evaluation /planning;health care personnel education;neoplasm /cancer education


application_id: 7111138
project_number: 5R01HL079583-03
project_title: Ribosomal Function and Diamond-Blackfan Anemia
administering_ic: NHLBI
award_notice_date: 2006-08-10
opportunity_number: RFA-HL-04-008
application_type: 5
activity_code: R01
ic: HL
serial_number: 079583
program_official: QASBA, PANKAJ
project_start_date: 2004-09-30
project_end_date: 2009-07-31
study_section: ZHL1-CSR-D(S1)
contact_pi_person_id: 1922324
contact_pi: ELLIS, STEVEN R
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):    Diamond-Blackfan anemia (DBA) is a rare pure red-cell aplasia that presents early in infancy. Virtually every aspect of DBA is heterogeneous posing considerable challenges to efforts to understand and treat this disease. Approximately 25% of DBA cases are linked to mutations in the ribosomal protein $19 gene whereas the remaining cases are of unknown etiology. A goal of this application is to address the molecular basis of DBA focusing on the role of Rps19 in ribosome synthesis. Our studies in yeast have shown that Rps19 is required for the maturation of 40S ribosomal subunits. We plan to extend these studies and examine ribosome synthesis in cell lines from DBA patients. We have also identified several other yeast ribosomal proteins that appear to cooperate with Rps19 in the maturation of 40S subunits. If patients with normal Rps19 were defective in ribosome synthesis genes encoding proteins that cooperate with Rps19 would become candidate genes for disease-causing mutations. Our studies in yeast have also pointed to a need for functional testing of putative disease-causing mutations identified in Rps19 genes from DBA patients. Finally we will study the relationship between ribosome synthesis and bone marrow failure in a transgenic mouse model.  The specific aims of this application are to:  1. continue studies characterizing the effect of DBA missense mutations on the function of the Rps19 protein in yeast.  2. determine if there are defects in the protein synthetic machinery in cell lines from DBA patients.  3. determine which ribosomal proteins depend on Rps19 for their assembly into 40S ribosomal subunits.  4. characterize the phenotype of mice hemizygous for LAMR1 including hematological analysis cancer incidence and the presence of other congenital abnormalities.

project_terms:
affinity chromatography;cell component structure /function;cell line;clinical research;congenital aplastic anemia;fibroblasts;fungal proteins;genetically modified animals;human subject;laboratory mouse;lymphoblast;lymphocyte;molecular pathology;phenotype;point mutation;posttranscriptional RNA processing;protein biosynthesis;protein structure function;ribosomal RNA;ribosomal proteins;ribosomes;yeasts


application_id: 7110371
project_number: 7R01HL078663-03
project_title: Lysolipid Signaling in Cardovascular Disease
administering_ic: NHLBI
award_notice_date: 2006-08-28
opportunity_number: RFA-HL-04-005
application_type: 7
activity_code: R01
ic: HL
serial_number: 078663
program_official: GOLDMAN, STEPHEN
project_start_date: 2004-09-24
project_end_date: 2008-08-31
study_section: ZHL1-CSR-I(S1)
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    Both thrombotic and inflammatory mediators contribute to the development of vascular disease. Blood platelets which are known to play an essential role in ischemic heart disease and stroke by contributing to acute thrombotic events also release potent inflammatory agents within the vasculature.  Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is produced by platelets and found in abundance in human atherosclerotic plaques.  LPA stimulates platelets leukocytes endothelial cells and smooth muscle cells by acting through specific cell surface G-protein coupled receptors (LPA1-3) to regulate cell growth differentiation survival motility and contractile activity. LPA may also be an agonist for the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma).  Thus LPA is poised to serve as a key mediator of both inflammatory and thrombotic responses and to be a pathophysiologic regulator of vascular cell function.  The objective of this application is to determine the physiologic contribution of LPA to events that are relevant to atherothrombotic vascular disease and to identify the LPA receptor(s) involved.  Our central hypothesis is that LPA generated in part by activated platelets stimulates phenotypic modulation of medial SMCs and that these responses regulate vascular tone and contribute to the development of intimal hyperplasia after arterial injury and in the setting of atherosclerosis.  We propose to test our hypothesis by integrating cellular pharmacologic and functional genomics approaches in the following three specific aims (1) establish a pathologic role for LPA in the vascular response to injury; (2) identify LPA receptors that mediate phentypic modulation of cultured vascular SMCs; (3) Identify the role of LPA receptors in the regulation of vascular tone.  To accomplish our goals we will use mice deficient in the three known G-protein coupled LPA receptors (LPA1-3) novel pharmacologic sub-type selective agonists and agonistists of LPA1-3 and mice with a PPARgamma mutation that abolishes ligand binding.  Our results will provide specific insights into the role of LPA signaling pathways in vascular physiology and pathology and may provide novels targets for the treatment and prevention of atherothrombotic disorders.

project_terms:
atherosclerosis;biological signal transduction;cardiovascular injury;cell differentiation;cell migration;cell proliferation;cell surface receptors;functional /structural genomics;gene deletion mutation;gene expression;genetically modified animals;hyperplasia;laboratory mouse;lysophospholipids;microarray technology;molecular pathology;muscle cells;muscle contraction;peroxisome proliferator activated receptor;phenotype;thromboplastin;thrombosis;tissue /cell culture;vascular smooth muscle


application_id: 7110134
project_number: 5K01AG024190-03
project_title: Calcineurin and Biobehavioral Markers of Brain Aging
administering_ic: NIA
award_notice_date: 2006-07-21
application_type: 5
activity_code: K01
ic: AG
serial_number: 024190
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2004-09-30
project_end_date: 2009-07-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant):   Our previous work indicates that protein phosphatase activity is increased in hippocampus of aged rats and contributes to age-related alterations in synaptic strength and cognition. The proposed studies investigate whether the protein phosphatase calcineurin interacts significantly with several other brain aging biomarkers including increased Ca2+ channel function and altered gene expression. In each aim of this project calcineurin activity in hippocampal cultures and in hippocampus of intact rats is manipulated using recombinant viruses (adeno- and lentivirus). The first specific aim tests whether constitutively active calcineurin causes aging-like changes in voltage sensitive Ca2+ channels (VSCC) (i.e. an increase in L-type VSCC currents and a decrease in N-type VSCC mRNA levels). Molecular interactions of calcineurin with VSCCs also will be explored. The second aim tests whether increased calcineurin activity leads to aging-like changes in global gene expression as assessed using gene microarrays. The specific role of the calcineurin/NF-AT transcriptional pathway will be explored using recombinant virus containing a potent NFAT inhibitor VIVIT. The third aim uses recombinant viruses to test whether the calcineurin/NF-AT pathway contributes to age-related memory deficits on the Morris swim task. After completion of behavioral training intact and partially dissociated hippocampal slices will be prepared from these rats to determine whether the calcineurin/NF-AT pathway also is responsible in part for age-related alterations in synaptic strength plasticity (i.e. long-term potentiation and long-term depression) and L-type VSCC activity. Furthermore individual neurons and glia will be harvested from zipper slices to examine single cell gene expression profiles using gene microarray technology.

project_terms:
aging;behavior test;biomarker;calcineurin;calcium channel;calcium ion;enzyme activity;gene expression;hippocampus;laboratory rat;microarray technology;neural plasticity;phosphoprotein phosphatase


application_id: 7109659
project_number: 1R41EY017473-01
project_title: Preventing choroidal neovascularization by long-term transscleral drug delivery
project_terms: angiogenesis;birth;collagen;drug delivery systems;eye;proteins;success
administering_ic: NEI
award_notice_date: 2006-05-01
application_type: 1
activity_code: R41
ic: EY
serial_number: 017473
program_official: WUJEK, JEROME R
project_start_date: 2006-05-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1 BDCN-F (12)]
contact_pi_person_id: 1867228
contact_pi: BORA, PURAN S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144375263
duns_number: 144375263
fips: US
organization_id: 10002039
organization_name: POTENTIA PHARMACEUTICALS, 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: 2006-05-01
budget_end_date: 2008-04-30
project_abstract:
DESCRIPTION (provided by applicant): Age-related Macular Degeneration (ARMD) is the leading cause of blindness for individuals over fifty-five years of age that live in the industrialized world. With the introduction of novel anti-angiogenic agents clinical intervention is currently possible but only for the wet form of the disease. However these treatments are severely limited by the fact that they must be directly injected into the eye. This procedure carries a significant risk of complication and generates understandable issues of patient acceptability. There is a clear need for a therapy that either bypasses the need for ocular injection or reduces its frequency. Transscleral drug delivery provides a convenient way for delivering drug to the posterior segment of the eye. We propose to test and develop a novel and powerful transscleral drug delivery system that holds promise for being non-toxic minimally invasive and highly customizable towards different therapies. The success of this proposal will offer a new method to the pharmaceutical industry and to patients worldwide to treat ARMD without the current burden of monthly or 6-weekly intraocular injections. For proof-of-concept we will use a novel human protein-based therapy that has shown great potential in preliminary animal studies.


application_id: 7109647
project_number: 3U60OH008483-02S1
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2006-07-21
opportunity_number: PAR-04-106
application_type: 3
activity_code: U60
ic: OH
serial_number: 008483
suffix: S1
program_official: FREDERICK, LINDA J
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZOH1 SBO (50)]
contact_pi_person_id: 6608944
contact_pi: MCCOOL, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Kentucky's occupational fatality rate is 6.9 deaths/100000 workers 72.5 percent above the national rate of 4/100000 workers. This project focuses on the population-based surveillance of work-related injury fatalities using the FACE methodology that includes a public health model of surveillance a systematic model of sentinel event case investigation and targeted interventions in a southeastern state Kentucky. The Kentucky FACE program continues to build a solid foundation of surveillance investigations epidemiological studies and innovative prevention strategies for translation of research into practice (R2P) for use by employers and legislative bodies. The objectives are to identify high risk sectors occupations and worker populations for fatal work injuries to advance the usefulness of surveillance data at the federal state and local level for the prevention of fatal occupational injuries and hazards and to develop and implement targeted strategies for dissemination of occupational injury data utilizing a sector-based approach to reduce Kentucky fatal occupational injuries. The methodology consists of conducting comprehensive and timely multi-source surveillance of Kentucky occupational fatalites to identify risk factors. On-site investigations of selected fatality cases involving motor vehicle collisions (MVCs) in the transportation and agriculture sectors and logging industry fatalities will be performed to provide case studies for employer/employee safety training at the company local and state levels by sector and across sectors. Narrative coding of transportation sector MVC fatality reports will be completed to identify company safety management practices collision characteristics and personal risk factors for a fatal occupational MVC. Epidemiological analyses of domestic violence-related occupational homicides using multiple sources of data will be conducted to target specific points for the development of workplace homicide interventions. We will provide targeted worker and employer groups with a sound evidence basis for improved worker safety by analyzing and disseminating occupational fatality surveillance data investigation reports fact sheets newsletters web-based information presentations and peer-reviewed publications for impact at both the state and national levels. A process impact and outcome evaluation of the major activities will be performed.


