# projects

application_id: 7371008
project_number: 5P01AG013494-10
project_title: MOTORIC DECLINES IN AGING: MRI STUDIES OF NIGROSTRIATAL DOPAMINERGIC SYSTEM
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 013494
project_start_date: 2007-03-15
project_end_date: 2008-01-31
study_section: ZAG1
subproject_number: 0003
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
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: 2007-03-15
budget_end_date: 2008-01-31
project_abstract:
The central hypothesis of this grant is that age-related declines in motor function result from functional changes in the nigrostriatal dopaminergic system in animals and humans. To address this issue our group has developed techniques to measure pharmacologically-evoked blood oxygen level-dependent (BOLD) changes in the basal ganglia of MRI-adapted awake rhesus monkeys using functional magnetic resonance imaging (fMRI). In the studies proposed for this project we will utilize fMRI to measure age-related changes in the BOLD response to various DA agonists. Specifically we plan to compare the effects of apomorphine with the DA receptor-specific agonists SKF-81297 (D1 agonist) and LY17155 (quinpirole a D2 agonist). We will then determine the relationship between pharmacologically evoked BOLD responses and underlying neural activity in specific regions of interest (ROD by using multiple single-unit electrophysiological recording. We will also utilize anatomical MRI to determine age-related changes in the volume of key basal ganglia structures. We will also measure iron accumulation in the globus pallidus and the substantia nigra. These anatomical measures will be conducted to test our hypothesis that age-related functional changes in these nuclei contribute more tobehavioral deficits than do structural changes. We will assess the effects of GDNF on these functional and morphological measures in order to determine whether the potent DA neurotrophic factor possesses restorative properties in the basal ganglia. These studies will complement the behavioral neurochemical and histopathological/biochemieal studies of Projects by Gash and Berhardt.

project_terms:
Address;Age;Age-Years;Aging;Agonist;Animals;Apomorphine;Basal Ganglia;Behavioral;Cell Line;Cell Nucleus;Complement;Condition;Disease regression;Dopamine D1 Receptor;Dopamine D2 Receptor;Electrodes;Electrophysiology (science);Globus Pallidus;Grant;Human;Imaging Techniques;Iron;Laboratories;Macaca mulatta;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Maps;Measures;Monkeys;Motor;Neuroglia;Pharmaceutical Preparations;Property;Purpose;Quinpirole;Rods (Retina);Science of neurochemistry;Signal Transduction;Standards of Weights and Measures;Structure;Substantia nigra structure;System;Techniques;Testing;Tissues;Transcriptional Activation;Up-Regulation (Physiology);Work;age effect;age related;aged;awake;behavior measurement;blood oxygen level dependent;extracellular;glial cell-line derived neurotrophic factor;improved;interest;middle age;motor deficit;neurotrophic factor;receptor;relating to nervous system;research study;response


application_id: 7371007
project_number: 5P01AG013494-10
project_title: NEUROCHEMICAL STUDIES OF THE AGING BASAL GANGLIA
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 013494
project_start_date: 2007-03-15
project_end_date: 2008-01-31
study_section: ZAG1
subproject_number: 0002
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG 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: 2007-03-15
budget_end_date: 2008-01-31
project_abstract:
It is our central hypothesis that changes in the functional properties of dopamine (DA) neuronsin the basal ganglia of the CNS contribute to age-related declines in motoric function in aged animals and humans. Prior studies from our laboratory and others support the hypothesis that age-related declines in motoric function are not associated with a robust decline in DA neurons. Rather functional properties of DA regulation and release are affected in DA-containing areas. A striking finding from our recent studies is that somatodendritic release of DA evoked by d-amphetamine and measured with in vivo microdialysis is greatly decreased in the substantia nigra of aged monkeys.  Using MRI guided stereotaxic surgery this  Project will use recently developed methods that allow for repeated in vivo microdialysis measures in anesthetized monkeys. This method has been combined  with postmortem Western blot immunoassays and HPLC-EC methods for studies of the putamen caudate nucleus GPe and SN of young adult (5-9 year old) adult (13-16 year old) and late middleage/aged (20-25 year old) rhesus monkeys. This project will perform functional studies of neurochemical changes to the monkey basal ganglia during aging in conjunction with the behavioral histological and immunohistochemical studies of Project by Gash and anatomical and functional MRIimaging studies in Project by Zhang. In addition recent results from our laboratory support that glial cell linederived neurotrophic factor (GDNF) may be capable of restoring function to aged DA neurons. Our second series of neurochemical studies will be performed in late middle-aged/aged monkeys that have received chronic intranigral infusions of vehicle or GDNF in an attempt to restore or enhancethe function of aged DA neurons. These studies address the role of DA in decreased motor behavior in aging and the neurochemical properties of aged dopaminergic neurons in nonhuman primates.

project_terms:
16 year old;9 year old;Address;Affect;Age;Aging;Animals;Area;Autopsy;Basal Ganglia;Behavior;Behavioral;Blotting Western;Caudate nucleus structure;Chronic;Dextroamphetamine;Dopamine;Elderly;Human;Immunoassay;Infusion procedures;Laboratories;Macaca mulatta;Magnetic Resonance Imaging;Measures;Methods;Microdialysis;Monkeys;Motor;Neuroglia;Operative Surgical Procedures;Property;Regulation;Role;Science of neurochemistry;Series;Strikes Employee;Structure of putamen;Substantia nigra structure;age related;aged;dopaminergic neuron;functional restoration;in vivo;middle age;neurotrophic factor;nonhuman primate;young adult


application_id: 7371006
project_number: 5P01AG013494-10
project_title: MOTORIC DECLINES IN AGING: BEHAVIOR AND QUANTITATIVE MORPHOLOGY
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 013494
project_start_date: 2007-03-15
project_end_date: 2008-01-31
study_section: ZAG1
subproject_number: 0001
contact_pi_person_id: 8535427
contact_pi: GASH, DON MARSHALL
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: 2007-03-15
budget_end_date: 2008-01-31
project_abstract:
Behavioral slowing is one of the cardinal features of human aging contributing to the debilitating deterioration of motor functions in senescence. Our principal hypothesis is that functional changes in central dopaminergic pathways contribute significantly to age-associated declines in motor functions. Our experimental plan for the next five years is designed to further our understanding of CNS processes underlying behavioral slowing and analyze therapeutic approaches for intervention. Specifically our studies focus on the dopamine (DA) neuronsin the substantia nigra (SN) and their projections to the caudate nucleus putamen and globus pallidus of the basal ganglia. The proposed studies will analyze key junctions in the neural circuitry regulating motor functions in the basal ganglia using behaviorally characterized female rhesus monkeys ranging in age from young adulthood to old age (5-25years+) as a model of human aging.The studies and methodology in this Project  are designed to quantify age-associated declines in motoric and  cognitive functions in rhesus monkeys from 5 -25+ years old. The ability of specific DA receptor agonists and GDNF to improve motor and cognitive performance levels of aged animals will be tested. The behavioral results are crucial for analyzing the functional neurochemical studies in Project by Gerhardt and the fMRI and anatomical MRI studies in Project by Zhang. In addition this Project will analyze mRNA expression levels of four importantmarkers of DA neurons TH DAT GFRalpha-1 and Ret. GFRalpha-1 and Ret form a receptor complex for GRNF that is found at high levels in the SN. Expression levels of GDNF mRNA in DA neuron target sites the caudate nucleus and putamen will also be evaluated. These data will be collated with parallel Western blot analyses of protein levels of the same markers in the Project by Gerhardt  to better understand molecular changes underlying functional changes in central DA neurons.

project_terms:
Age;Age Group Unspecified;Aging;Animals;Basal Ganglia;Behavior;Behavioral;Blotting Western;CNS processing;Caudate nucleus structure;Cell Nucleus;Cognitive;Complex;Data;Deterioration;Dopamine;Dopamine Agonists;Dopamine Receptor;Female;Globus Pallidus;Human;Intervention;Laboratories;Macaca mulatta;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Methodology;Modeling;Molecular;Morphology;Motor;Pathway interactions;Performance;Process;Proteins;RNA Messenger;Range;Science of neurochemistry;Site;Structure of putamen;Substantia nigra structure;System;Testing;Therapeutic;Tyrosine 3-Monooxygenase;aged;cognitive function;design;dopamine transporter;dopaminergic neuron;glial cell-line derived neurotrophic factor;improved;mRNA Expression;neural circuit;normal aging;programs;receptor;relating to nervous system;repaired;senescence


application_id: 7367324
project_number: 1R01CA125166-01A1
project_title: Transcriptional Repression of Sodium-Iodide Symporter in Thyroid Carcinoma
administering_ic: NCI
award_notice_date: 2008-06-16
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 125166
suffix: A1
program_official: OKANO, PAUL
project_start_date: 2008-07-01
project_end_date: 2012-06-30
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 7875253
contact_pi: AIN, KENNETH BRUCE
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
project_terms:
ADP Ribose Transferases;Accounting;Age-Years;Anisomycin;Aortic Aneurysm;Azacitidine;Binding (Molecular Function);Binding Proteins;Binding Sites;Biological Assay;Blotting Western;Bos taurus;Butyrates;C-terminal;CREB1 gene;Calcium;Calmodulin;Cancer Patient;Cancer cell line;Catalytic Domain;Cattle;Cell Line;Cells;Chromatin;Chromatin Structure;Chromatography Affinity;Chromatography Gel;Chromosomes;Clinical;Clinical Trials;Clinical Trials Other;Co-Immunoprecipitations;Complex;Condition;Consensus;Coupled;CpG Islands;Cross-Linking Reagents;Cycloheximide;DNA Binding;DNA Binding Domain;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Repair;DNA Topoisomerases Type I;DNA ligase III;DNA Complementary;Data;Deoxyribonuclease I;Depsipeptides;Development;Digestion;Disease;Distal;Distant;Distantly Metastatic;Dominant-Negative Mutation;Dose;Drug usage;Effectiveness;Egtazic Acid;Electrophoretic Mobility Shift Assay;Elements;Emetine;Enhancers;Epigenetic Process;Fractionation;Functional disorder;Gel;Gene Expression;Gene Expression Regulation;Genes;Genomics;Globulins;Goals;Grant;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;Hypermethylation;I131 isotope;Immunoglobulin G;Immunohistochemistry;In Vitro;Incubated;Iodides;Iodine;Isotopically-Coded Affinity Tagging;Label;Life;Ligands;Light;Liquid Chromatography;Luciferases;Lung;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of thyroid;Maps;Measures;Membrane;Methodology;Methods;Mice Nude;Molecular Conformation;Molecular Weight;Mus;Neoplasm Metastasis;Nuclear;Nuclear Extract;Numbers;Oligonucleotides;Operative Surgical Procedures;Orphan Drugs;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Physiological;Physiology;Plasmids;Poly(ADP-ribose) Polymerases;Polymerase Chain Reaction;Precipitation;Probability;Production;Promoter Regions (Genetics);Promotor (Genetics);Protein Binding;Protein Structure Initiative;Protein Synthesis Inhibitors;Proteins;Publishing;Pulmonary Surfactant-Associated Protein B;Pulmonary Surfactant-Associated Proteins;RNA Messenger;RNA Small Interfering;Radiation;Radioactive;Radioactive Iodine;Radiolabeled;Range;Rate;Rattus;Reagent;Recombinants;Regulatory Element;Relative (related person);Reporter;Reporting;Repression;Repressor Proteins;Research;Run-On Assays;Running;SLC5A5 protein human;Score;Site;Sodium Butyrate;Streptavidin;Systemic Therapy;TEV protease;TNFSF11 gene;Techniques;Testing;Thinking function;Thyroglobulin;Thyroid Gland;Thyroid carcinoma;Thyrotropin;Time;Tissues;Transcription Initiation Site;Transcription factor genes;Transcription Genetic;Transfection;Translations;Treatment Failure;Tretinoin;Trichostatin A;Trypsin;United States;United States Food and Drug Administration;Upstream Enhancer;Validation;Valproic Acid;Vorinostat;Weight;Woman;activating transcription factor;base;butyrate;cancer cell;cell type;chelation;expectation;functional restoration;gene repression;human tissue;in vivo;inhibitor/antagonist;mRNA Expression;men;mutant;novel;pre-clinical;public health medicine (field);radiotracer;receptor;repaired;research study;response;restoration;sodium-iodide symporter;tandem mass spectrometry;therapeutic target;thyroid transcription factor 1;transcription factor;tumor;tumor xenograft;uptake


application_id: 7367195
project_number: 5R01HL078976-03
project_title: Saturated Fatty Acid and Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2008-03-07
application_type: 5
activity_code: R01
ic: HL
serial_number: 078976
program_official: ERSHOW, ABBY
project_start_date: 2006-03-15
project_end_date: 2011-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
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
budget_start_date: 2008-03-01
project_abstract:
The central hypothesis to betested in this proposal is that binding of saturated fatty acid to SR-BIactivates AMP kinase which results in the production of eNOS-dependent peroxynitrite andsubsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heartdisease for decades however numerous studies have demonstrated that the type of fat may be moreimportant than the total amount of fat in the diet. Unsaturated fats such as n-3 and n-6 fatty acids arethought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e. myristic acid andpalmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenicin part by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearlyinfluence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorialdisease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause anincrease in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal isto determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasmacholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acidsthat involve SR-BI caveolin AMP kinase and eNOS which subsequently results in the generation of the pro-atherogenic compound peroxynitrite. Three specific aims are proposed.Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolinand to determine the domain within caveolin that interacts with SR-BI.Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains withincaveolin and AMP kinase that interact.Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fattyacid-induced peroxynitrite production andsubsequently atherosclerosis.

project_terms:
5'-AMP-activated protein kinase;Acids;Antiatherogenic;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological Assay;Bos taurus;Breeding;Carbon;Cardiovascular Diseases;Cattle;Caveolins;Cell membrane;Cells;Cholesterol;Coronary;Coronary heart disease;Data;Development;Diet;Dietary Fats;Disease;Endothelial Cells;Fats Unsaturated;Fatty Acids;Fatty acid glycerol esters;Fibrinogen;Generations;Goals;Intake;Ligands;Low Density Lipoprotein Receptor;Methods;Mice Knockout;Modeling;Mus;Mutate;Myristic Acids;Nitric Oxide;Palmitic Acids;Peroxonitrite;Phosphorylation;Plasma;Production;Reactive Oxygen Species;Recruitment Activity;Research Personnel;Risk;Saturated Fatty Acids;Signal Transduction;Standards of Weights and Measures;System;Thinking function;adenylate kinase;base;caveolin 1;feeding;novel;programs;receptor


application_id: 7367068
project_number: 5R01DC007194-03
project_title: Genomic of Olfactory Regeneration
administering_ic: NIDCD
award_notice_date: 2008-02-15
application_type: 5
activity_code: R01
ic: DC
serial_number: 007194
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)M]
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
budget_start_date: 2008-03-01
project_terms:
ASCL1 protein human;Abbreviations;Adult;Affect;Analysis of Variance;Animals;Axon;Basal Cell;CDKN1A gene;Cell Cycle;Cell Proliferation;Cells;Cessation of life;Data Set;Development;Differentiation and Growth;Embryo;Epithelium;Epithelium Olfactory;Erinaceidae;Excision;Fibroblast Growth Factor;Fluorescent in Situ Hybridization;Galactosidase;Genes;Genes LacZ;Genomics;Green Fluorescent Proteins;Growth Associated Protein 43;Helix-Turn-Helix Motifs;Life;Link;Measures;Methods;Mice Knockout;Molecular;Mouse Strains;Mus;Natural regeneration;Neuro-Oncological Ventral Antigen 2;Neurodegenerative Disorders;Neurons;Neurons Afferent;Neurosciences Research;Numbers;Pattern;Play;Polymerase Chain Reaction;Process;Proteins;RNA Messenger;Receptors Odorant;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Reverse Transcription;Role;Series;Signal Transduction;Signaling Protein;Stem cells;Structure of olfactory bulb;Testing;Time;Transcript;Transcription factor genes;Transcriptional Activation;Trauma Nervous System;Up-Regulation (Physiology);Week;Work;cell type;day;interest;mutant;neurodevelopment;neurogenesis;null mutation;olfactory marker protein;oncoprotein p21;postnatal;progenitor;programs;protein function;receptor;receptor expression;research study;response;sustentacular cell;transcription factor


application_id: 7365189
project_number: 5R01DC007176-04
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2008-02-14
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2010-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
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: 2008-03-01
project_terms:
Axon;Biological Assay;Birth;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Cell Count;Cell Cycle;Cell Death;Cell Nucleus;Cessation of life;Development;Development Computer Systems;Developmental Process;Disruption;Embryo;Embryonic Development;End Point;Epithelium;Fiber;Fungiform Papilla;Future;Ganglia;Ganglia Sensory;Genotype;Goals;Growth;Hybrids;Immunohistochemistry;In Situ Hybridization;Injury;Knowledge;Label;Location;Maintenance;Mediating;Mice Knockout;Microscopy Electron Scanning;Molecular;Mus;Myxoid cyst;Nerve Fibers;Nerve Regeneration;Neurites;Neuronal Differentiation;Neurons;Neurons Afferent;Numbers;Oral cavity;Palate;Papilla of tongue;Pathway interactions;Pattern;Peripheral;Principal Investigator;Process;Rate;Regulation;Research;Robin bird;Role;Sensory;Signal Pathway;Signaling Molecule;Staging;Structure of geniculate ganglion;System;Taste Buds;Taste Perception;TdT-Mediated dUTP Nick End Labeling Assay;Testing;Therapeutic Uses;Time;Tongue;Withdrawal;axon regeneration;design;ganglion cell;knockout gene;nerve supply;neural circuit;neuron loss;neurotrophic factor;neurotrophin 4;postnatal;programs;receptor;research study;response;synaptogenesis


application_id: 7364949
project_number: 1R01ES015518-01A1
project_title: Reactive oxygen species in Ni(II) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2008-02-28
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: ES
serial_number: 015518
suffix: A1
program_official: QUINN, ASHLINN KO
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Animals;Antioxidants;Biological Assay;Breathing;Carcinogenicity Tests;Carcinogens;Cells;Chemicals;Complement Factor B;Development;Dominant-Negative Mutation;Down-Regulation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Embryo;Enzymes;Epithelial Cells;Experiments Animal;Exposure to;Fibroblasts;Gene Expression Regulation;Generations;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;I Kappa B-Alpha;In Vitro;Intervention;Investigation;Link;Luciferases;Malignant Neoplasms;Manganese Superoxide Dismutase;Measures;Mediating;Mediator of activation protein;Methods;Mice Inbred BALB C;Mice Nude;Mice Transgenic;Microscopy Confocal;Mitochondria;Molecular;Mus;NADPH Oxidase;NF-AT;Nature;Nickel;Nuclear;Plasmids;Play;Prevention strategy;Protein Overexpression;Reaction;Reactive Oxygen Species;Reporter;Research;Risk Assessment;Role;Signal Transduction;Signaling Protein;Source;Spin Trapping;Structure of parenchyma of lung;Superoxides;Techniques;Testing;Transfection;Tumor Promotion;activating transcription factor;cancer risk;carcinogenesis;catalase;cell transformation;in vivo;nuclear factors of activated T-cells;response;transcription factor;tumorigenesis