application_id: 7109581
project_number: 1R41EY017518-01
project_title: Targeting drug-delivery nanoparticles to sites of inflammation
administering_ic: NEI
award_notice_date: 2006-06-19
application_type: 1
activity_code: R41
ic: EY
serial_number: 017518
program_official: WUJEK, JEROME R
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1 BDCN-F (12)]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144375263
duns_number: 144375263
fips: US
organization_id: 10002039
organization_name: POTENTIA PHARMACEUTICALS, 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: 2006-07-01
budget_end_date: 2008-06-30
assistance_listing_number: 93.867
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this project is to develop a nanoparticle-based drug delivery system for use in the treatment of the exudative form of aged-related macular degeneration (ARMD). ARMD is the leading cause of blindness for individuals over fifty-five years of age that live in the industrialized world. It affects approximately 10 million people in the US and as many as 30 million worldwide. There are two forms of the disease both of which cause a loss of central vision. Approximately eighty-five percent of patients have the less severe dry form that produces gradual but rarely complete vision loss. The remaining fifteen percent have the severe wet or exudative form that causes rapid disabling blindness. Wet ARMD is further characterized by choroidal neovascularization (CNV) a growth under the macula of abnormal blood vessels originating from the choroidal capillary bed. Research has linked chronic inflammation to both forms of ARMD. The advent of novel anti-angiogenic agents has enabled pharmaceutical treatment of ARMD but only for the wet form of the disease. These treatments are severely limited by the fact that the drug must be directly injected into the eye. This procedure carries a significant risk of complication and generates understandable issues of patient acceptability. Estimates predict that as many as one half of patients will discontinue treatment because of ocular injection. Thus there is a clear need for a therapy that either bypasses the need for ocular injection or reduces its frequency. The chitosan-based nanoparticle delivery system we propose to develop intends to meet this need. Successful completion of this Phase I project will result in a prototype nanoparticle that can be injected intravenously and home to inflamed blood vessels in the eye and release an anti-angiogenic agent locally over a period of weeks to months.

project_terms:
aging;angiogenesis;birth;blindness;blood vessels;drug delivery systems;emotions;eye;inflammation;lasers;lead;macular degeneration;model;particle;person with disability;selectins;vision


application_id: 7109296
project_number: 5F31CA117235-02
project_title: Mechanisms of ER and PPAR Crosstalk in Breast Cancer
administering_ic: NCI
award_notice_date: 2006-08-03
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: CA
serial_number: 117235
program_official: BINI, ALESSANDRA M
project_start_date: 2005-08-01
project_end_date: 2007-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-P(29)L]
contact_pi_person_id: 7521883
contact_pi: TALBERT, DOMINIQUE R
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Peroxisome proliferators activated receptor gamma like estrogen receptor alpha is a nuclear receptor that is highly expressed in breast cancer. However as opposed to ER alpha ligands which activate proliferation PPAR gamma ligands have been shown to induce differentiation in breast cancer cells. Furthermore PPAR and ER have been shown to crosstalk. The exact mechanism of this interaction however is unclear. Elucidation of the interaction between ER and PPAR will be critical in the understanding of hormone receptor crosstalk in hormone dependent breast cancer and its application in the development of improved treatments. Our objective is to identify novel therapeutic targets for hormone dependent breast cancer by defining mechanism(s) involved in ER/PPAR crosstalk. Aim 1 will test the hypothesis that the selective regulation of critical target genes involved in breast cancer is dependent on ER/PPAR crosstalk. Aim 2 will test the hypothesis that a protein-protein interaction mediates ER/PPAR crosstalk in breast cancer cells. Aim 3 will test the hypothesis that activation of the MAPK (MEK) phosphorylation cascade contributes to ER/PPAR crosstalk in breast cancer by altering receptor mediated gene expression and cell function.


application_id: 7108556
project_number: 5R01CA116658-02
project_title: Regulation of Cell Survival and Tumor Progression by Akt
administering_ic: NCI
award_notice_date: 2006-07-06
application_type: 5
activity_code: R01
ic: CA
serial_number: 116658
program_official: JHAPPAN, CHAMELLI
project_start_date: 2005-08-01
project_end_date: 2010-05-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-06
project_terms:
SDS polyacrylamide gel electrophoresis;apoptosis;athymic mouse;biological signal transduction;cell growth regulation;cell line;immunoprecipitation;molecular oncology;neoplastic growth;phosphorylation;polymerase chain reaction;prostate neoplasms;protein isoforms;protein protein interaction;protein structure function;serine threonine protein kinase;tumor suppressor proteins


application_id: 7106614
project_number: 5R03AG025144-02
project_title: Effects of dietary phytoestrogens on the aging brain
administering_ic: NIA
award_notice_date: 2006-08-16
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AG
serial_number: 025144
program_official: FOX, JENNIFER THERESA
project_start_date: 2005-09-01
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1-ASG(01)Q]
contact_pi_person_id: 2095188
contact_pi: CORBITT, CYNTHIA
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:
The overall objective of this proposal is to investigate the hypothesis that dietary levels of phytoestrogens are neuroprotective to the aging central nervous system (CNS). Perimenopausal women are encouraged to increase their intake of phytoestrogens (found in soy) as an alternative to synthetic hormone replacement therapy. Evidence suggests that phytoestrogens can protect against osteoporosis and cardiovascular disease but little is known about what CNS effects they may have. Endogenous and synthetic estrogens have been found to affect brain morphology (e.g. dendritic spine density) and gene transcription (e.g. estrogen receptor mRNA) provide resistance to brain damage from ischemic events and enhance cognitive performance. Phytoestrogens bind the estrogen receptors (ERalpha and ERbeta)and at dietary levels may have neuroprotective actions similar to 17beta estradiol (E2) on the CNS. For this proposal effects of phytoestrogens on brain regions involved in cognitive function are of particular interest.Using an aging rodent model 2 specific aims will be addressed in small self-contained research projects:1) assessment of cognitive effects of dietary phytoestrogens; 2) assessment of the neuroprotective role of dietary phytoestrogens in a rodent model of ischemic stroke. For specific aim 1 end points include acquisition and performance of memory-intensive tasks as well as neuroanatomical and neurochemical measures after intake of diets made of soy protein with or without phytoestrogens. For specific aim 2 end points include morphological measures (size of infarct) and number of cells with ischemia-induced damage in regions surrounding the infarct.

project_terms:
aging;behavior test;biological products;brain disorders;brain morphology;central nervous system;cerebral ischemia /hypoxia;cognition disorders;dietary constituent;infarct;laboratory rat;memory disorders;neurochemistry;neuroprotectants;nutrition related tag;phytoestrogens;plants;soybeans;stroke;terminal nick end labeling;urinalysis


application_id: 7106579
project_number: 5P01DA019398-02
project_title: Opiate drug abuse and CNS vulnerability to HIV
administering_ic: NIDA
award_notice_date: 2006-08-03
application_type: 5
activity_code: P01
ic: DA
serial_number: 019398
program_official: LAWRENCE, DIANE M
project_start_date: 2005-08-01
project_end_date: 2007-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-A(42)P]
contact_pi_person_id: 8536116
contact_pi: HAUSER, KURT F
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): The goal of the Program Project is to understand how opiate drugs exacerbate the effects of HIV in the CNS. To achieve this goal we will address the following hypothesis: Opiate drugs through selective actions at f-opioid receptors (MOR) exacerbate the pathogenesis of HIV-1 by disrupting glial homeostasis increasing inflammation and decreasing the threshold for pro-apoptotic events in neurons. Inflammatory processes and viral products released by human immunodeficiency virus type one (HIV-1) infected cells cause widespread metabolic derangement immune dysregulation disruption of neuron-glial relationships and neuronal dysfunction which contribute to HIV encephalitis and perhaps dementia. Opiate drugs such as heroin and oxycodone intrinsically disrupt CNS function by interfering with endogenous opioid and neuroimmune function. CNS disruption and neurotoxicity are exacerbated when opiates are combined with HIV. Project 1 will examine neurodegenerative mechanisms in opioid and HIV protein-exposed cell cultures and mice. Neuron death and non-lethal effects (e.g. neuritic pruning will be examined in + MOR-expressing populations of striatal neurons in vitro. Signaling between premitochondrial pathways involving PTEN and Akt will be examined for both caspase-3 dependent and independent cell death using pharmacological transfection (silencing/overexpression vectors) and genetic strategies (MOR-knockout and PTEN-deficient mice). Project 2 will explore opioid and HIV disruption of astroglial function (e.g. Ca2+ oxyradical production and EAAT1/2 glutamate transporters) and the release of inflammatory cytokines (e.g. TNFa IL-6) in vitro and in vivo and will identify aspects of astroglial destabilization that contribute to pathological changes in neurons. Project 3 will examine opioid-HIV-induced changes in free radical production redox-sensitive intracellular signaling pathways (e.g. proteasome activity/immunoproteasome subunit expression NFkappaB MAP kinase) and inflammatory signaling in microglia. Last studies using conditional transgenic mice expressing Tat or gp120 and severe combined immunodeficient (SCID) mice injected with HIV-infected human monocytes will assess opioid-HIV effects in neurons astroglia and microglia in vivo. The Projects are supported by an administrative core (Core A) and a transgenic/SCID mouse core (Core B) and recombinant viral protein core (Core B) and common findings e.g. on neuronal dysfunction/death will be integrated in Project 1.


application_id: 7106358
project_number: 5R01DA010325-10
project_title: Human Cocaine Discrimination
administering_ic: NIDA
award_notice_date: 2006-06-23
application_type: 5
activity_code: R01
ic: DA
serial_number: 010325
program_official: AIGNER, THOMAS G
project_start_date: 1997-03-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-1(01)S]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): The present application is a request for continued funding of a project entitled "Cocaine Discrimination in Humans: Pharmacological Specificity" (DA010325). Recent data indicate that nearly 2 million Americans used cocaine in the past month. Alarmingly between 1991 and 2001 the number of 8th 10th and 12th graders that reported using cocaine in the past 30 days increased 140 86 and 50 percent respectively. Thus cocaine abuse continues to represent a significant public health concern and will likely remain a problem for the foreseeable future. Intensive research efforts have been aimed at elucidating the neuropharmacological mechanisms that mediate the effects of cocaine. Drug-discrimination studies with laboratory animals that used the substitution and pretreatment methodologies have implicated a prominent role of dopamine in mediating the effects of cocaine. During the initial funding period of this project we used a drug discrimination task and the substitution methodology to demonstrate that dopamine systems are involved in mediating the discriminative-stimulus effects of cocaine in humans.  We are not aware of any published studies in which the discriminative-stimulus effects of cocaine were assessed in humans following pretreatment with another drug even though drug-discrimination procedures may be particularly well suited for studying agonist-antagonist interactions. The aim of this application is to further characterize the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans using a pretreatment methodology. To accomplish this aim 3 laboratory experiments will be conducted with volunteers with histories of cocaine abuse.  The discriminative-stimulus and subjective effects of cocaine will be assessed alone and following pretreatment with mazindol a dopamine uptake blocker (Exp. 1); fluphenazine a D1-D2 dopamine receptor antagonist (Exp. 2); and haloperidol a D2 dopamine receptor antagonist (Exp. 3).  We predict that pretreating volunteers with a dopamine agonist or antagonist will shift the cocaine dose-response curve leftward and rightward respectively.  The experiments proposed in this "proof-of-concept" continuation application will provide additional information concerning the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans. Elucidating the role of dopamine in mediating the effects of cocaine may guide the development of pharmacological interventions for cocaine.