application_id: 7364926
project_number: 3R01GM066152-04S1
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2007-04-20
application_type: 3
activity_code: R01
ic: GM
serial_number: 066152
suffix: S1
program_official: FABIAN, MILES
project_start_date: 2002-05-01
project_end_date: 2008-04-30
study_section: Bio-Organic and Natural Products Chemistry Study Section[BNP]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
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:
Synthetic Probes of Protein Prenylation: Covalent modification by isoprenoid lipids (prenylation) is a criticalpost-translational event for many proteins involved in cellular signaling. The discovery that the members of theRas family of protooncogenes are modified by the farnesyl isoprenoid (farnesylation) and that prenylation isrequired for the oncogenic forms of these proteins to express their transforming potential has led to intenseinvestigation of protein-farnesyltransferase (FTase) inhibitors (FTIs) as promising cancer chemotherapeuticagents. However recent developments have made it clear that the mechanism of FTI action is unexpectedly complex although it involves inhibition of FTase. In addition the contribution of isoprenoid lipids to the overallbiology of Ras is incompletely understood. Therefore a key to applying FTase-based pharmacologicalintervention is a thorough understanding of the in vivo farnesylation pathways. Knowledge of the substrate specifities for FTase and the cellular function of the prenyl moiety are critical to improving the design of futureFTIs. The central hypothesis of this study is that the prenyl group plays an active role in directing both post- translational processing and cellular membrane localization of prenylated proteins. An important corollary to this hypothesis is that modifications to the prenyl structure may lead to significant biologically relevant effects on the activity of the unnaturally prenylated protein. We have synthesized FPP analogs that are transferred to oncogenicRas but fail to support transformation. These molecules are leads for a unique class of potential anti-cancertherapeutics we term RFIs (Ras function inhibitors). The specific aims of this project are: 1) specificallysubstituted unnatural analogs of farnesyl pyrophosphate and the homologous isoprenoid geranylgeranyl pyrophosphate will be synthesized in a combinatorial scheme; 2) these compounds will be screened as substrates or inhibitors of FTase and the closely related enzyme geranylgeranyltransferase I; 3) building upon promisingpreliminary results in this area an in vivo isoprenoid structure-function relationship will be established by replacing the H-Ras farnesyl group with a select subset of the analogs available from the studies described in specific aim 1and 2 and analyzing their biological functions following microinjection intoXenopus oocytes. Theresults of these experiments will provide further insight into the mechanisms of Ras processing and transformation a greater understanding of the specific functions of the H-Ras farnesyl group in vivo and fruitful directions for improvements in FTIs as well as novel transferable analogs which might act as RFIs.

project_terms:
Address;Area;Biochemical;Biological;Biological Assay;Biological Models;Biological Process;Biology;Cell Line Transformed;Cell physiology;Cellular Membrane;Class;Combinatorial Synthesis;Complex;Data;Development;Diphosphates;Enzymes;Event;Family;Farnesyl Transferase Inhibitor;Future;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;HRAS gene;Individual;Intervention;Investigation;Knowledge;Lead;Libraries;Lipids;Malignant Neoplasms;Metabolism;Microinjections;Modification;Molecular;Oncogenic;Oocytes;Pathway interactions;Play;Process;Protein Isoprenylation;Proteins;Proto-Oncogenes;Ras Inhibitor;Role;Scheme;Signal Transduction;Solid;Structure;Structure-Activity Relationship;Testing;Transferase;Xenopus laevis;analog;anti-cancer therapeutic;base;cancer therapy;chemotherapeutic agent;combinatorial;design;farnesyl pyrophosphate;farnesylation;geranylgeranyl pyrophosphate;high throughput screening;improved;in vivo;inhibitor/antagonist;insight;interest;isoprenoid;isoprenylation;member;novel;prenyl;prenylation;prevent;protein farnesyltransferase;protein geranylgeranyltransferase;ras Proteins;research study


application_id: 7364727
project_number: 1R15GM079775-01A1
project_title: Microbial metabolic mutualism in starved environments.
administering_ic: NIGMS
award_notice_date: 2008-01-28
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 079775
suffix: A1
program_official: ANDERSON, JAMES J
project_start_date: 2008-02-01
project_end_date: 2011-01-31
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 7614787
contact_pi: BARTON, HAZEL A
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal aims to accomplish the AREA program objectives of 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment at non-research intensive universities. The goal of this project is to understand the metabolic activity that supports microbial growth under extreme starvation. In understanding the interactions and processes that sustain microbial communities in starved environments we hope to better understand one of the outstanding questions of microbial ecology: why are the majority of organisms identified in the environment unculturable in the laboratory? This unculturability is presumed to be due to the inability to reproduce the fastidious growth requirements of many of these species making them viable within the environment but unculturable under laboratory conditions. Through this proposal we aim to test our hypothesis that microbial communities subsist in extremely oligotrophic environments by establishing mutualistic interactions allowing species to more efficiently utilize the complex nutrient sources entering the system. While such interactions may promote diversity under extreme starvation obligate mutualism prevents cultivation of these species using traditional techniques. The experiments proposed are geared toward understanding the role that the amount and type of available energy entering these systems have on community diversity and mutualism. The specific aims are: 1) to determine whether microbial mutualistic interactions are occurring under extreme starvation conditions and what role they play in supporting community growth; 2) to determine whether such mutualism increases the usable energy sources and metabolic efficiency under extreme starvation driving community diversity; and 3) to increase the number of previously unculturable bacterial species from these extremely oligotrophic environments by separating previously interdependent species. By using a combination of techniques to monitor how nutrient flow affects community diversity we endeavor to understand some of the more complex metabolic interactions capable of supporting life under starvation while increasing the diversity and number of culturable microbial species. The majority of microbial life on our planet remains unculturable and unknown. Nonetheless in recent years there has been an upsurge in the number of beneficial products from pharmaceuticals to common household detergents isolated from these organisms. This proposal aims to understand the mechanisms that support the growth of such microorganisms and increase the number of species that can be successfully isolated.

project_terms:
Accounting;Affect;Automobile Driving;Carbon;Communities;Complex;Condition;Detergents;Ecology;Energy-Generating Resources;Environment;Exclusion;Goals;Growth;Household;Investigation;Kentucky;Laboratories;Learning;Life;Literature;Metabolic;Methodology Research;Monitor;Nature;Numbers;Nutrient;Organism;Pharmacologic Substance;Planets;Play;Process;Research;Research Activity;Role;Role playing therapy;Source;Starvation;Students;System;Techniques;Testing;Time;Universities;Work;career;community living;design;microbial;microbial community;microorganism;mutualism;prevent;programs;research study


application_id: 7364629
project_number: 5K25DK072085-02
project_title: Intelligent Control Approach to Anemia Management
administering_ic: NIDDK
award_notice_date: 2008-03-27
opportunity_number: PA-06-087
application_type: 5
activity_code: K25
ic: DK
serial_number: 072085
program_official: RANKIN, TRACY L
project_start_date: 2007-04-01
project_end_date: 2012-01-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
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:
Adverse event;Algorithms;Anemia;Anti-Arrhythmia Agents;Artificial Intelligence;Arts;Biological Models;Biological Neural Networks;Biomedical Engineering;Blood;Blood Vessels;Caring;Chronic;Clinical;Clinical Research;Collection;Complex;Computer Assisted;Computer Simulation;Computer software;Computing Methodologies;Controlled Clinical Trials;Data;Decision Support Systems;Development;Dialysis procedure;Disease;Doctor of Philosophy;Dose;Effectiveness;Electrical Engineering;End stage renal failure;Engineering;Enrollment;Epidemiology;Erythropoietin;Evaluation;Feedback;Frequencies (time pattern);Funding;Goals;Guidelines;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Human;Individual;Information Sciences;Insulin;Iron;Learning Machine;Measures;Medicine;Methodology;Methods;Monitoring Patient;Morbidity - disease rate;Nephrology;Outcome;Patients;Pharmaceutical Preparations;Physical Dialysis;Physiological;Population;Prescriptions Drug;Process;Protocols documentation;Range;Research;Research Personnel;Safety;Sampling;Savings;Schools Public Health;Science of Statistics;Standards of Weights and Measures;Techniques;Technology;Testing;Training;Training Programs;Translations;Universities;Veterans;Waran;Work;base;computer science;cost effectiveness;data management;desire;experience;improved;insight;instructor;mathematical algorithm;novel;prescription document;prescription procedure;programs;recombinant human erythropoietin;research clinical testing;response;simulation;theories;tool


application_id: 7364599
project_number: 5K23DE015760-04
project_title: Chlorhexidine and Pneumonia in Nursing Home Residents
administering_ic: NIDCR
award_notice_date: 2008-02-27
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015760
program_official: HARDWICK, KEVIN S
project_start_date: 2005-03-01
project_end_date: 2010-02-28
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE 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:
The immediate goal of this four-year research career award is to further the candidate's development as a patient-oriented researcher with a focus on oral health and systemic disease. The career development plan will build on her clinical experience as a General Practice Residency Program director and on her research training in Epidemiology. The long-term goal of the career development plan is to enable the candidate to become an independent investigator in oral and systemic health research and to serve as a mentor for junior patient-oriented researchers. The specific training targets are as follows: 1) Attainment of a solid knowledge base in the design and conduct of clinical trials; 2) coursework and consultation in clinical trial and data analytic methods; 3) understanding of procedural philosophical and ethical issues arising in the design and conduct of clinical trials; 4) development based on results and questions raised by the proposed study of a multi-site clinical effectiveness trial to improve the oral and systemic health of dependent nursing home patients and 6) dissemination of research findings to investigators in dentistry and other biomedical fields. Under the mentorship of Dr. Dan Sessler a senior investigator in clinical trials and Director of the Outcomes Research Institute Dr. Denis Kinane a senior research scientist and Director of the Center for Oral Health and Systemic Disease and Dr. Christine Ritchie a Geriatric Medicine physician at the Center for Oral Health and Systemic Disease the candidate will pursue a focused clinical research project and will receive formal and practical instruction in all aspects of clinical investigation. The proposed clinical research is needed to add to the knowledge concerning the role of oral health and systemic disease in a population with health disparities. The candidate's firsthand research training will involve the implementation of a pilot randomized placebo controlled clinical trial of the effects of chlorhexidine oral spray in reducing pneumonia in dependent nursing home patients. The results of the proposed research will serve as the basis for the design and submission of an investigator-initiated research proposal before the end of the award.

project_terms:
Accounting;Address;Affect;Analysis of Variance;Aspirate substance;Award;Bacteria;Chlorhexidine;Clinical;Clinical Research;Clinical Trials;Communities;Condition;Conduct Clinical Trials;Consultations;Control Groups;Controlled Clinical Trials;Daily;Data;Databases;Dentistry;Dentures;Development;Diagnosis;Dorsum of tongue;Drug resistance;Economics;Effectiveness;Elderly;Epidemiology;Event;Faculty;Future;Geriatrics;Gingival Indexes;Goals;Health;Health Care Costs;Incidence;Individual;Infection;Instruction;Intensive Care Units;Intervention;Investigator-Initiated Research;Issues Ethical;Knowledge;Lead;Length of Stay;Life;Longevity;Lung;Manuals;Measures;Medical Records;Medical Surveillance;Mentors;Mentorship;Methods;Morbidity - disease rate;Mortality Vital Statistics;Mouthwash;Mucous Membrane;Multi-Drug Resistance;Multi-Institutional Clinical Trial;Numbers;Nursing Homes;Oral;Oral Examination;Oral cavity;Oral health;Oropharyngeal;Outcome;Palate;Patients;Physicians;Placebo Control;Placebos;Plans Development;Pneumonia;Population;Practices General;Preventive;Prophylactic treatment;Randomized;Rate;Rates Case Fatality;Reporting;Research;Research Institute;Research Personnel;Research Project Grants;Research Proposals;Research Training;Residencies;Resources;Role;Saline;Sampling;Scientist;Site;Solid;Solutions;Supervision;Surface;Swab;Systemic disease;Testing;Time;Tongue;Tooth structure;Toothbrushing;Training;United States;United States National Institutes of Health;antimicrobial;base;career;cost;day;design;disorder control;dissemination research;effectiveness clinical trial;experience;hazard;health disparity;human disease;improved;knowledge base;older patient;oral care;pathogen;patient oriented;prevent;programs;respiratory;toothbrush;trend


application_id: 7364165
project_number: 5R01DK074720-02
project_title: Novel hematopoietic effects of C3 cleavage fragments
administering_ic: NIDDK
award_notice_date: 2008-03-03
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: WRIGHT, DANIEL G
project_start_date: 2007-03-01
project_end_date: 2012-02-29
study_section: Hematopoiesis Study Section[HP]
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: 2008-03-01
project_terms:
Address;Adhesions;Animals;Antibodies;Apoptosis;Appendix;B-Lymphocytes;Binding (Molecular Function);Biological;Blood;Bone Marrow;Bone Marrow Cells;C3bi;CD34 gene;CSF3 gene;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotaxis;Cleaved cell;Clinic;Complement;Complement 3 Convertase;Complement 3a;Complement 3b;Complement Activation;Condition;Cytostatics;Data;Defect;Deposition;Dose;Engraftment;Exhibits;Exposure to;Generations;Half-Life;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homing;Human;Hypoxia;Immunodeficient Mouse;Immunoglobulin M;Immunoglobulins;In Vitro;Inflammation;Infusion procedures;Injury;Laboratories;Lead;Ligands;Link;Liquid substance;Macrophage-1 Antigen;Marrow;Mediating;Membrane Lipids;Membrane Microdomains;Molecular;Mus;Numbers;Organ;Pathway interactions;Patient Care;Patients;Peptides;Phase;Phenotype;Play;Process;Progenitor Cell Engraftment;Proteolysis;Radiation therapy;Radio;Recovery;Reporting;Research;Research Personnel;Role;SCID Mice;Serum;Signal Transduction;Site;Solid;Staging;Stem cells;Stress;Stromal Cell-Derived Factor 1;Stromal Cells;Supplementation;System;Testing;Tissues;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Work;Zymosan;base;cell motility;chemotherapy;citrate carrier;conditioning;in vivo;in vivo Model;injured;insight;irradiation;mouse model;novel;prevent;progenitor;programs;stem;trafficking


application_id: 7364068
project_number: 7R01HL081525-02
project_title: MAPK/PKR Modulation of Diaphragm Weakness
administering_ic: NHLBI
award_notice_date: 2007-03-12
application_type: 7
activity_code: R01
ic: HL
serial_number: 081525
program_official: SMITH, ROBERT A
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-K(07)M]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD 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: 2007-03-15
project_terms:
JUN kinase;NAD(P)H dehydrogenase;apoptosis;biological signal transduction;cell line;cysteine endopeptidases;diaphragm;endotoxins;enzyme activity;enzyme induction /repression;inflammation;kinase inhibitor;laboratory mouse;mitogen activated protein kinase;muscle contraction;muscle strength;myotubes;protein kinase;protein localization;proteomics;receptor expression;tumor necrosis factor alpha;western blottings


application_id: 7364014
project_number: 1R01HD053509-01A2
project_title: Transcriptional Coactivators and Pregnancy Outcomes
administering_ic: NICHD
award_notice_date: 2008-04-16
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HD
serial_number: 053509
suffix: A2
program_official: HENKEN, DEBORAH B
project_start_date: 2008-07-01
project_end_date: 2013-06-30
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
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
project_terms:
Child;Complex;Condition;Congenital Abnormality;Data;Defect;Development;E1A-associated p300 protein;EP300 gene;Embryo;Fetus;Folate;Folic Acid;Folic Acid Deficiency;Genes;Health;Health Status;Healthcare;Human;Incidence;Investments;Link;Mediating;Medical;Molecular;Morphogenesis;Nature;Neural Tube Defects;Neural Tube Development;Neural tube;Neuraxis;Nuclear;Nutritional;Pathway interactions;Pattern;Polymorphism Genetic;Predisposition;Pregnancy Outcome;Pregnant Women;Proteins;Recurrence;Regulon;Research Design;Risk;Role;Science;Signal Transduction;TFAP2A gene;Testing;Transcription Coactivator;Transcription Genetic;United States;United States Public Health Service;Variation (Genetics);Women's Health;developmental disease/disorder;genetic association;malformation;nervous system development;prenatal;research study;social


application_id: 7360319
project_number: 5R01HL080394-02
project_title: Fibrinogen-induced vasoconstriction during hypertension
administering_ic: NHLBI
award_notice_date: 2008-02-25
application_type: 5
activity_code: R01
ic: HL
serial_number: 080394
program_official: RABADAN-DIEHL, CRISTINA
project_start_date: 2007-03-01
project_end_date: 2012-02-28
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
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: 2008-03-01
project_terms:
Acetates;Age;Animals;Attenuated;Binding (Molecular Function);Blood;Blood Pressure;Cardiovascular system;Cerebrovascular Disorders;Control Animal;Deoxycorticosterone;Development;Dose;Elevation;Endothelial Cells;Endothelin;Endothelin Big;Endothelin-1;Endothelium;Endothelium Vascular;Enzymes;Exocytosis;Extracellular Signal Regulated Kinases;F-Actin;Fibrinogen;Figs - dietary;Flow Cytometry;Genetic;Hypertension;Inflammatory;Integrin alpha5beta1;Integrins;Intercellular adhesion molecule 1;JUN gene;MALDI-TOF Mass Spectrometry;Maintenance;Mediating;Microscopy Confocal;Mitogen-Activated Protein Kinases;Mitogens;Modeling;Models Genetic;Operative Surgical Procedures;PD-98059;Phosphorylation;Plasma;Polyacrylamide Gel Electrophoresis Two-Dimensional;Production;Protein Kinase;Proteins;Proteome;Proteomics;RNA Small Interfering;Rats Inbred SHR;Rats Inbred WKY;Rats Sprague-Dawley;Rattus;Reporting;Research Personnel;Resolution;Risk Factors;Role;SP600125;Signal Pathway;Signal Transduction;Smc1l1 protein mouse;Smc1l2 protein mouse;Sodium Chloride;Staging;Structure of arteriole;Surface;Time;Transfection;Vascular constriction (function);Week;Weibel-Palade Bodies;animal data;base;inhibitor/antagonist;novel;programs;receptor;research study;response;salicylhydroxamic acid;stress-activated protein kinase 1


application_id: 7360316
project_number: 5R01NS049209-05
project_title: Plasticity of Human Spinal Neural Networks After Injury
administering_ic: NINDS
award_notice_date: 2008-02-22
application_type: 5
activity_code: R01
ic: NS
serial_number: 049209
program_official: KLEITMAN, NAOMI
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Special Emphasis Panel[ZRG1-MRS(01)Q]
contact_pi_person_id: 1884506
contact_pi: HARKEMA, SUSAN J
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): Clonus is one manifestation of spasticity and produces involuntary neuromuscular responses that can interfere with the ability to walk after spinal cord injury (SCI). Clonus results in oscillatory efferent output generated by repetitive afferent input and the activation of central neural oscillators. The frequency of clonus is similar when driven by different types of repetitive afferent stimuli such as during standing and stepping. Clonus can radiate across several spinal cord segments and the oscillatory efferent output is modulated by interneurons. Thus clonus can be used as a physiological probe to understand the functional organization of interneuronal circuits.  
We propose to study clonus during manual stretch of the plantarflexors standing and stepping to assess whether repetitive afferent input can alter the functional interneuronal organization of the human spinal cord.  
We will assess whether the specific afferent input related to loading modulates the central oscillators that generate clonus to modify efferent output after severe SCI. We hypothesize that manual stretch of the plantarflexors standing and stepping will result in different co-activation patterns of clonic EMG among ipsilateral and contralateral flexors and extensors. Also if a higher level of load to the legs is provided during standing and stepping the clonic EMG activity will be reduced with an increase in tonic activity of bilateral flexors and extensors. We have observed that when individuals after severe spinal cord injury undergo multiple stand or step training sessions clonus and spasticity are reduced. We propose that intensive training that provides specific sensory information related to loading can reconfigure spinal networks to modify and reduce clonus after severe SCI. We suggest that the repetitive afferent input related to loading induces significant and persistent functional reorganization of interneuronal circuits. We hypothesize that after intensive training the same afferent input will alter clonic EMG activity.  
The proposed studies will further our understanding of the mechanisms of clonus after severe SCI. Further we will learn whether the spinal neural networks responsible for clonus interact with those that generate standing and stepping. We will also understand whether the repetitive presentation of specific sensory information by training can reconfigure spinal neural networks to generate more functional motor output. Clonus is routinely treated with drugs or even invasive strategies with the intent to diminish clonus to enhance motor function. Unfortunately side effects rebound spasticity and limited recovery of function are often reported. We suggest that anti-spasticity medication may actually be interfering with the neural circuits needed for standing and walking. If this is the case then specific training that uses task appropriate sensory cues for standing and walking may alleviate clonus and spasticity reduce the need for medication and improve motor function in individuals with severe SCI.