project_terms:
behavioral /social science research tag;clinical research;cocaine;discrimination learning;dopamine;dosage;drug abuse;fluphenazine;haloperidol;human subject;mazindol;psychopharmacology;questionnaires


application_id: 7105662
project_number: 5R01AA014623-02
project_title: Zinc and Alcohol-Induced Oxidative Liver Injury
administering_ic: NIAAA
award_notice_date: 2006-05-24
opportunity_number: PA-02-035
application_type: 5
activity_code: R01
ic: AA
serial_number: 014623
program_official: PUROHIT, VISHNU
project_start_date: 2005-08-10
project_end_date: 2009-05-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 6870954
contact_pi: ZHOU, ZHANXIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
alcoholism /alcohol abuse;antioxidants;cytoprotection;cytotoxicity;dietary supplements;dietary trace element;ethanol;free radical scavengers;genetically modified animals;hepatotoxin;laboratory mouse;liver cells;liver disorder;microarray technology;nutrition related tag;oxidative stress;polymerase chain reaction;transcription factor;zinc


application_id: 7105047
project_number: 5R01HL045721-16
project_title: Physiology of the Respiratory Muscles
administering_ic: NHLBI
award_notice_date: 2006-07-28
application_type: 5
activity_code: R01
ic: HL
serial_number: 045721
program_official: SMITH, ROBERT A
project_start_date: 1992-07-01
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1-SMB(01)]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant):  For the past decade this project has focused on the physiology of reactive oxygen species (ROS) and nitric oxide (NO) derivatives in respiratory and limb skeletal muscle. We have shown that these molecular cascades affect contractile function modulating force in unfatigued muscle and contributing to fatigue during strenuous contraction. In the absence of disease ROS and NO have also been shown to influence other aspects of cellular function in skeletal muscle. These include glucose uptake metabolic regulation and transcriptional control of muscle adaptation. Despite growing recognition of their physiological importance the factors that regulate ROS and NO levels within skeletal muscle cells remain poorly understood. Speculation persists about the factors that affect cytosolic ROS and NO levels the intracellular sites of production and the signaling pathways that regulate ROS and NO homeostasis. The current project is designed to address these issues by evaluating redox homeostasis in skeletal muscle cells. We propose to evaluate cellular regulation of ROS and NO by diaphragm muscle fibers. A panel of established techniques will be used to detect ROS and NO in the cytosol and extracellular space. Cause-and-effect will be tested by disrupting ROS or NO signaling via pharmacologic probes and genetic engineering. We will address three Specific Aims: Aim 1. To evaluate endogenous ROS and NO activities in resting and mechanically-loaded diaphragm fibers. Aim 2. To determine the molecular source(s) and distribution of muscle-derived NO. Aim3. To evaluate principal source(s) of intracellular ROS and mechanisms that regulate ROS activity.

project_terms:
NAD(P)H oxidoreductase;SDS polyacrylamide gel electrophoresis;biological signal transduction;biomechanics;cytoplasm;diaphragm;electrodes;fiber cell;fluorescence microscopy;free radical oxygen;isozymes;laboratory mouse;mitogen activated protein kinase;muscle cells;muscle contraction;muscle pharmacology;nitric oxide;oxidation reduction reaction;polymerase chain reaction;protein kinase C;striated muscles;western blottings;xanthine oxidase


application_id: 7105000
project_number: 5R01HL074185-04
project_title: Inhibitor ameliorates oxidative and proteolytic strees
administering_ic: NHLBI
award_notice_date: 2006-07-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2008-08-31
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
DESCRIPTION (provided by applicant): Endocardial endothelial (EE) dysfunction and accumulation of oxidized-matrix between endothelial and muscle are the hallmarks of congestive heart failure (CHF). The overall objective of this project is to understand the mechanism of oxidized-matrix accumulation and EE dysfunction in CHF. Previous studies have suggested an association between induction of oxidative stress decrease in endothelial cell density activation of matrix metalloproteinase (MMP) collagenolysis and repression of cardiac tissue inhibitor of metalloproteinase (CIMP) in CHF. The novelty of this proposal is that among all known tissue inhibitors of metalloproteinase (TIMP) the TIMP-4 (i.e. CIMP) is highly expressed in the heart. The purpose of this proposal is to test a central hypothesis that oxidized-matrix accumulation and EE dysfunction are due to increased levels of MMP activity and collagenolysis. These levels are associated with decreased levels of EE nitric oxide and CIMP in response to increased levels of reactive oxygen species (ROS) during protracted cycles of ischemia/reperfusion in volume overload. The increased levels of CIMP protects EE against oxidative and proteolytic stresses. We will test the central hypothesis by the following three specific aims: 1. To determine whether CIMP decreases oxidative stress by increasing EE nitric oxide concentration. Plasma and left ventricle levels of nitric oxide ROS and nitrotyrosine will be measured in chronic volume overload arteriovenous fistula mice treated with and without CIMP. 2. To determine whether CIMP protein transfer inhibits collagenolysis. MMP activity will be measured by in situ zymography. The levels of CIMP activity will be measured by reverse zymography. Total collagen and its degradation fragments will be measured by Western-blot analysis using anti-collagen antibody. 3. To determine whether CIMP ameliorates endocardial endothelial dysfunction. Contractile responses to acetylcholine bradykinin and nitroprusside in cardiac rings will be measured in a tissue myobath. These studies will enable us to determine whether CIMP improves the hearts response to nitric oxide donors. Identification of major players involved in the control of oxidative and proteolytic stresses will help to develop strategies to prevent CHF.

project_terms:
acetylcholine;bradykinin;collagen;congestive heart failure;endocardium;enzyme activity;free radical oxygen;heart contraction;laboratory mouse;metalloendopeptidases;myocardial ischemia /hypoxia;nitric oxide;nitroferricyanide;oxidative stress;proteolysis;reperfusion;tissue /cell culture;tissue inhibitor of metalloproteinases;vascular endothelium;western blottings


application_id: 7104839
project_number: 5R01CA095609-03
project_title: Transcriptional Control of Breast Cancer Through PPARg
administering_ic: NCI
award_notice_date: 2006-05-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 095609
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2004-08-05
project_end_date: 2008-05-31
study_section: Biochemical Endocrinology Study Section[BCE]
contact_pi_person_id: 8288294
contact_pi: KILGORE, MICHAEL
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
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of these studies is to develop therapeutic strategies to treat or prevent breast cancer. Since our demonstration that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed and functionally active in breast cancer cells a rapidly growing body of evidence has accumulated indicating that PPARgamma plays a central role in many types of cancer including breast cancer. Ligands include the antidiabetic thiazolidinediones prostaglandin J2 fatty acids and others. Treating breast cancer cells with PPARgamma ligands have alternatively been reported to induce cell cycle withdrawal apoptosis or mediate the expression of genes leading to a more differentiated less malignant state. Other ligands including fatty acids have been reported to mediate the expression of genes that alter the malignancy and metastatic potential of breast cancer cells. The mechanism underlying these divergent actions has not been established. We have recently reported that the expression of ERalpha inhibits PPARgamma transactivation. Thus we will test the hypothesis that selective transactivation of PPARgamma by different ligands mediates gene expression profiles that favor either differentiation or proliferation depending on the specific ligand used and the functional status of the ER in the same cells. Therefore in Specific Aim 1 we will test the hypothesis that different PPARgamma ligands induce conformational changes that result in selective regulation of gene expression profiles and physiological responses in normal epithelia and in breast cancer cells. In Specific Aim 2 we will examine the necessity of PPARgamma in mediating the gene expression profiles involved in proliferation differentiation and apoptosis. In Specific Aim 3 we will examine the mechanism whereby the estrogen receptor alters the transactivation of PPARgamma and examine the physiological consequences of this interaction. This represents a novel approach to understanding the role PPARy plays in breast cancer and its selective modulation could point to novel mechanisms of action and to therapeutic targets.

project_terms:
apoptosis;breast neoplasms;cell differentiation;cell proliferation;conformation;gene expression;gene expression profiling;genetic transcription;ligands;mammary epithelium;microarray technology;neoplastic process;peroxisome proliferator activated receptor;polymerase chain reaction;prostaglandins;rosiglitazone;western blottings


application_id: 7103905
project_number: 1R21AG026521-01A1
project_title: Oxidation of cysteine-proteases in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2006-07-28
opportunity_number: PA-03-107
application_type: 1
activity_code: R21
ic: AG
serial_number: 026521
suffix: A1
program_official: SUNEJA, SANOJ
project_start_date: 2006-08-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1 CDIN-D (01)]
contact_pi_person_id: 3079616
contact_pi: GUTTMANN, RODNEY P
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): Alzheimer's disease is the most common cause of dementia affecting nearly 18 million people worldwide and projected to double over the next 20 years. Without new and significant preventative or curative measures this growing problem will place a substantial burden on society in terms of both financial and emotional strains. Previous research has implicated over activation of thiol-proteases in AD progression. This is based primarily on the observation of an increased 'activation' state of various thiol-proteases in AD brain. However other data suggest that thiol-proteases are not fully proteolytically active and that inhibition of thiol-proteases is more likely to contribute to AD pathology. Thus there is an important discrepancy between the observed activation of thiol-proteases and their proteolytic activity in Alzheimer's disease. These contradictory findings regarding thiol-protease 'activation1 and thiol-protease 'activity' need to be resolved in order to move forward and determine the role of thiol-proteases in tau and Abeta accumulation as well as cell death/ dysfunction during Alzheimer's disease. To address this gap in our knowledge we will test the hypothesis that the 'activated' thiol-proteases are oxidatively inhibited at their active-site cysteines by specific oxidants in the hippocampus of Alzheimer's disease. Aim 1: Determine the activity of thiol-dependent proteases in Alzheimer's disease brain compared to age-matched controls within the vulnerable hippocampus and the non-vulnerable cerebellum. Based on our recently published work we will show that thiol-protease activity including calcium-dependent thiol-protease activity is oxidatively inhibited in the hippocampus of AD brain compared to age-matched controls. Because AD degeneration is progressive we will also determine the extent of thiol-protease oxidation over the progression of the disease using brain samples from various stages of Alzheimer's disease. Aim 2: Determine the oxidants responsible for thiol-protease oxidation in the hippocampus of AD brain. These studies will determine the extent of oxidation and the oxidants responsible for oxidation of active-site cysteines within individual thiol- dependent proteases in AD hippocampus. This hypothesis challenges an existing paradigm by suggesting thiol-protease activity in Alzheimer's disease is decreased (rather than increased) due to oxidation of the active site. The proposed research will have impact on future therapeutics involving anti-oxidant or protease inhibitor strategies in the treatment or prevention of Alzheimer's disease.