project_terms:
Adverse effects;Bilateral;Biological Neural Networks;Chronic;Clonus;Condition;Contralateral;Cues;Daily;Electromyography;Figs - dietary;Flexor;Frequencies (time pattern);Human;Individual;Injury;Interneurons;Invasive;Ipsilateral;Learning;Leg;Life;Manuals;Motor;Motor Activity;Motor output;Output;Pattern;Pharmaceutical Preparations;Physiological;Principal Investigator;Recovery;Recovery of Function;Reporting;Sensory;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Step training;Stimulus;Stretching;Testing;Training;Walking;experience;improved;neural circuit;programs;relating to nervous system;response


application_id: 7360275
project_number: 5R01NS052292-03
project_title: Re-training locomotor circuitry in a rat model of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2008-02-25
application_type: 5
activity_code: R01
ic: NS
serial_number: 052292
program_official: KLEITMAN, NAOMI
project_start_date: 2006-05-15
project_end_date: 2011-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): One of the most promising therapeutic strategies for spinal cord injury is weight-supported treadmill training. This rehabilitation therapy seeks to re-train the spinal cord circuitry below the level of injury to participate in functional locomotion. The mammalian spinal cord humans included contains complex neuronal circuitry that participates in the generation of the repeating pattern of motor activity (step-cycle) associated with normal over-ground locomotion. Both animal and human studies have demonstrated that moving the hindlimbs to mimic normal walking usually on a treadmill with rehabilitation assistants can lead to improved hindlimb locomotor function. However the treadmill speed that is used is very slow compared to normal walking and much of the body weight of the animal or patient must be supported externally. Consequently relatively few step-cycles are generated during a re-training session certainly far fewer than normal walking. We hypothesized that a re-training strategy that allowed for many more step-cycles to be completed would be more effective and that re-training the locomotor circuitry would be much more successful. Some of the components that are thought to be important for the re-training process include step-cycle number cutaneous feedback from the foot limb position and weight-bearing feedback from the leg. How each of these individual components contribute to successful rehabilitation and the physiological and cellular mechanisms underlying the re-training process are not known. We have devised a strategy to use buoyancy during swimming to provide weight-support which allows for high numbers of step-cycles to be completed during a rehabilitation session. We have also incorporated a simple approach to provide phasic cutaneous feedback during swimming and partial limb-loading (weight- bearing) during walking in shallow water. We hope to uncover what relative contributions step-cycle number and frequency cutaneous feedback and limb-loading make to the overall success of a locomotor rehabilitation strategy. In addition we will begin to look at the mechanisms of rehabilitation associated plasticity using a custom made array to detect changes in mRNA levels in spinal cord tissue following different training protocols.

project_terms:
Animal Model;Animals;Axon;Body Weight;Class;Complex;Contusions;Custom;Cutaneous;Dorsal;Electromyography;Feedback;Felis catus;Flexor;Frequencies (time pattern);Generations;Golgi Tendon Organs;Hindlimb;Hip region structure;Human;Individual;Injury;Joint Capsule;Lead;Learning;Left;Leg;Length;Limb structure;Link;Locomotion;Locomotor Recovery;Lumbar spinal cord structure;Methods;Modeling;Motor;Motor Activity;Motor Neurons;Motor output;Movement;Muscle;Muscle Spindles;Nerve;Nervous system structure;Numbers;Output;Pathway interactions;Patients;Pattern;Pes;Phase;Physiological;Placement;Positioning Attribute;Principal Investigator;Process;Protocols documentation;RNA Messenger;Range of Motion Articular;Rate;Rattus;Recovery of Function;Rehabilitation therapy;Relative (related person);Research Personnel;Role playing therapy;Speed (motion);Spinal Cord;Spinal cord injury;Staging;Stress;Surface;Swimming;Testing;Therapeutic;Thinking function;Tissues;Training;Walkers;Walking;Water;Week;Weight;Weight-Bearing state;Work;base;cane includes canes of all materials adjustable or fixed with tip;functional improvement;human study;human subject;improved;injured;neuronal circuitry;programs;receptor;rehabilitation strategy;research study;response;success


application_id: 7359863
project_number: 1R21ES016367-01
project_title: Priming of liver disease by arsenic exposure
administering_ic: NIEHS
award_notice_date: 2009-05-08
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: ES
serial_number: 016367
program_official: SHREFFLER, CAROL A
project_start_date: 2009-05-01
project_end_date: 2011-04-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Inorganic arsenic is a natural drinking water contaminant and a known hepatotoxin. However the exposure levels of arsenic required to cause overt liver damage may be higher than found in the US water supply. In preliminary studies it was shown that chronic exposure to arsenic at exposure levels that caused no overt hepatoxicity sensitized the liver to a subsequent inflammatory `hit' owing to injection of lipopolysaccharide (LPS). This new finding suggests that arsenic even at exposure levels that are not hepatotoxic per se may increase the risk of liver disease owing to a second hepatotoxic event. Based on these Preliminary Studies it is hypothesized that low-dose arsenic primes liver to a subsequent hepatotoxic insult. This hypothesis will be tested via the following specific aims. 1). To test the hypothesis that arsenic sensitizes to LPS-induced liver injury in the mouse. In the Preliminary Studies it was shown chronic exposure of arsenic in drinking water enhances hepatic inflammation and damage caused by LPS. However the drinking water concentration of arsenic used in this preliminary study is still higher than relevant to human exposure in the US. We will therefore test our hypothesis with lower more relevant water concentrations of arsenic. Specific subaims are: a) To determine the minimal low dose arsenic exposure conditions to cause sensitization to LPS. b) To identify potential mechanisms by which arsenic preexposure enhances liver damage caused by LPS. 2). To test the hypothesis that low-dose arsenic exposure sensitizes liver to hepatotoxicity in mouse models of non alcoholic fatty liver disease (NAFLD). A liver disease that is currently endemic to the US population is obesity-induced NAFLD. Here using minimal exposure conditions determined in Specific Aim 1 the hypothesis that low dose arsenic exposure will enhance chronic liver damage in established models of NAFLD will be tested. Specific subaims are: a) To determine the effect of arsenic on early intermediate and late stages of fatty liver diseases. b) To determine whether arsenic enhances the formation of progenitor cells and/or preneoplastic lesions in experimental NAFLD. Taken together these results will also establish new models of arsenic priming of liver disease in which new hypotheses and/or treatment regimens may be tested. Should arsenic cause such a priming effect the significance of this work to the US population is significant. Specifically such results would suggest that the relative risk of hepatic damage caused by arsenic exposure may have to be modified to take into account other mitigating factors such as type II diabetes and/or NAFLD. Exposure to arsenic in the drinking water is a major health concern. Our preliminary studies indicate that arsenic exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver possibly increasing the risk of serious chronic liver diseases (e.g. non-alcoholic fatty liver diseases). The project will develop a new model of arsenic exposure that will not investigate direct toxicity per se but rather test the hypothesis that arsenic exacerbates the response in established liver toxicity models.

project_terms:
Accounting;Acute;Animal Model;Animals;Arsenic;Biochemical;Chronic;Chronic Disease;Cirrhosis;Development;Disease;Dose;Environmental Exposure;Environmental Risk Factor;Epidemiology;Event;Exposure to;Fatty Liver;Fibrosis;Health;Hepatic;Hepatotoxicity;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Lesion;Lipopolysaccharides;Liver;Liver diseases;Malignant - descriptor;Malignant Neoplasms;Modeling;Mus;Non-Insulin-Dependent Diabetes Mellitus;Non-Malignant;Obesity;Physiological;Population;Relative Risks;Risk;Risk Factors;Role;Staging;Stem cells;Stimulus;Testing;Toxic effect;Treatment Protocols;Water;Water Supply;Work;base;drinking water;exposed human population;hepatotoxin;mouse model;non-alcoholic fatty liver;pandemic disease;response


application_id: 7359613
project_number: 5R01NS050242-02
project_title: Relationship between BOLD effects on DA degeneration
administering_ic: NINDS
award_notice_date: 2008-01-29
application_type: 5
activity_code: R01
ic: NS
serial_number: 050242
program_official: SIEBER, BETH-ANNE
project_start_date: 2007-02-16
project_end_date: 2012-01-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
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: 2008-02-01
project_terms:
Address;Amphetamines;Animal Model;Animals;Apomorphine;Appearance;Attenuated;Basal Ganglia;Behavioral;Biological Markers;Biological Process;Chronic;Clinical;Condition;Corpus striatum structure;Deterioration;Development;Dextroamphetamine;Disease;Disease Progression;Dopamine;Dopamine Agonists;Dopamine Receptor;Dopaminergic Cell;Early Diagnosis;Fiber;Future;General Population;Geographic Locations;Goals;Image;Imaging Techniques;Infusion procedures;Intervention;Invasive;Kentucky;Lesion;Levodopa;MPTP Poisoning;Macaca mulatta;Magnetic Resonance Imaging;Measures;Methods;Modeling;Monitor;Motor;Numbers;Outcome;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Pathological Staging;Patients;Positron-Emission Tomography;Process;Protocols documentation;Published Comment;Purpose;Recovery of Function;Research;Research Personnel;Research Proposals;Rest;Scans MRI;Severities;Signal Transduction;Signs and Symptoms;Specificity;Staging;Structure of putamen;Substantia nigra structure;Suggestion;Symptoms;System;Techniques;Testing;Therapeutic Agents;Universities;base;blood oxygen level dependent;blood oxygenation level dependent response;cost;cost effective;desire;dopamine system;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;interest;motor impairment;neurorestoration;nigrostriatal system;novel therapeutics;programs;response;treatment center