project_terms:
Alzheimer&apos;s disease;active sites;amyloid proteins;cerebellum;cysteine;endopeptidases;enzyme activity;hippocampus;human tissue;neuritic plaques;neuropathology;oxidative stress;oxidizing agents;pathologic process;postmortem;proteolysis;tau proteins;thiols


application_id: 7103719
project_number: 5F31ES013360-03
project_title: Minority Predoctoral Fellowship program
administering_ic: NIEHS
award_notice_date: 2006-07-28
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: ES
serial_number: 013360
program_official: HUMBLE, MICHAEL C
project_start_date: 2004-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-F10(29)L]
contact_pi_person_id: 6190682
contact_pi: NANEZ, ADRIAN
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):  Benzo(a)pyrene (BaP) is a ligand for the aryl hydrocarbon receptor (Ahr) and a potent genotoxic carcinogen. Environmental exposure to BaP has been associated with tumorigenesis atherosclerosis and developmental deficits in several organ systems. The Ramos laboratory has recently shown that treatment of metanephric cultures with BaP is associated with Ahr-dependent disruption of nephrogenesis as evidenced by inhibition of glomerulogenesis and branching morphogenesis. Nephrogenesis is characterized by mesenchymal-to-epithelial transition and this process is regulated by the Wilm's tumor suppressor gene (Wt-1). Disruption of nephrogenesis by BaP involves interference with Wt-1 splicing and reductions in Wt-1 protein. Studies are proposed in this application to test the hypothesis that ligands of Ahr disrupt nephrogenesis in vivo by altering Wt-1 mRNA splicing. Aim 1 examines the impact of in utero BaP exposure on nephrogenesis and Wt-1 mRNA splicing. Aim 2 will determine the kinetic profiles of BaP-induced inhibition of nephrogenesis and altered Wt-1 splice variant expression. Aim 3 will characterize the mouse mesonephric M15 cell line as a model to evaluate downstream effects of increased -KTS/+KTS mRNA ratios.

project_terms:
RNA splicing;SDS polyacrylamide gel electrophoresis;Wilms&apos; tumor;aromatic hydrocarbon receptor;benzopyrenes;biological models;cell differentiation;embryo /fetus;gene expression;gene induction /repression;gene targeting;genetic transcription;genetically modified animals;kidney;laboratory mouse;ligands;messenger RNA;nephrogenesis;nucleic acid purification;organ culture;predoctoral investigator;protein purification;renal glomerulus;transfection /expression vector;tumor suppressor genes


application_id: 7103669
project_number: 5R01MH069991-03
project_title: Modular Abnormalities of Brain Organization in Autism
administering_ic: NIMH
award_notice_date: 2006-05-26
application_type: 5
activity_code: R01
ic: MH
serial_number: 069991
program_official: MEINECKE, DOUGLAS L
project_start_date: 2004-07-01
project_end_date: 2008-05-31
study_section: Special Emphasis Panel[ZRG1-DBD(01)Q]
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): All subcortical arrangements are primarily nuclear in type. The cortex was the first part of the brain to evolve a radial and laminar arrangement of cells. The resultant modular arrangement is based on the cell minicolumn: a self-contained ecosystem of connectivity linking afferent efferent and interneuronal connections. Our preliminary study of the fundamental processing unit of the cortex the minicolumn indicates that the modular neocortical organization in the brains of autistic individuals differs from that of controls. More specifically a study of 3 neocortical sites in 9 autistic brains and an equal number of normal controls has shown significant differences in the horizontal spacing that separates minicolumns. It also revealed differences in their internal structure: less neuropil space in the periphery of the minicolumn and increased mean cell spacing. Similar abnormalities have now been reported in Asperger's syndrome but appear absent in Down syndrome (a control group added for mental retardation). This study will examine differences in minicolumnar morphometry between 24 autistic brains and 24 controls matched for age and sex from both the Autism Tissue Program and the Yakovlev-Haleem Collection (Armed Forces Institute of Pathology). The patients provide a new cohort not previously examined by the investigator. Ten Down syndrome brains will provide a second control group. Sampled cortical regions include Brodmann's areas 4 9 10 17 21 22 30 33 and 39 which represent sensory motor association and limbic cortex obtained from 4 different brain lobes. The study will utilize quantified computer imaging and stereology in both Nissl and myelin-stained material. The parameters tested include the width of minicolumns the amount of neuropil space within them the mean cell density within each minicolumn individual lamina depth cell size and type (pyramidal versus non pyramidal) and the distribution of cell types among different lamina. The study will employ inter-myelinated bundle measurements as a way of corroborating our minicolumnar width parameters. We will compare the results within multiple regions of the cortex as well as for lateralization. Finally we will correlate our minicolunmar parameters with different dimensions on the ADI. This study aims at better understanding the neuroanatomical basis of autism. If validated positive results from our studies will yield a great understanding of autism. For example many alleged animal models of autism lack the human neuroanatomic information to justify their utility. Candidate gene studies could also be refined if neuroanatomic development in autism was better understood. Treatment modalities especially neuropharmaceutical agents will prove more specific as their targets are better understood.

project_terms:
autism;basal lamina;brain disorders;brain imaging /visualization /scanning;brain morphology;cell morphology;cell population study;cell type;cerebral dominance;clinical research;digital imaging;human tissue;mental disorder diagnosis;morphometry;neuropathology;parietal lobe /cortex;postmortem;temporal lobe /cortex;visual cortex


application_id: 7103493
project_number: 5R01GM075248-02
project_title: Role of USP Ligand Binding Pocket During Development
administering_ic: NIGMS
award_notice_date: 2006-07-31
application_type: 5
activity_code: R01
ic: GM
serial_number: 075248
program_official: ANDERSON, JAMES J
project_start_date: 2005-08-01
project_end_date: 2009-07-31
study_section: Special Emphasis Panel[ZRG1-VB(01)Q]
contact_pi_person_id: 1898656
contact_pi: JONES, GRACE M
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): A major unresolved question in insect endocrinology is whether the nuclear receptor ultraspiracle (USP) has an active ligand-binding function or alternatively is a non-liganded even passive heterodimer partner. Our previous NIH-funded protein biochemical studies emphasized screening of many point mutants to the ligand-binding domain of the Drosophila USP. The specific aims were to identify optimal mutant USPs for future testing of an in vivo USP ligand binding function of 2 transgenic fly assays. Our studies  supported by recent studies by others were successful in demonstrating in cultured cell assays that the USP of Drosophila (flies) and Aedes (mosquitoes) can transduce transcriptional signaling by methyl epoxyfarnesoate a natural juvenile hormone (JH) in flies and mosquitoes. The studies also show that this intracellular JH signaling requires a surface region on USP corresponding to a ligand-activated co-activator binding surface of the vertebrate counterpart RXR. Using the cultured cell functional assay we were successful in preparing point mutants to the USP ligand-binding pocket and co-activator binding surface that act as dominant negatives to block USP-dependent JH signaling in the cultured cells. On this basis the recent NIH study section panel summary directed that our next proposal move past the protein biochemical studies by using "the mutants already in hand rather than looking for more mutants" and to now orient the studies "into a direct biological context". Therefore in this new proposal we take these Drosophila USP mutants (and corresponding Aedes USP mutants) will be used in the transgenic fly assays in order to ask the following questions: 1) Is the USP ligand-binding pocket needed for USP function in JH/ecdysone-driven larval-to-larval molting? 2) Does the USP ligand-binding pocket transduce JH effects on pupal-adult metamorphosis? These in vivo studies are the next logical step building upon protein biochemical and cultured-cell assays and are insect endocirinology's first direct in vivo tests of a ligand-binding function for any USP. The outcome will have broad implications for insect endocrinology enabling specific tests on the Aedes USP the results of which will yield new insights on hormonal signaling in the technically more difficult mosquito.

project_terms:
Aedes;Drosophilidae;ecdysone;genetically modified animals;histogenesis;hormone binding protein;hormone receptor;hormone regulation /control mechanism;invertebrate endocrinology;invertebrate hormone;ligands;metamorphosis;molting;nuclear receptors;receptor binding;receptor expression;tissue /cell culture


application_id: 7103387
project_number: 5F31AA014467-03
project_title: Risk factors for alcohol dependence in Native Americans
administering_ic: NIAAA
award_notice_date: 2006-06-26
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: AA
serial_number: 014467
program_official: ARROYO, JUDITH A
project_start_date: 2004-08-01
project_end_date: 2007-07-31
study_section: Special Emphasis Panel[ZRG1-BBBP-H(29)L]
contact_pi_person_id: 9708777
contact_pi: SPILLANE, NICHEA SOLOMON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of the proposed program of research is to begin testing a more complete model of Native American (NA) drinking. The first part of the model adapts drinking behavioral choice theory to help explain high mean NA drinking levels. Standard Life Reinforcers (SLRs) are a basic set of rewarding experiences or consequences that individuals strive for such as housing economic security work opportunity family closeness and knowledge. Some NAs experience less access to some SLRs less loss of other SLRs from drinking and less contingency between drinking and access to yet other SLRs. As a result they experience fewer incentives to avoid heavy drinking and hence they drink more heavily. The second part of the model applies acquired preparedness theory to explain individual differences in drinking levels among NAs. This model incorporates both personality and psychosocial learning. It proposes that disinhibition/impulsivity operates as a general distal risk factor for a range of acting out behaviors. Impulsivity is likely to lead to problem drinking when one also acquires a proximal risk factor i.e. expectancies for reinforcement from drinking. The overall model addresses both group and individual difference factors.

project_terms:
Native Americans;alcoholic beverage consumption;alcoholism /alcohol abuse;behavioral /social science research tag;caucasian American;choice;clinical research;disease /disorder proneness /risk;drug addiction;gender difference;human subject;impulsive behavior;low socioeconomic status;personality;predoctoral investigator;psychometrics;questionnaires;racial /ethnic difference;reinforcer;substance abuse epidemiology;substance abuse related behavior


application_id: 7102582
project_number: 5R01DK046923-10
project_title: PROLACTIN AND BILE SECRETORY FUNCTION
administering_ic: NIDDK
award_notice_date: 2006-07-27
application_type: 5
activity_code: R01
ic: DK
serial_number: 046923
program_official: SERRANO, JOSE
project_start_date: 1994-05-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-B(04)M]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
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
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Lactation is a physiological state characterized by a 4-5-fold increase in energy demand and a 2-3-fold increase in food consumption to meet this demand. We have demonstrated a coordinated up-regulation of expression of the hepatic sodium/taurocholate cotransporter (ntcp) and bile salt export pump (bsep) and of the intestinal apical sodium-dependent bile acid transporter (asbt) during lactation in the rat. There is also a 3-fold increase in the size of the bile acid pool during lactation. We postulate that these increases function to enhance absorption of dietary lipids to meet the energy demands of the lactating dam and for incorporation into milk. However the increased bile acid pool occurs at times when expression of Cyp7a1 the major regulated enzyme in the synthesis of bile acids from cholesterol is decreased and ntcp expression is increased. We will test the following hypotheses: 1) hepatic expression of enzymes involved in the alternate bile acid synthesis pathway is increased at the time of maximal expansion of the bile acid pool; 2) the expanded bile acid pool leads to activation of FXR and increased hepatic expression of bsep and SHP; and 3) while increased expression of SHP leads to repression of Cyp7a1 prolactin-mediated activation of the Jak2/Stat5 signal transduction pathway activates ntcp and overrides SHP-mediated repression. Specific Aims designed to test these hypotheses will use control female and lactating rats at various times postpartum to characterize 1) the size and composition of the bile acid pool and in lipid and cholesterol absorption; 2) expression of bile acid transporters and key enzymes in the synthesis of bile acids from cholesterol and expression; 3) signaling pathways that regulate bile acid synthesis and transport. The lactating female is unique in terms of the high-energy demands; investigation in this model offers an opportunity for increased understanding of the regulation of cholesterol and bile acid homeostasis under stressful conditions. In addition to the need to understand the changes that potentially occur in nursing women this model may enable identification of new regulatory pathways not otherwise observed and which may be exploited for therapeutic purposes. The high burden of disease related to elevated cholesterol makes this a highly significant and compelling opportunity.

project_terms:
JAK kinase;P glycoprotein;bile;bile circulation;biological signal transduction;biological transport;cell line;cholanate compound;estradiol;estrogen receptors;female;genetic promoter element;hormone regulation /control mechanism;hypophysectomy;laboratory rat;lactation;liver cells;membrane transport proteins;ovariectomy;postpartum;pregnancy;prolactin;secretion;somatostatin;transcription factor;transfection


application_id: 7101221
project_number: 2R01HL068440-05
project_title: Factor XIII Activation and Substrate Specificity
administering_ic: NHLBI
award_notice_date: 2006-04-15
application_type: 2
activity_code: R01
ic: HL
serial_number: 068440
program_official: LINK, REBECCA P
project_start_date: 2001-07-01
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1 HEME-C (03)]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
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
budget_start_date: 2006-06-01
project_terms:
SDS polyacrylamide gel electrophoresis;activation product;active sites;antifibrinolytic agents;binding sites;blood coagulation;caseins;computer simulation;conformation;crosslink;deuterium;enzyme substrate;fibrin;fibrin stabilizing factor;fibronectins;high performance liquid chromatography;hydrogen;hydrolysis;mass spectrometry;matrix assisted laser desorption ionization;membrane transport proteins;molecular dynamics;nuclear magnetic resonance spectroscopy;protein glutamine gamma glutamyltransferase;protein structure function;thrombin


application_id: 7101214
project_number: 1R25HL084695-01
project_title: Summer Undergraduate Experiences In Biomedical Research
administering_ic: NHLBI
award_notice_date: 2006-04-07
opportunity_number: RFA-HL-05-018
application_type: 1
activity_code: R25
ic: HL
serial_number: 084695
program_official: COMMARATO, MICHAEL
project_start_date: 2006-04-07
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZHL1 CSR-B (F1)]
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The primary goal of this program is to provide minority and disadvantaged undergraduate students with an initial exposure to basic science and clinical researchers and their areas of cardiovascular research at the University Of Louisville School Of Medicine. It is anticipated that significant number of minority undergraduate students will elect to enter into graduate research programs at either this university or others around the country as a results of the experiences in our program. We also expect a limited number of medical students to participate in this program. It is hoped that these students will either pursue a research experience during their residency or in a few cases pursue a combined degree in medicine and research (Ph.D. or M.S.). Specifically the program will emphasize the following: a. To develop an appreciation for the scientific method of investigation. Emphasis will be placed on exposing students to literature-based hypothesis generation proper experimental design and appropriate data analysis procedures. b. Exposure to a biomedical research environment that emphasizes collaboration between basic science and clinical researchers and that clearly demonstrates the clinical relevance of cardiovascular research that is being conducted at this university. c. To provide an accurate perception of the importance of animal research with emphasis on proper use of animals and an initial exposure to ethics in the conducting of these types of research studies; (End of Abstract)

project_terms:
animal care;cardiovascular surgery;data collection methodology /evaluation;ethics;experimental designs;health science research;health science research potential;literature citation;medical education;minority health professional;university student


application_id: 7101111
project_number: 5R37HD029957-14
project_title: Early Development with Williams or Down Syndrome
administering_ic: NICHD
award_notice_date: 2006-08-05
application_type: 5
activity_code: R37
ic: HD
serial_number: 029957
program_official: KAU, ALICE S
project_start_date: 2004-09-15
project_end_date: 2009-07-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of the proposed research is to delineate and make sense of the process of lexical development and its relations to communicative development grammatical development and both general and specific aspects of nonlinguistic cognitive development.  The research will focus on the language and cognitive development of three groups: children with Williams syndrome children with Down syndrome and typically developing children.  Out research during the current grant period indicates that the language skills of children with Williams syndrome are more advanced than their nonverbal cognitive skills; children with Down syndrome show the opposite pattern.  Children who are typically developing tend to have equivalent levels of language and cognitive skills.  Because of these differences in the general nature of the relations between language and nonlinguistic cognition inclusion of all three groups in the same studies provides a unique opportunity to identify factors that are universal and necessary to lexical communicative or grammatical development versus those that are specific to particular rates or paths to language acquisitions.  The proposed research consists of a 5-year longitudinal study beginning in late infancy and both longitudinal and cross-sectional studies involving preschool-and school-age children.  Both observational and experimental methods will be used.  There are four specific aims.  The first is to delineate the nature of early lexical growth curves.  The second is to further examine the role of lexical operating principles (heuristics) and foundational social cognitive abilities in the acquisition and extension of new words.  The third is to begin to delineate the development of communicative abilities by toddlers and young children who have Williams syndrome.  The fourth is to determine longitudinally the developmental trajectories of language and cognitive abilities for children with Williams syndrome.  The research will have implications both for theoretical models of the relations between language and cognition and for the design of cognitive and language intervention strategies for children with developmental disabilities.

project_terms:
Downs syndrome;Williams syndrome;behavioral /social science research tag;child (0-11);child behavior;child psychology;clinical research;cognition;data collection;early experience;human subject;language development;longitudinal human study;low birth weight infant human;mother child interaction;neuromuscular system;paralinguistic behavior;personal log /diary;play;semantics;syntax;videotape /videodisc


application_id: 7100898
project_number: 5R01NS040919-06
project_title: Male Urogenital Function and Chronic Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: NS
serial_number: 040919
program_official: KLEITMAN, NAOMI
project_start_date: 2000-09-28
project_end_date: 2010-06-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H
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
budget_start_date: 2006-07-01
project_terms:
afferent nerve;central neural pathway /tract;electrophysiology;excretion;immunocytochemistry;laboratory rat;male;male reproductive system;morphometry;neural plasticity;neuromuscular function;neuroregulation;reproduction;spinal cord injury;urination;white matter


application_id: 7100119
project_number: 5R01EY013813-04
project_title: TNF-alpha in cell death & neuroprotection in glaucoma
administering_ic: NEI
award_notice_date: 2006-07-24
application_type: 5
activity_code: R01
ic: EY
serial_number: 013813
program_official: LIBERMAN, ELLEN S
project_start_date: 2003-08-01
project_end_date: 2007-07-31
study_section: Special Emphasis Panel[ZRG1-VISA(01)Q]
contact_pi_person_id: 6803489
contact_pi: TEZEL, GULGUN
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
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): Although glaucoma is a leading cause of worldwide blindness neither the precise pathogenic mechanisms which lead to retinal ganglion cell death in glaucoma nor effective strategies for neuroprotection are known. Tumor necrosis factor-alpha (TNF-alpha) has recently been identified to be a mediator of retinal ganglion cell death in glaucoma. In vitro evidence demonstrates that TNF-alpha secreted by activated glial cells in response to glaucomatous stressors such as elevated intraocular pressure and ischemia can induce apoptotic death of retinal ganglion cells. Glial production of TNF-alpha is increased and TNF receptor-1 a death receptor is upregulated in retinal ganglion cells and their axons in glaucomatous human eyes. There is also compelling in vivo evidence obtained from a rat model of high-pressure glaucoma which demonstrates the pathogenic role of TNF-a in these eyes. (1) Similar to glaucomatous human eyes the expression of TNF-alpha and TNF receptor-1 are increased in rat eyes following intraocular pressure elevation; (2) TNF-alpha signaling is involved in cell death in these eyes as evidenced by the activation of retinal caspase-8 -a proximal effector protein in the TNF receptor family cell death pathway; (3) anti-TNF-alpha treatment in ocular hypertensive rat eyes can provide neuroprotection. Additional in vivo evidence comes from studies using the optic nerve crush injury model in mice deficient for TNF receptor-1. Although this is not a model for glaucoma findings of these studies provide evidence that TNF-alpha signaling is involved in the death of retinal ganglion cells following optic nerve injury. Thus current evidence presented in this application collectively provides a strong rationale for further evaluation of the TNF-alpha mediated cell death in glaucoma. The proposed experiments aim to identify the precise mechanisms of TNF-alpha-mediated cell death and neuroprotection in retinal ganglion cells and glial cells using in vitro and in vivo models. Using primary co-cultures activation of caspases and mitochondrial events and activation of native protection mechanisms and selected kinase pathways will be separately studied in retinal ganglion cells and glial cells exposed to exogenous TNF-alpha. Using a rat glaucoma model the relationship between the induction of endogenous TNF-alpha and cell death will be studied in vivo. In addition the effectiveness of a specific anti-TNF-alpha treatment to provide neuroprotection will be further determined in this in vivo model using both the functional and the anatomical outcomes. An improved understanding of the precise mechanisms of cell death and protection in studies proposed in this application should facilitate efforts to effectively manipulate the survival of retinal ganglion cells in glaucoma.

project_terms:
BCL2 gene /protein;apoptosis;cysteine endopeptidases;cytokine receptors;enzyme activity;glaucoma;glia;intraocular pressure;laboratory rat;mitochondria;mixed tissue /cell culture;neuroprotectants;nuclear factor kappa beta;protein kinase;retinal ganglion;tumor necrosis factor alpha


application_id: 7099666
project_number: 5R01DA017711-02
project_title: Stimulant Abuse Pharmacotherapy: Novel Antipsychotics
administering_ic: NIDA
award_notice_date: 2006-04-28
application_type: 5
activity_code: R01
ic: DA
serial_number: 017711
program_official: OVERSBY, STEVEN
project_start_date: 2005-08-01
project_end_date: 2010-04-30
study_section: ZDA1-RXL-E(07)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_terms:
adult human (21+);antipsychotic agents;central nervous system stimulants;clinical research;dopamine agonists;drug abuse;drug abuse chemotherapy;drug addiction;drug interactions;drug screening /evaluation;human subject;human therapy evaluation;methamphetamine;neurotransmitter agonist;neurotransmitter antagonist;patient oriented research;psychopharmacology;public health;serotonin;substance abuse related behavior


application_id: 7098728
project_number: 5R44HD041820-04
project_title: Adaptive Stimulator for Exercise and Rehabilitation
administering_ic: NICHD
award_notice_date: 2006-07-31
opportunity_number: PA-02-071
application_type: 5
activity_code: R44
ic: HD
serial_number: 041820
program_official: QUATRANO, LOUIS A
project_start_date: 2002-02-25
project_end_date: 2009-07-31
study_section: Special Emphasis Panel[ZRG1-GRM(10)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: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
budget_end_date: 2009-07-31
project_abstract:
DESCRIPTION (provided by applicant):  We propose to develop an electrical stimulation system with adaptive capabilities for exercise and rehabilitation. The target populations are: 1) individuals with complete or incomplete SCI who are interested in improving their physical fitness through electrically stimulated lower-extremity exercise 2) individuals with complete or incomplete SCI who seek to develop or maintain adequate muscle strength to allow routine use of an FES system for standing and 3) individuals with incomplete spinal cord injury brain injury or stroke who have the potential to regain voluntary lower extremity motor function through motor retraining therapy.  The proposed portable exercise unit will include sensors and an adaptive control algorithm to provide repeatable movements. We anticipate that the adaptive controller will provide safe and effective exercise and that the adaptive controller will allow the exercise goals to be defined in movement rather than stimulation-specific parameters. For motor retraining the system will encourage maximum voluntary effort by providing only the stimulation required to supplement the user's effort.  The Phase I aims were achieved successfully. Phase I results clearly demonstrate the feasibility of our approach and have laid a strong foundation for the proposed Phase II effort.  In Phase II we will: 1) develop sensors to provide direct knee angle measurements and simplify donning and calibration 2) develop a prototype adaptive stimulator for use by individuals with complete or incomplete SCI 3) develop a clinical software suite for protocol programming performance evaluation and documentation 4) assess the efficacy of the device in a study involving individuals with complete injuries who wish to increase muscle mass strength and endurance through a long-term electrical stimulation based training protocol and 5) assess the efficacy of the device in a study involving individuals with incomplete injuries who have some degree of voluntary control over the target muscles and who wish to improve muscle condition and potentially improve their ability to perform functional voluntary activities.