application_id: 7356434
project_number: 5R01HL082772-02
project_title: Angiotensin Induced Proteoglycans in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2008-02-06
application_type: 5
activity_code: R01
ic: HL
serial_number: 082772
program_official: GOLDMAN, STEPHEN
project_start_date: 2007-02-15
project_end_date: 2012-01-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA 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
budget_start_date: 2008-02-01
project_terms:
AGTR2 gene;Angiotensins;Animals;Apolipoproteins;Apolipoproteins B;Arteries;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinical Trials;Data;Development;Diabetes Mellitus;Event;Foam Cells;Goals;Grant;High Prevalence;Human;In Vitro;Infusion procedures;Intervention;Kidney Failure;Link;Lipoproteins;Localized;Low-Density Lipoproteins;Mediating;Modeling;Mus;Myocardial Infarction;Myocytes Smooth Muscle;Peptides;Play;Promotor (Genetics);Proteoglycan;Range;Relative (related person);Renin-Angiotensin System;Research Personnel;Risk;Risk Factors;Role;Saline;Strikes Employee;Testing;Thinking function;Transcriptional Regulation;biglycan;in vivo;macrophage;mouse model;novel;oxidation;oxidized low density lipoprotein;prevent;programs;protective effect;receptor;research study;response;stroke


application_id: 7356403
project_number: 5R01CA049797-17
project_title: Mechanisms of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2008-02-29
application_type: 5
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2010-02-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this research is to determine the molecular mechanisms that control the expression of the human MnSOD gene during tumor promotion. It is well documented that MnSOD level is altered in transformed cells. Our previous studies demonstrate that overexpression of the MnSOD gene suppresses tumorigenesis in a multistage skin cancer model. However when and how MnSOD expression is modulated during carcinogenesis is unknown. We have generated several lines of transgenic mice expressing a luciferase reporter gene under the control of MnSOD promoter/enhancer elements. This unique animal model provides an outstanding opportunity for investigating changes in MnSOD expression during the carcinogenesis process in animals by a non-invasive method. We hypothesize that repetitive exposure to tumor promoter leads to inactivation of MnSOD expression. Specific Aim 1 will determine at what point the expression of MnSOD is reduced during the process of cancer development using transgenic mice harboring a MnSOD promoter-driven luciferase reporter and bioluminescence-imaging strategies to noninvasively and quantitatively image MnSOD expression in living mice. Specific Aim 2 will investigate how changes in MnSOD expression occur in vivo using chromatin immunoprecipitation (ChIP) assays DNA sequencing and proteomic analyses. Specific Aim 3 will identify transcription factors and co-activators/repressors necessary for transcriptional modulation of the MnSOD gene using DNA binding siRNA and protein/protein interaction methods. The results of the proposed studies will provide information on when and how the expression of MnSOD is altered during tumorigenesis. Because of the essential role of MnSOD for the survival of aerobic life and its well documented role in the prevention of oxidative stress-mediated tissue injury and cancer formation understanding how the expression of MnSOD can be regulated during cancer development is likely to have broad implications for the prevention of cancer.

project_terms:
910-Dimethyl-12-benzanthracene;Acetates;Address;Aerobic;Animal Model;Animals;Anthracenes;Antioxidants;Biochemical;Biological;Biological Assay;Bioluminescence;Cancer Control;Cancer Model;Cells;Complex;Coupled;DNA;DNA Binding;DNA Sequence;DNA Structure;DNA-Binding Proteins;Depth;Development;Discipline;Enhancer Elements (Genetics);Enhancers;Enzymes;Epithelial;Exposure to;Family;Future;Gene Expression;Gene Silencing;Genes;Genes Reporter;Goals;Human;Image;Image Analysis;Incidence;Injury;Invasive;Lead;Life;Luciferases;Malignant Neoplasms;Manganese;Measures;Mediating;Methods;Mice Transgenic;Mitochondria;Modeling;Molecular;Molecular Biology;Monitor;Mus;Mutagenesis Site-Directed;Ontology;Oxidative Stress;Papilloma;Personal Satisfaction;Phase;Polymerase Chain Reaction;Prevention;Process;Promoters Tumor;Promotor (Genetics);Protein Overexpression;Proteins;Proteomics;Protocols documentation;RNA Small Interfering;Regulation;Reporter;Research;Research Personnel;Reverse Transcription;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Tissue;Staging;Superoxide Dismutase;Testing;Time;Tissues;Transcription Genetic;Tumor Promotion;Tumor Suppressor Genes;anthracene;base;cancer prevention;carcinogenesis;cell transformation;chromatin immunoprecipitation;design;in vivo;insight;member;neoplastic cell;novel;prevent;protein protein interaction;tool;transcription factor;tumor;tumorigenesis


application_id: 7356396
project_number: 5R01CA112197-04
project_title: Mutagenesis as a novel target for cancer prevention
administering_ic: NCI
award_notice_date: 2008-03-10
application_type: 5
activity_code: R01
ic: CA
serial_number: 112197
program_official: OKANO, PAUL
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 1969289
contact_pi: MCGREGOR, WILLIAM G
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: 2008-03-10
project_abstract:
DESCRIPTION (provided by applicant):  The overall aim of this project is to apply new knowledge of fundamental mechanisms of mutagenesis to directly test the somatic mutation hypothesis of cancer and to translate this knowledge into a clinically useful regimen to reduce the incidence of sunlight-associated skin cancer. Mutations in DNA are generally considered to have an etiologic role in the development of cancer but until recently it has not been possible to directly examine the relative contribution of mutagenesis and epigenetic alterations in cellular physiology induced by carcinogen exposure. We hypothesize that mutations induced by ultraviolet light (UV) in the DNA of actively dividing skin cells are causally involved in skin carcinogenesis and reducing the frequency of such mutations will reduce the risk of skin cancer induced by UV. There is now abundant evidence that virtually all mutations induced by UV in eukaryotic cells are dependent on the gene products encoded by the REV1 and REV3 genes. We showed further that targeting the mRNA of one of these genes (REV1) with gene-specific ribozymes virtually abolishes UV mutagenesis. To test our hypothesis we propose to expose newly-developed REV3-depleted transgenic mice to UV. We anticipate that these mice will have a greatly reduced risk of developing skin cancer compared with control animals. Further we propose to translate our data into a practical method to prevent UV-induced skin cancer. We will develop and optimize gene-specific ribozymes expressed in cultured cells using several different systems to target them to the cytoplasm or to the nucleus. Then we propose to deliver such ribozyme expression vectors into mouse skin cells. These ribozymes will specifically target REV1 mRNA a protein that may coordinate the activity of several proteins that are required for the mutagenic replication of UVdamaged DNA. The mice and the appropriate controls will be exposed to UV protocols that are known to induce skin cancer. Our hypothesis predicts that reducing the level of this protein will reduce the mutagenic response of skin cells to UV and will result in a greatly reduced incidence of skin cancer. If so these data will provide the experimental rationale to develop similar strategies to reduce the incidence of skin cancer in humans. Most importantly such a strategy should be successful as a preventive measure after UV exposure and prior to appearance of disease symptoms.

project_terms:
Antisense RNA;Appearance;Carcinogen exposure;Carcinogens;Catalytic Domain;Catalytic RNA;Cell Nucleus;Cell physiology;Cells;Complex;Control Animal;Cultured Cells;Cytoplasm;DNA;DNA-Directed DNA Polymerase;Data;Development;Disease;Epigenetic Process;Eukaryotic Cell;Exposure to;Fibroblasts;Frequencies (time pattern);Gene Targeting;Genes;Genes Reporter;HPRT1 gene;Human;Hypoxanthine Phosphoribosyltransferase;Incidence;Induced Mutation;Knowledge;Lesion;Lipids;Malignant Neoplasms;Measures;Methods;Mice Inbred HRS;Mice Transgenic;Mus;Mutagenesis;Mutation;Nuclear;Plasmids;Polymerase;Preventive;Promotor (Genetics);Proteins;Protocols documentation;Protocols Treatment;RNA Messenger;Relative (related person);Risk;Role;Skin;Skin Cancer;Skin Carcinogenesis;Somatic Mutation;Sunlight;Symptoms;System;Testing;Thinking function;Transgenic Organisms;Translating;Ultraviolet Rays;cancer prevention;expression vector;gene therapy;mouse model;mutant;novel;plasmid DNA;pol genes;prevent;response;sunlight-induced;vector


application_id: 7356391
project_number: 5R01CA113735-04
project_title: Development of Nucleolin targeted Anticancer Compounds
administering_ic: NCI
award_notice_date: 2008-02-11
application_type: 5
activity_code: R01
ic: CA
serial_number: 113735
program_official: LEES, ROBERT G
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): GRO26B and GRO29A are G-quartet forming aptamer oligonucleotides that have potent antiproliferative activity against cancer cells in vitro and in vivo. GRO26B has already entered Phase I clinical trials. They are active against a diverse range of tumor types (including lung prostate breast and colon cancers) and are highly selective for malignant cells. The molecular target for these aptamers has been identified as nucleolin a multifunctional phosphoprotein that is highly expressed in the nucleoli and plasma membrane of cancer cells. It is already well established that high levels of nucleolin expression predict rapid tumor growth rate and poor prognosis in many tumor types. Nucleolin is on the surface of tumor cells and not on the surface of normal cells and we have shown that molecules selectively targeting it enter tumor cells preferentially over normal cells. Therefore nucleolin is a cancer selective target with targeted molecules potentially having lower side effects and toxicity by not entering normal cells. We are undertaking an interdisciplinary approach to the discovery of new small molecules targeting nucleolin. Preliminary data indicate that molecules targeting nucleolin (for example GRO26B and small molecules that we have already identified using our approach) can also exhibit growth inhibitory activity against cancer cells while not effecting normal cells. We propose that in understanding how GROs and small molecules bind to nucleolin we can use structure-based drug design to generate new small molecule that have increased efficacy over oligonucleotide-based therapy. Specifically we need to understand the properties and structures of the GROs and how they are related. Using that information we can examine the complexes with nucleolin to identify specific interactions that are favorable. We will target these regions to screen for new compounds that will be subsequently tested for anticancer effects. The significance of this research is that we could establish a new class of low toxicity small molecule anticancer agents targeted to nucleolin.