project_terms:
bioengineering /biomedical engineering;biomechanics;biomedical equipment development;biosensor device;body movement;brain injury;clinical research;clinical trials;computer program /software;computer system design /evaluation;electronic stimulator;electrostimulus;exercise;human subject;medical rehabilitation related tag;muscle function;muscle strength;orthopedics;paralysis;patient oriented research;portable biomedical equipment;rehabilitation;spinal cord injury;stroke


application_id: 7098606
project_number: 1R03DC007315-01A1
project_title: Neural Substrates of Component Lexical Semantic Processes
administering_ic: NIDCD
award_notice_date: 2006-03-10
opportunity_number: PAR-04-062
application_type: 1
activity_code: R03
ic: DC
serial_number: 007315
suffix: A1
program_official: COOPER, JUDITH
project_start_date: 2006-04-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZDC1 SRB-Y (56)]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Extracting meaning from words (lexical semantics) is critical to normal language functioning. Lexical semantic impairment can result from a variety of causes including developmental abnormalities stroke and degenerative diseases but may reflect damage to one or more component processes. Current language models have identified two qualitatively different components of the lexical semantic system: 1) An automatic component enables rapid access to semantics within milliseconds of lexical input; and 2) a controlled component evolves more slowly and guides strategic retrieval of semantic information not recovered automatically. In addition some processes associated with these components are thought to depend upon the modality of incoming stimuli. The objective of the project is to identify the neural correlates of these behaviorally separable automatic and controlled components of the lexical semantic system within and across visual and auditory modalities. In a preliminary study we identified dissociable neural correlates of visually cued automatic and controlled lexical semantic processing in healthy volunteers using event-related fMRI and a primed lexical decision task. A series of similar studies are proposed to characterize more precisely the roles of several frontal and temporal lobe brain regions in components of the lexical semantic system. The design is novel in that automatic and controlled semantic priming conditions will be compared directly using randomized designs identical to those used in behavioral research. There are three goals. The first goal is to characterize more precisely the role of a left frontal region in visually cued controlled retrieval of lexical semantic information. The second goal is to characterize more precisely the role of a left temporal region in visually cued automatic lexical semantic processing. The third goal is to identify neural regions involved in auditorily cued lexical semantics that overlap and are dissociable from those involved in visually cued lexical semantics. Identifying neural systems associated with component processes involved in extracting meaning from words is of central importance to understanding the structure and organization of the lexical semantic system and should aid diagnosis and rehabilitation of language disorders.

project_terms:
aphasia;auditory stimulus;brain mapping;clinical research;communication;cues;functional magnetic resonance imaging;human subject;neural information processing;phonology;semantics;temporal lobe /cortex;visual pathways;visual stimulus


application_id: 7097924
project_number: 7R01HL074219-03
project_title: Integrin Signaling In Vascular Cells
administering_ic: NHLBI
award_notice_date: 2006-09-01
application_type: 7
activity_code: R01
ic: HL
serial_number: 074219
program_official: SRINIVAS, POTHUR R
project_start_date: 2004-08-01
project_end_date: 2009-06-30
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S
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: 2006-09-01
project_terms:
biological signal transduction;cell adhesion;cell growth regulation;cell migration;guanosinetriphosphatases;hyperplasia;integrins;laboratory mouse;mitogen activated protein kinase;vascular smooth muscle


application_id: 7097016
project_number: 3P42ES007380-09S1
project_title: Recent Advances in the Environmental Toxicology and Health Effects of PCBs
administering_ic: NIEHS
award_notice_date: 2006-01-03
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HOLLANDER, JONATHAN
project_start_date: 1997-04-07
project_end_date: 2006-03-31
study_section: Special Emphasis Panel[ZES1 SET-B (P4)]
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION  
  
This proposal seeks support for the fourth International Workshop on "Environmental Toxicology and Health Effects of PCBs" to be held in Zakopane Poland in September 2006.  This would be the fourth PCB workshop which has alternated every 2 years starting in 2000 between the US and Europe. The 3 previous workshops have been supported by NIEHS and have been attended by 130 to 200 participants. The stated objectives of the workshop are to 1) bring researchers together to facilitate interaction and exchange of information; 2) to generate a current collection of findings on PCBs and human health in book form; and 3) to facilitate interaction with researchers in East Europe.

project_terms:
clinical research;environmental toxicology;halobiphenyl /halotriphenyl compound;nutrition related tag;toxin metabolism


application_id: 7096316
project_number: 1R01AG024040-01A2
project_title: Genetic and Environmental Risk Factors for PSP
administering_ic: NIA
award_notice_date: 2006-07-12
opportunity_number: PAS-03-092
application_type: 1
activity_code: R01
ic: AG
serial_number: 024040
suffix: A2
program_official: MILLER, MARILYN
project_start_date: 2006-07-15
project_end_date: 2011-06-30
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 2452926
contact_pi: LITVAN, IRENE
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
alpha synuclein;brain injury;clinical research;disease /disorder etiology;disease /disorder proneness /risk;environmental exposure;gene environment interaction;gene interaction;gene mutation;genetic polymorphism;genetic screening;haploidy;human subject;hypertension;interview;leucine;medical records;occupational health /safety;parkin gene /protein;pathologic process;patient oriented research;plant insecticide;progressive supranuclear palsy;telecommunications;trauma


application_id: 7096113
project_number: 5R21AI057903-02
project_title: A Novel Approach to Prevent and Treat Type 1 Diabetes
administering_ic: NIAID
award_notice_date: 2005-08-09
opportunity_number: PA-91-011
application_type: 5
activity_code: R21
ic: AI
serial_number: 057903
program_official: RIDGE, JOHN P
project_start_date: 2004-09-01
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-SAT(90)S]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The primary objective of this grant proposal is to use a novel Fas Ligand molecule (SA-FasL) with potent apoptotic activity and a unique method designated as ProtExTM to rapidly and effectively display SA-FasL at the protein level on antigen-presenting cells (APCs) or pancreatic islets as an immunomodulatory approach to prevent and/or treat insulin-dependent Type I diabetes mellitus (T1D). T1D is a chronic autoimmune disorder that affects a large number of people worldwide. Transplantation of whole pancreas or purified islets promises an efficient approach to achieving euglycemia in T1D patients. However immune rejection limits long-term graft survival. Islet cell destruction is primarily mediated by T cells directed at unique pancreatic beta cell antigens. In this application we propose to use SA-FasL to induce apoptosis in pathogenic autoreactive and alloreactive T cells for the prevention and treatment of diabetes. FasL-induced apoptosis is the main mechanism of activation-induced cell death responsible for immune homeostasis and is also important for tolerance to self-antigens. There is evidence in the literature suggesting that FasL is not only important for the induction of tolerance by inducing apoptosis in antigen-activated lymphocytes but also for the maintenance of tolerance by facilitating the generation and function of immunoregulatory lymphocytes. Therefore we hypothesize that immunomodulation with SA-FasL will effectively eliminate pathogenic autoreactive and alloreactive lvmphocytes and induce immunoregulatory mechanisms that will maintain tolerance. We have recently generated a modified form of FasL molecule SA-FasL with potent apoptotic activity and developed a novel approach to display SA-FasL at the protein level on the surface of any cell of interest within a short period of time (-2 hrs). In preliminary studies we demonstrated that SA-FasL can also be effectively displayed on the surface of pancreatic islets without toxicity and these islets restored euglycemia upon transplantation into syngeneic diabetic mice. In this application we propose to use SA-FasL with the ProtExTM technology to prevent diabetes in prediabetic NOD and treat diabetes in diabetic animals using allogeneic islet transplantation. Diabetes in NOD will be prevented by the treatment of prediabetic mice with SA-FasL as soluble protein or displayed on APCs pulsed with islet antigens. Diabetes in NOD will be treated by the transplantation ofC57BL/6 allogeneic islets displaying SA-FasL with and without FasL-APCs. The recognition of auto/alloantigens in the context of SA-FasL is expected to result in physical/functional elimination of pathogenic auto/alloreactive T cells and generation of protective immune mechanisms that maintain tolerance. Induction of tolerance will be followed by a series of studies to delineate the implicated mechanisms. Rapid and durable display of functional proteins on cells or tissues offers a whole new means of intervention in the areas of autoimmunity transplantation and vaccines. This approach possesses the simplicity safety and efficacy required to make it a clinically relevant alternative to gene therapy in the treatment of a broad spectrum of immune-based diseases.

project_terms:
CD95 molecule;NOD mouse;T lymphocyte;apoptosis;binding proteins;biotherapeutic agent;biotin;cell proliferation;chimeric proteins;dendritic cells;diabetes mellitus therapy;disease /disorder prevention /control;enzyme linked immunosorbent assay;gene expression;genetically modified animals;homologous transplantation;immune tolerance /unresponsiveness;immunomodulators;insulin dependent diabetes mellitus;ligands;metabolism disorder chemotherapy;nonhuman therapy evaluation;pancreatic islet transplantation;pancreatic islets;therapy design /development;tissue /cell culture


application_id: 7095994
project_number: 5R21DE016316-02
project_title: Identifying Periodontal Antigens By Protein Microarray
administering_ic: NIDCR
award_notice_date: 2006-05-16
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: DE
serial_number: 016316
program_official: LUNSFORD, DWAYNE
project_start_date: 2005-07-19
project_end_date: 2008-05-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: Periodontitis is a chronic inflammatory response to bacterial pathogens that causes damage to both bone and soft tissues that support the teeth. Extensive effort has identified the genes for relatively few bacterial antigens related to periodontitis. Therefore the host immune response to oral bacteria during periodontal disease has not been adequately characterized. Analysis of the molecular interactions that occur between oral bacteria and host cells is a high priority of NIDCR and will contribute to our basic understanding and clinical tools for periodontal disease. The overall goal of this project is to define the bacterial proteins (antigens) that elicit humoral immune responses during periodontal disease and determine how the different antibody specificities relate to the severity of disease or response to treatment. Our hypothesis is that the presence of antibodies to certain groups of bacterial antigens is associated with the severity of periodontal disease or the response to treatment in patients. To address this hypothesis we propose to use bacterial genomic DMA to create bacteriophage lambda expression libraries for Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans. We will screen the libraries with periodontitis patient and control sera to identify antigenic peptides. The antigenic proteins will be arrayed on microarray slides and screened with individual patient serum. The presence of specific antibodies or groups of antibodies will be related to the clinical indices of the patient using hierarchical cluster analyses. This approach takes advantage of the extremely high gene density of the bacterial genome which lacks introns and of the technological advances for construction of microarrays. The R21 Exploratory Grant is an appropriate mechanism since proteomics have not been used for periodontal disease and bacterial genomic expression libraries and antigen microarrays need to be developed.

project_terms:
Actinobacillus actinomycetemcomitans;Bacteroides gingivalis;antigen antibody reaction;bacterial antigens;bacterial cytopathogenic effect;bacterial proteins;bacteriophage lambda;clinical research;dental disorder diagnosis;genetic library;genetic screening;host organism interaction;human tissue;humoral immunity;immune response;microarray technology;pathologic process;periodontium disorder;polymerase chain reaction;protein quantitation /detection;tissue /cell culture;virulence


application_id: 7095895
project_number: 5R01DK072032-02
project_title: Podocytes and oxidative stress in diabetic kidney
administering_ic: NIDDK
award_notice_date: 2006-07-14
application_type: 5
activity_code: R01
ic: DK
serial_number: 072032
program_official: NIHALANI, DEEPAK
project_start_date: 2005-09-01
project_end_date: 2010-07-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N.
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_terms:
antioxidants;ascorbate;cellular pathology;chronic renal failure;diabetes mellitus therapy;diabetic nephropathy;disease /disorder model;free radical oxygen;gene expression;genetic manipulation;genetically modified animals;insulin dependent diabetes mellitus;kidney disorder chemotherapy;laboratory mouse;laser capture microdissection;metallothionein;microarray technology;nonhuman therapy evaluation;nutrition related tag;oral administration;oxidative stress;pathologic process;podocyte;short chain fatty acid;tocopherols;vitamin therapy


application_id: 7095852
project_number: 5R01HL074296-04
project_title: Hypoxia-induced Akt Signaling module in Neuronal Cells.
administering_ic: NHLBI
award_notice_date: 2006-07-29
application_type: 5
activity_code: R01
ic: HL
serial_number: 074296
program_official: GOLDEN, AL
project_start_date: 2003-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-SSS-3(03)M]
contact_pi_person_id: 6155708
contact_pi: GOZAL, EVELYNE
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this proposal is to elucidate hypoxia-induced Akt-related pathways induced in neuronal PC- 12 and RN46A neuronal cells by sustained hypoxia and by intermittent hypoxia and to determine how these signaling pathways affect cell survival. We will test the hypothesis that hypoxia-induced interactions between different signaling molecules within the Akt signaling module modulate tolerance or vulnerability to sustained and intermittent hypoxia in neuronal cells. We propose: (1) To identify using proteomic approaches members of the Akt signaling module in normoxic and hypoxic neuronal cells and to identify differences in Akt-associated proteins during sustained and intermittent hypoxia; (2) To characterize protein-protein interactions within the Akt signaling modules; (3) To identify selective Akt - protein interactions within the signaling module that underlie neuronal survival to sustained and intermittent hypoxia; (4). To examine the effect of disruption of protein-protein interactions within the Akt signaling module on downstream genes involved in regulation of hypoxia-induced cellular apoptosis. We will use proteomic techniques SDS-PAGE and MALDI-MS to identify the Akt-binding proteins co-immunoprecipitating with Akt in normoxic cells or cells exposed to sustained or intermittent hypoxia. Interactions of the components of the Akt signalosomes will be determined by TnT coupled transcription translation co-immunoprecipitation and GST pull-down methods. Transformer kits will be used to make in frame and serial deletion mutants of Akt and its binding proteins in order to identify their Akt docking sites. Finally we will introduce into the cells TAT-fusion peptides corresponding to specific docking sites of targeted proteins binding to Akt signaling module and disrupt their interaction with the Akt signaling complex to assess the effect of protein association/dissociation with the Akt signaling module on cell survival to sustained and intermittent hypoxia. These studies will provide the groundwork for future intervention strategies aiming to prevent neuronal cell loss in diseases associated with intermittent and sustained hypoxia such as sleep apnea and lung disease.

project_terms:
SDS polyacrylamide gel electrophoresis;apoptosis;binding proteins;biological signal transduction;chimeric proteins;enzyme complex;enzyme mechanism;gene deletion mutation;hypoxia;immunoprecipitation;matrix assisted laser desorption ionization;neurogenetics;neurons;phosphorylation;protein kinase;protein protein interaction;protein sequence;proteomics;tissue /cell culture;western blottings


application_id: 7095839
project_number: 5K01DK065039-04
project_title: Inhibition of NADPH oxidase by Anaplasma phagocytophila
administering_ic: NIDDK
award_notice_date: 2006-07-28
opportunity_number: PAR-02-065
application_type: 5
activity_code: K01
ic: DK
serial_number: 065039
program_official: ROY, CINDY
project_start_date: 2003-08-15
project_end_date: 2008-07-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 6434147
contact_pi: CARLYON, JASON A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Human granulocytic ehrlichiosis (HGE) is an emerging infection of the blood that results in leukopenia and thrombocytopenia. If left untreated the disease can manifest itself as severe neutropenia hypotension shock and may potentially be fatal due to myocarditis pancarditis or to opportunistic infections resulting from impaired host defense mechanisms. Recent evidence suggests that kidney and pancreas transplant recipients are at risk for contracting HGE. A. phagocytophila the etiologic agent of HGE persists within its mammalian host by colonizing neutrophils. Neutrophils are primary effector cells involved in phagocytosing and killing bacterial invaders. This bactericidal activity is partially dependent on the superoxide anion produced by the rapidly activatable multi-component enzyme NADPH oxidase. A. phagocytophila however utilizes multiple strategies to prevent superoxide anion production. It is established that the bacterium inhibits the mRNA expression of gp91phox a component of NADPH oxidase. Preliminary data presented here demonstrates that A. phagocytophila also prevents transcription of rac2 the key factor of NADPH oxidase. Aims 1 and 2 seek to define the mechanisms responsible for the inhibition of rac2 transcription. Evidence suggests that prior to preventing rac2 and gp91phox mRNA expression once inside the host cell A. phagocytophila initially inhibits activation of preformed NADPH oxidase components during invasion. Activation of Rac2 represents the initial integral step of NADPH oxidase assembly. Therefore Aim 3 will investigate whether A. phagocytophila inhibits Rac2 activation during invasion. Collectively these studies will decipher the complex means by which A. phagocytophila prevents the neutrophil respiratory burst. In addition these studies will lead to a more thorough understanding of neutrophil biology specifically he factors that regulate rac2 mRNA expression and NADPH oxidase activation.

project_terms:
NAD(P)H dehydrogenase;SDS polyacrylamide gel electrophoresis;bacteria infection mechanism;bacterial proteins;bactericidal immunity;cell component structure /function;cell line;cell migration;clinical research;confocal scanning microscopy;ehrlichiosis;enzyme induction /repression;enzyme inhibitors;gel mobility shift assay;gene expression;genetic promoter element;genetic transcription;host organism interaction;human subject;leukocyte oxidative burst;messenger RNA;microorganism reproduction;neutrophil;pathologic process;protein binding;transcription factor


application_id: 7095301
project_number: 5R01EY013632-04
project_title: Cannabinoid Receptors and Novel Antiglaucoma Drugs
administering_ic: NEI
award_notice_date: 2006-07-24
application_type: 5
activity_code: R01
ic: EY
serial_number: 013632
program_official: LIBERMAN, ELLEN S
project_start_date: 2003-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-VISA(02)]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms for cannabinoids to lower intraocular pressure (IOP) and to provide a basis for developing novel cannabinoids with improved IOP-lowering properties and devoid of psychoactive side-effects of marijuana. The central hypothesis to be tested in this proposal is that cannabinoids act on specific cannabinoid receptors in multiple targets of the outflow pathways to exert their IOP-lowering effects. To test this hypothesis the following specific aims are planned. (1) To test the effects of cannabinoid ligands and the roles of cannabinoid receptors on outflow facility with perfused human ocular anterior segment using recently developed high affinity and/or subtype-selective cannabinoid ligands. (2) To map the distribution of cannabinoid receptor subtypes in two potential targets of cannabinoids trabecular meshwork and ciliary muscle. (3) To characterize ligand binding properties and signal transduction mechanisms of cannabinoid receptors in trabecular meshwork and ciliary muscle cells. (4) To determine the effects of cannabinoid ligands the roles of cannabinoid receptors and cannabinoid signaling pathways in regulating the cellular functions (such as cell cytoskeleton and matrix metalloproteases) of trabecular meshwork and ciliary muscle cells. A combination of molecular biology cell biology and pharmacology approaches will be applied to the proposed research. Attempts will be made to correlate information gained from in vitro experiments with ex vivo organ perfusion studies in order to understand the roles of cannabinoid receptors and the mechanisms for the effects of cannabinoids on aqueous humor outflow. By investigating the mechanisms underlying the IOP-lowering effects of cannabinoids this study may facilitate the discovery of more effective anti-glaucoma cannabinoid ligands. By deciphering specific ocular cannabinoid receptor subtypes that are involved in the IOP-lowering effects of cannabinoids this study may help to separate the desired IOP-lowering effects of cannabinoids from their undesired psychoactive side-effects.

project_terms:
binding sites;biological signal transduction;cannabinoid receptor;cannabinoids;cell biology;chemical binding;cytoskeleton;eye pharmacology;gene expression;glaucoma;human tissue;intraocular aqueous flow;intraocular pressure;metalloendopeptidases;molecular biology;ocular hypotensive;organ culture;perfusion;postmortem;protein localization;protein structure function;tissue /cell culture;trabecular meshwork;uvea ciliary body


application_id: 7095166
project_number: 5R01AG021981-04
project_title: RESPONSE OF THE AGING NERVOUS SYSTEM TO TRAUMA
administering_ic: NIA
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: AG
serial_number: 021981
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)Q]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Abundant clinical data indicate increased morbidity and mortality following trauma to the aging nervous system. Little is currently known about the cellular substrates underlying this amplified adverse response. The proposed studies lead to testing of the hypothesis that age-related changes associated with traumatic brain injury (TBI) can be negated by enhancing the ability of neurons to produce ATP. This idea is based on the theory that age-related changes in brain mitochondria lead to a disruption of ATP necessary to meet the energy demands of neurons following trauma. Mitochondria are the major source of ATP required for neuronal function. Age-related defects in mitochondrial oxidative phosphorylation result in deceased energy production impaired cellular calcium buffering activation of proteases and phospholipases and the generation of increased free radicals. All of these pathways can lead to enhanced cell death depending on the severity of the insult. Preliminary data from our laboratory demonstrate age-related differences following experimental TBI supporting its usefulness as an aging animal model. We also present data that a diet supplemented by creatine provides a neuroprotective intervention for TBI. Because of a lack of sufficient information on aged animal models of TBI this study will first characterize age-related changes. Specific aim #1 will characterize age-related decline in morphologic and behavioral changes following TBI employing an animal model of controlled cortical contusion. Specific aim #2 will characterize age-related changes in synaptic and non-synaptic mitochondria following TBI. Specific aim #3 will explore age-related changes in the generation of lactic acid and free fatty acids sensitive markers of secondary injury and changes in isoprostanes and neuroprostanes markers of lipid peroxidation following TBI. Specific aim #4 will use a 'creatine-supplemented' dietary intervention that enhances cytosolic phosphocreatine and increases the ability of neurons to produce ATP an intervention to reverse the age-related response to TBI.