project_terms:
Address;Adverse effects;Affect;Affinity;Animals;Antineoplastic Agents;Apoptotic;Binding (Molecular Function);Binding Sites;Biodistribution;Biological;Biological Assay;Biological Testing;Biophysics;Breast;Buffers;Calorimetry;Calorimetry Differential Scanning;Cell Nucleolus;Cell membrane;Cell surface;Circular Dichroism;Class;Clinical Research;Clinical Trials;Clinical Trials Phase I;Colon Carcinoma;Complex;Computational Biology;Condition;Cultured Cells;Data;Databases;Dependence;Development;Disease;Drug Design;Drugs Investigational;Electrophoretic Mobility Shift Assay;Electrostatics;Entropy;Equilibrium;Exhibits;Fluorescence Anisotropy;Forecast of outcome;Free Energy;G-Quartets;Grant;Growth;Guidelines;Homology Modeling;Hour;Human;In Vitro;Individual;Ions;Isotope Labeling;Label;Laboratories;Lead;Length;Ligand Binding;Lung;Malignant - descriptor;Malignant Neoplasms;Mediating;Methods;Molecular;Molecular Biology;Molecular Conformation;Molecular Target;Molecular Weight;Morphology;Mus;Normal Cell;Normal tissue morphology;Numbers;Oligonucleotides;Patients;Pharmaceutical Preparations;Phase;Phosphoproteins;Process;Property;Prostate;Proteins;Range;Rate;Reporting;Research;Research Personnel;Screening procedure;Sodium;Solutions;Spectroscopy NMR;Structure;Surface;Techniques;Temperature;Testing;Thermodynamics;Titrations;Toxic effect;United States Food and Drug Administration;United States National Institutes of Health;Work;analytical ultracentrifugation;anticancer activity;aptamer;base;cancer cell;cell transformation;comparative;design;dimer;enthalpy;in vivo;inhibitor/antagonist;interdisciplinary approach;melting;monomer;neoplastic cell;novel therapeutics;nucleolin;pharmacophore;phosphodiester;potassium ion;programs;small molecule;stoichiometry;structural biology;therapeutic target;tumor;tumor growth;tumor xenograft;virtual


application_id: 7356097
project_number: 1R21DA024089-01
project_title: Human Lab Model of Behavioral/Pharmacological Treatment for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2008-04-04
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: DA
serial_number: 024089
program_official: BOUGH, KRISTOPHER J
project_start_date: 2008-04-10
project_end_date: 2010-03-31
study_section: Special Emphasis Panel[ZDA1 RXL-E (03)]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine dependence continues to be a significant public health concern. Data from the National Survey on Drug Use and Health indicate that the number of Americans who had used cocaine in the past month has remained relatively stable since 2002 and cocaine remains the most frequently mentioned drug in emergency-room admissions according to the Drug Abuse Warning Network. Because of the public-health concerns and costs associated with its abuse identifying a pharmacotherapy for the treatment of cocaine dependence is a priority for the National Institute on Drug Abuse (NIDA). Despite intense research efforts a widely accepted medication for cocaine dependence has not yet been identified. A number of non-pharmacological treatments for cocaine dependence have also been examined. Specifically behavioral treatments for cocaine dependence seek to reinforce non- drug related behaviors. For example contingency management uses monetary incentives to decrease cocaine use and is associated with high rates of prolonged cocaine abstinence. Given the effectiveness but also high relative cost of behavioral treatments for cocaine dependence some have theorized that pharmacotherapies may be able to enhance the effectiveness of behavioral therapies and decrease costs associated with delivery of these therapies. Indeed pharmacotherapies (i.e. desipramine and bupropion) have been shown to enhance the effectiveness of behavioral therapies for cocaine dependence. The purpose of the experiments proposed in this application is to "reverse engineer" a human laboratory model of combined pharmacological and behavioral treatments for cocaine dependence using an already existing and validated model of contingency management the cocaine versus money choice paradigm. The research proposed in this application has two specific aims. The first specific aim is to adapt a model of the cocaine versus money choice paradigm that is sensitive to pharmacological pretreatment (Higgins et al. 1996) and determine optimal parameters (i.e. cocaine dose monetary values). In Experiment 1 eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values. These data will be used to guide which cocaine dose and monetary values will be used in Experiment 2. The second specific aim is to validate the sensitivity of the cocaine versus money choice paradigm as a model of combined pharmacological and behavioral treatment. In Experiment 2 eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values following maintenance for seven days on placebo or 300 mg bupropion. The research proposed in this application will serve to develop an efficient and valid human laboratory screen of medications for cocaine dependence. Project Narrative The research proposed in this application seeks to develop a model of combined behavioral and pharmacological treatment for cocaine dependence. With this model we hope to more efficiently screen medications that might enhance the efficacy of contingency management a behavioral treatment that is successful in managing cocaine dependence.

project_terms:
Abstinence;Accident and Emergency department;Admission activity;American;Behavior;Behavior Therapy;Behavioral Model;Bupropion;Clinical Trials;Cocaine;Cognitive Therapy;Combined Pharmacological and Behavioral Treatment;Crime;Data;Dependences Cocaine;Desipramine;Dose;Drug abuse;Drug usage;Educational process of instructing;Effectiveness;Engineering;Equilibrium;Future;Health;Human;Incentives;Institutes;Laboratories;Maintenance;Medical;Modeling;Monitor;National Institute of Drug Abuse;Numbers;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Placebos;Population;Productivity;Purpose;Range;Rate;Relapse;Relative (related person);Reporting;Research;Societies;Surveys;Testing;Treatment Cost;Treatment Effectiveness;contingency management;cost;day;economic value;public health medicine (field);research study;skills;voucher


application_id: 7354856
project_number: 5R01NR008567-05
project_title: Biobehavioral Intervention in Heart Failure
administering_ic: NINR
award_notice_date: 2008-02-28
application_type: 5
activity_code: R01
ic: NR
serial_number: 008567
program_official: HUSS, KAREN
project_start_date: 2004-06-01
project_end_date: 2010-02-28
study_section: Nursing Science: Adults and Older Adults Study Section[NSAA]
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
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
budget_start_date: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): Heart failure has been called the most important public health problem facing cardiovascular clinicians and researchers because of its high and increasing incidence prevalence morbidity and mortality.  Despite substantial advances in pharmacologic therapy made in recent years clinical improvements seen among patients are relatively modest and quality of life often remains poor.  Nonpharmacologic therapy has received relatively little attention yet has potential to serve as an important adjunct to pharmacologic therapy.  Biofeedback-relaxation a cognitive biobehavioral nonpharmacologic intervention has been demonstrated to be effective in conditions with pathophysiological and psychological manifestations of heart failure.  Accordingly specific aims of this project are to determine the impact of biofeedback-relaxation training on 1) the combined primary end-point of heart failure rehospitalizations or cardiac mortality 2) quality of life; 3) intermediate (mediating) patient outcomes of perceived control anxiety and depression and 4) intermediate (mediating) physiologic outcomes of finger and foot skin temperature heart rate variability and plasma norepinephrine.  We hypothesize that biofeedback-relaxation training will result in decreased heart failure rehospitalizations or cardiac death improved quality of life increased perceived control decreased anxiety and depression increased finger and foot temperature improved heart rate variability and decreased plasma norepinephrine.  To test these hypotheses 420 patients with advanced heart failure will be randomized to one of three groups: 1) biofeedback-relaxation (intervention); 2) sham biofeedback-relaxation (placebo-control); or 3) usual care control.  Within these groups patients will be stratified such that each group will include 50% taking and 50% not taking angiotensin converting enzyme inhibitors.  Data will be collected at baseline 3 and 12 months and will be analyzed using survival analyses and repeated measure ANOVA.  Biofeedback-relaxation training for patients with heart failure may have potential long-term clinical benefits and may serve as an important adjunct to pharmacologic therapy.

project_terms:
Activities of Daily Living;Adult;Analysis of Variance;Angiotensin-Converting Enzyme Inhibitors;Anxiety;Attention;Biofeedback;Cardiac;Cardiovascular system;Caring;Cessation of life;Chronic;Clinical;Cognitive;Condition;Control Groups;Controlled Clinical Trials Randomized;Data;Death Cardiac;Educational Intervention;End Point;Epidemic;Feeling;Fingers;Functional disorder;Goals;Heart Rate;Heart failure;Hospitalization;Hospitals;Incidence;Individual;Intervention;Measures;Mediating;Mental Depression;Mental Health;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Neuro-Oncological Ventral Antigen 2;Norepinephrine;Outcome;Pathway interactions;Patients;Pes;Pharmacotherapy;Physiological;Placebo Control;Plasma;Prevalence;Purpose;Quality of life;Randomized;Rate;Recruitment Activity;Relaxation;Relaxation Therapy;Research;Research Personnel;Resources;Role;Skin Temperature;Stratification;Stress;Survival Analysis;Sympathetic Nervous System;Symptoms;Temperature;Testing;Time;Vascular constriction (function);Vasodilation;biobehavior;emotional distress;follow-up;improved;innovation;programs;psychologic;public health medicine (field);response;size