project_terms:
adenosine triphosphate;aging;brain injury;cognition;creatine;diet therapy;dietary supplements;disease /disorder model;free fatty acids;laboratory rat;lactates;mitochondria;neurochemistry;nonhuman therapy evaluation;peroxidation;psychological aspect of aging


application_id: 7095132
project_number: 5R01CA111987-02
project_title: Sphingosine Kinase Compartmentalization in Tumorogenesis
administering_ic: NCI
award_notice_date: 2006-05-26
application_type: 5
activity_code: R01
ic: CA
serial_number: 111987
program_official: YASSIN, RIHAB R
project_start_date: 2005-07-15
project_end_date: 2010-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1923480
contact_pi: WATTENBERG, BRIAN W
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: 2006-05-26
project_terms:
3T3 cells;active sites;biological signal transduction;carcinogenesis;cell membrane;cell proliferation;cell transformation;chloride channels;confocal scanning microscopy;density gradient ultracentrifugation;enzyme activity;immunofluorescence technique;molecular oncology;neoplasm /cancer therapy;phosphorylation;protein kinase;protein localization;second messengers;sphingosine;tumor suppressor proteins;western blottings


application_id: 7095068
project_number: 5F30ES012557-04
project_title: Genetic polymorphisms in 5'-UTR of human NAT1 and NAT2
administering_ic: NIEHS
award_notice_date: 2006-06-30
opportunity_number: PA-99-089
application_type: 5
activity_code: F30
ic: ES
serial_number: 012557
program_official: HUMBLE, MICHAEL C
project_start_date: 2003-07-15
project_end_date: 2007-05-31
study_section: Special Emphasis Panel[ZRG1-F09(20)L]
contact_pi_person_id: 7550069
contact_pi: HUSAIN, ANWAR
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This project will characterize the minimal promoter region of human NAT1 and NAT2 and study effects of genetic polymorphisms on expression in human mammary cells.  Specific Aim 1 involves identifying the NAT1 and NAT2 transcriptional start site in human mammary epithelial cells by 5'-RLM-RACE.  Specific Aims 2 and 3 will identify the functional promoter of NAT1 and NAT2 by construction of luciferase reporter genes containing 5'-UTR regions of NAT1 and  AT2 and site-directed mutagenesis and deletion analysis and assessing the transcriptional effects of these regions by transient expression in MCF-7 and MCF-10A cell lines.  Specific Aim 4 involves investigating transcriptional regulation of NAT1 and NAT2 in normal human mammary tissues by determining NAT1 and NAT2 mRNA levels protein expression intrinsic protein stability and catalytic activity for N- and O-acetylation activities as a function of 5'-UTR and coding region genotypes.  Specific Aim 5 involves sequencing the 5'-UTR of NAT1 and NAT2 in human mammary tissues to identify and characterize effects of polymorphisms in the 5'-UTR of NAT1 and NAT2.  Knowledge of transcriptional regulation in the 5'-UTR of NAT1 and NAT2 will allow for an increased understanding the role of genetic polymorphisms towards genetic predisposition to breast cancer from environmental carcinogens.

project_terms:
MCF7 cell;acetylation;acyltransferase;breast neoplasms;clinical research;environment related neoplasm /cancer;enzyme activity;gene environment interaction;genetic polymorphism;genetic regulation;genetic susceptibility;genetic transcription;human tissue;luciferin monooxygenase;mammary epithelium;neoplasm /cancer epidemiology;neoplasm /cancer genetics;predoctoral investigator;site directed mutagenesis;transfection;women&apos;s health


application_id: 7094778
project_number: 1R01AG025159-01A2
project_title: Imaging Brain Function/Structure in Presymptomatic FTD
administering_ic: NIA
award_notice_date: 2006-09-06
application_type: 1
activity_code: R01
ic: AG
serial_number: 025159
suffix: A2
program_official: BUCKHOLTZ, NEIL
project_start_date: 2006-09-15
project_end_date: 2009-06-30
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
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): Frontotemporal dementia (FTD) represents only 10-20% of all dementias but remains important clinically because of its earlier age of onset compared to Alzheimer's disease (AD) and its characteristic attack on core human qualities e.g..compassion insight and verbal communication. Treatment of FTD as in AD is more likely to succeed when applied in the early stages of the underlying pathology than in later stages when symptoms appear and worsen. Detection of brain pathology is needed prior to these symptoms in order to develop and evaluate such treatments. We propose to use functional and structural magnetic resonance imaging (MRI) to detect brain network functional alterations and subtle changes in cortical density in the frontal and anterior temporal lobes in persons without dementia symptoms but who are destined to develop FTD. The high likelihood of developing FTD is well-defined in identified subjects with mutations in the valosin-containing protein (VCP) gene on chromosome 9 associated with FTD Paget's disease of bone and inclusion-body myopathy. These persons will be tested to insure the absence of symptoms and typical cognitive impairments in FTD. Mutation carriers will be compared to non-carrier members of the same families. The first specific aim is to perform functional MRI studies to measure frontal and parietal activation during standard working memory and letter fluency tasks typically performed poorly in persons with early symptoms of FTD. We will also perform a control confrontation naming task shown in preliminary studies to activate regions of the posterior temporal and occipital regions equally in VCP mutation carriers and in non-carriers. These data will be analyzed using advanced analytical and statisitical techniques discriminant analysis and hierarchical clustering to identify carriers most likely to develop future dementia. The second specific aim is to compare regional cortical density measured from three-dimensional structural images between VCP mutation carriers and non-carriers. We will combine the functional and structural measures with cognitive test results to refine our predictive model for dementia. These fundamental studies are expected to demonstrate brain network functional alterations and regionally decreased cortical density in rigorously-defined presymptomatic FTD.

project_terms:
aging;behavioral /social science research tag;bioimaging /biomedical imaging;brain disorder diagnosis;brain imaging /visualization /scanning;brain mapping;clinical research;cognition;dementia;disease /disorder onset;early diagnosis;executive function;family genetics;functional magnetic resonance imaging;gene mutation;genetic carriers;human subject;language;magnetic resonance imaging;mathematical model;neurogenetics;neuropsychological tests;short term memory


application_id: 7094567
project_number: 1R01DC007194-01A2
project_title: Genomics of Olfactory Regeneration
administering_ic: NIDCD
award_notice_date: 2006-02-04
application_type: 1
activity_code: R01
ic: DC
serial_number: 007194
suffix: A2
program_official: DAVIS, BARRY
project_start_date: 2006-03-01
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZRG1 IFCN-K (03)]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The sensory neurons of the mammalian olfactory epithelium can be regenerated even if they are completely eliminated. This capacity which lasts throughout the life of the animal is of significant interest for both basic and applied neuroscience research. Its mechanisms are presumed to be relevant to the search for regeneration-promoting therapies for neurodegenerative disorders and trauma of the nervous system. To extend our understanding of olfactory regeneration we have identified 1260 transcripts whose abundance within the olfactory epithelium changes after removal of the olfactory bulbs a manipulation that causes the selective death and subsequent regeneration of the olfactory sensory neurons. Of these transcripts 303 increase contemporaneously with the proliferation of sensory neuron progenitors. The functions of the proteins encoded by these 303 transcripts predict several underlying processes including transcriptional activation of cell proliferation and differentiation up-regulation of the cell cycle axon outgrowth and cell signaling. Only a handful of these proteins have previously been linked to olfactory regeneration. In this application we propose to focus on a subset of gene products that are likely to be critical for proliferation and differentiation of the olfactory sensory neurons. The first specific aim is to define the capacity for each transcript to be involved in olfactory regeneration by determining which cell types express them including spatial and temporal overlap with markers of known progenitor cell types. The second and third aims focus further on a small subset of genes for which targeted deletions are available. These aims test whether the absence of the gene alters the development or regeneration of the olfactory epithelium leading to changes at the behavioral cellular or molecular level. The proposed experiments will definitively test whether several proteins are dispensable for olfactory regeneration and will define the potential roles of a couple dozen additional proteins.

project_terms:
afferent nerve;biomarker;cell differentiation;cell proliferation;developmental neurobiology;gene deletion mutation;gene expression;genetic transcription;genetically modified animals;laboratory mouse;messenger RNA;microarray technology;nervous system regeneration;neurogenesis;neurogenetics;olfactory lobe;polymerase chain reaction;protein localization;protein structure function;receptor expression;respiratory epithelium;transcription factor


application_id: 7094376
project_number: 1R21AG024902-01A2
project_title: Intimate Partner Violence and Inflammatory Processes
administering_ic: NIA
award_notice_date: 2006-09-05
opportunity_number: PA-03-107
application_type: 1
activity_code: R21
ic: AG
serial_number: 024902
suffix: A2
program_official: NIELSEN, LISBETH
project_start_date: 2006-09-15
project_end_date: 2008-08-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1859875
contact_pi: NEWTON, TAMARA L.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant): This study will test associations between prior exposure to adult intimate partner violence (IPV) and inflammatory markers and processes that have been implicated in a variety of conditions associated with aging (e.g. cardiovascular diseases cognitive decline). It is proposed that IPV can have long-standing consequences for inflammatory processes particularly via the pathway of intrusive re-experiencing (e.g. recurrent unwanted memories of prior stressful events and physiological reactions to events reminders). Aim 1 is to establish the relationship between prior exposure to adult IPV and inflammatory markers and processes. Aim 2 is to examine how severity of IPV and severity of intrusive re-experiencing interactively contribute to inflammatory markers and processes. These aims will be examined in a cross-sectional study of two groups of healthy women who are newly postmenopausal; (1) women who are divorced/separated from violent marriages or heterosexual cohabiting relationships (n = 67) and (2) a comparison group of women divorced/separated from non-violent marriages/heterosexual cohabiting relationships (n = 33). The latter group will serve as a control for the stress of divorce/separation. Women will have blood drawn for assessment of basal concentrations of the acute-phase protein high-sensitivity C-reactive protein and the proinflammatory cytokine interleukin-6. lnterleukin-6 production by peripheral blood mononuclear cells in response to in vitro immunological challenge will also be assessed. All women will be interviewed to assess history of victimization including IPV and posttraumatic stress symptoms including intrusive re-experiencing. Recent research reveals that older adults' health status is associated with potentially traumatic events experienced decades earlier in adulthood. IPV is endorsed by 25% of adult women in the United States is a risk factor for posttraumatic stress disorder and has been associated with prevalence of chronic diseases in several cross-sectional studies. If the proposed hypotheses are supported they will suggest a plausible basis for linkages among IPV posttraumatic stress symptoms and inflammatory conditions associated with aging. One long-term implication would be that evidence-based behavioral interventions that effectively treat posttraumatic stress disorder may also reduce this disorder's contribution to women's risk for developing conditions associated with aging.

project_terms:
C reactive protein;aggression;behavioral /social science research tag;biomarker;chronic disease /disorder;clinical research;disease /disorder proneness /risk;divorce /separation;domestic violence;dyadic interaction;female;human subject;inflammation;interleukin 6;interview;postmenopause;posttraumatic stress disorder;psychological aspect of aging;psychological stressor;psychoneuroimmunology;psychosocial separation;sex partner;spouse abuse;women&apos;s health