application_id: 7354617
project_number: 1R01HL091202-01
project_title: The SDF1-CXCR4 Axis in Cardiac Homeostasis and Regeneration
administering_ic: NHLBI
award_notice_date: 2008-08-19
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 091202
program_official: LIANG, ISABELLA Y
project_start_date: 2008-09-01
project_end_date: 2012-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
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
project_terms:
Activities of Daily Living;Acute;Address;Adult;Area;Arrestin;Arrestins;Attenuated;Biological;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cardiac;Cell Maintenance;Cell physiology;Cells;Chemotactic Factors;Chemotaxis;Chronic;Cicatrix;Clear Cell;Condition;Coupled;Disease;Down-Regulation;Effectiveness;Embryo;Engraftment;Environment;Fibroblasts;Functional disorder;G-Protein-Coupled Receptors;GRK6 gene;GTP-Binding Protein Regulators;GTP-Binding Proteins;GTPase-Activating Proteins;Growth Factor Receptors;Heart;Heart Defects Congenital;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homeostasis;Homing;In Vitro;Infarction;Infection;Inflammatory;Injury;Ischemia;Knock-out;Lead;MAP Kinase Gene;Maintenance;Mediating;Mesenchymal Stem Cell Transplantation;Mice Knockout;Modeling;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardium;Myocytes Cardiac;Myofibroblast;Natural regeneration;Numbers;Osteoblasts;Patients;Perception;Personal Satisfaction;Phosphotransferases;Physiological reperfusion;Play;Population;Process;Protein Overexpression;Proto-Oncogene Proteins c-akt;Rate;Rattus;Recovery of Function;Recruitment Activity;Reperfusion Injury;Reperfusion Therapy;Research;Role;Seminal;Signal Transduction;Site;Stem cells;Stress;Stromal Cell-Derived Factor 1;Stromal Cells;Supporting Cell;System;Testing;Therapeutic;Therapy Cell;Tissues;Transgenic Organisms;Transplantation;adult stem cell;attenuation;autocrine;base;biological adaptation to stress;cell type;chemokine;day;desensitization;design;improved;in vivo;injured;insight;novel;novel strategies;novel therapeutics;paracrine;progenitor;protein function;receptor;repaired;residence;response;response to injury;tissue regeneration;trafficking


application_id: 7353436
project_number: 1R01HD057501-01
project_title: The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
administering_ic: NICHD
award_notice_date: 2008-04-01
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HD
serial_number: 057501
program_official: TAYMANS, SUSAN
project_start_date: 2008-04-01
project_end_date: 2013-03-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 2220008
contact_pi: LEI, ZHENMIN
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
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:
Adult;Age;Androgen Receptor;Androgens;Animals;Bilateral;Blood Circulation;Cell Proliferation;Cell division;Cells;Congenital Abnormality;Cryptorchidism;Defect;Development;Disruption;Estradiol;Estrogens;Exhibits;G-Protein-Coupled Receptors;Gene Expression;Gene Targeting;Genes;Grants Applications;Histology;Human;In Vitro;Incidence;Insulin;Leucine-Rich Repeat;Mediating;Mesenchymal;Mice Mutant Strains;Molecular;Mus;Muscle Cells;Nerve;Notch Signaling Pathway;Numbers;Organ Culture Techniques;Pathway interactions;Peptides;Phase;Phenotype;Play;Process;RNA Messenger;Receptors LH;Recovery;Relaxin;Role;Scrotum;Serum;Siblings;Signal Pathway;Signal Transduction;Staging;Structure of cremaster muscle;Structure of interstitial cell of Leydig;System;Testis;Testosterone;insight;knockout animal;male;morphometry;myogenesis;notch protein;postnatal;prevent;testosterone replacement therapy


application_id: 7352797
project_number: 5U10NS053368-03
project_title: Neuroprotection Exploratory Trials in PD (NET-PD)
administering_ic: NINDS
award_notice_date: 2008-01-22
opportunity_number: RFA-NS-05-004
application_type: 5
activity_code: U10
ic: NS
serial_number: 053368
program_official: MOY, CLAUDIA S
project_start_date: 2006-05-17
project_end_date: 2010-11-30
study_section: ZNS1-SRB-K(30)
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Affect;Age;Age of Onset;Anxiety;Area;Autonomic Dysfunction;Back;Basal Nucleus of Meynert;Bradykinesia;Chromosome Pairing;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Communities;Corpus striatum structure;County;Deterioration;Diagnosis;Disease;Disease Progression;Dopamine;Double-Blind Method;Enrollment;Environmental Risk Factor;Etiology;Functional disorder;Futility;Gait;Gait abnormality;Genetic;Impaired cognition;Incidence;Individual;Kentucky;Lead;Life Style;Mental Depression;Motor;Motor Manifestations;Movement Disorders;Multicenter Trials;Muscle Rigidity;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neuroprotective Agents;Numbers;Occupations;Ohio;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pigments;Productivity;Range;Request for Applications;Residual state;Rest Tremor;Rural;Signs and Symptoms;Smell Perception;Staging;Structure of locus ceruleus;Structure of putamen;Substantia nigra structure;Symptoms;Synapses;Testing;Thinking function;Time;Toxic Environmental Substances;Toxin;Universities;West Virginia;career;disability;dopamine system;executive function;functional disability;neuropathology;neuroprotection;nigrostriatal system;pars compacta;pilot trial;placebo controlled study;raphe nuclei;repaired


application_id: 7352705
project_number: 5R01CA116697-02
project_title: Oxidative Stress in Cr(VI)-induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2008-01-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 116697
program_official: POLAND, ALAN P
project_start_date: 2007-02-07
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-T(04)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-02-01
project_terms:
Animals;Antioxidants;Biology;CDC42 gene;California;Cancer Etiology;Carcinogens;Carcinogens Environmental;Cells;Chemical Structure;Chemicals;Consumption;DNA Damage;Detection;Development;Dominant-Negative Mutation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental Exposure;Enzymes;Epithelial;Exposure to;Free Radicals;Frequencies (time pattern);Generations;Goals;Human;Hydroxyl Radical;Incidence;Inhalation Exposure;International Agency for Research on Cancer;Intervention;JUN gene;Life;Link;Lipid Peroxidation;Lung;MAPK1 gene;Malignant neoplasm of lung;Medicine;Methods;Mice Nude;Mice Transgenic;Molecular;NADPH Oxidase;NF-kappa B;Nose;Nuclear;Occupational;Occupational Groups;Oral;Organ;Oxidative Stress;Pathway interactions;Play;Prevention strategy;Production;Protein Processing Post-Translational;Reaction;Reactive Oxygen Species;Risk Assessment;Role;Signal Transduction;Spin Trapping;Stress;Superoxides;Techniques;Testing;Transcription Factor AP-1;Water;cancer risk;carcinogenesis;carcinogenicity;cdc42 GTP-Binding Protein;cell injury;cell transformation;chromium hexavalent ion;free radical oxygen;in vivo;oxidation;response;transcription factor;tumorigenesis


application_id: 7350756
project_number: 1R01EY018603-01
project_title: Molecular Regulation of Epithelial-Mesenchymal Transitions
administering_ic: NEI
award_notice_date: 2009-07-17
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: EY
serial_number: 018603
program_official: SHEN, GRACE L
project_start_date: 2009-08-01
project_end_date: 2011-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Heterozygous mutations in the ZFHX1A zinc finger homeodomain transcriptional repressor in humans cause posterior polymorphous corneal dystrophy a pathologic epithelization of the corneal endothelium. In mutant mice there are also epithelial vs. mesenchymal-like transition defects in the corneal endothelium with acquisition of E cadherin expression and loss of vimentin expression. Such epithelial/ectodermal vs. mesenchymal transition defects are also evident in the embryonic retina optic nerve cartilage mesenchyme and subventricular zones of the brain. These defects are also characterized by expansion of the epithelial marker E-cadherin and contraction of the mescenchymal/ectodermal markers vimentin and GFAP. At these affected sites there is also induction of cell proliferation inhibitor genes and accordingly diminished proliferation is seen at these sites in mutant embryonic tissues in mice injected with BrdU. Similar epithelial vs. mesenchymal transition defects are recapitulated in cells cultured from mutant embryos and the proliferative defects are also evident thereby providing a culture model to study the biochemistry of ZFHX1A action. We propose a series of experiments to assess the mechanism of transcriptional control by ZFHX1a and thus its molecular role in defining a balance between epithelia vs. mesenchymal phenotype and control of cell proliferation in vivo and in cultured cells.

project_terms:
Affect;Binding (Molecular Function);Biochemistry;Boxing;Brain;Bromodeoxyuridine;CDKN2A gene;Cartilage;Cell Aging;Cell Culture Techniques;Cell Cycle;Cell Cycle Arrest;Cell Proliferation;Cells;Complex;Corneal Endothelium;Corneal dystrophy;Cultured Cells;Defect;Dependence;Diagnostic Neoplasm Staging;Disease;E-Cadherin;EP300 gene;Ectoderm Cell;Elements;Embryo;Epigenetic Process;Epithelial;Epithelial Cells;Epithelium;Equilibrium;Eye;Face;Family;Fibroblasts;Foundations;Gene Targeting;Genes;Genetic Transcription;Glial Fibrillary Acidic Protein;Human;Knowledge;Loss of E-cadherin Expression;Lysine;Malignant Neoplasms;Mediating;Mesenchymal;Mesenchyme;Modeling;Modification;Molecular;Mus;Mutant Strains Mice;Mutation;Neoplasm Metastasis;Optic Nerve;Palate;Pathologic;Pathway interactions;Phenotype;Pigment Epithelium;Plasminogen Activator Inhibitor 1;Proliferating;Promotor (Genetics);Regulation;Repression;Retina;Role;Series;Serum Response Factor;Signal Transduction;Site;Smooth Muscle Actin Staining Method;Snails;T-Lymphocyte;TP53 gene;Therapeutic;Transcription Coactivator;Transcription Repressor/Corepressor;Transcriptional Regulation;Transferase;Up-Regulation (Physiology);Vimentin;Zinc Fingers;cancer cell;design;embryo tissue;epithelial to mesenchymal transition;falls;gene repression;homeodomain;in vivo;inhibitor/antagonist;mutant;outcome forecast;overexpression;premature;research study;senescence;skeletal;subventricular zone;transcription factor

public_health_relevance:
Transition of cells from and epithelial to a mesenchymal phenotype is a key initiator in all fibrotic diseases. And it also initiates a metastatic phenotype in late stage cancers. A set of transcription factors including ZFHX1a regulate epithelial and mesenchymal genes to control normal epithelial vs. mesenchymal balance in vivo and deregulation of these factors is important for initiation of fibrotic disease and cancer metastasis. Studies proposed here are directed at the molecular mechanism of how ZFHX1a regulates transcription. Such fundamental knowledge should provide a foundation for developing therapeutic approaches aimed at controlling fibrotic disease and cancer metastasis.


application_id: 7350421
project_number: 1R01HL090826-01
project_title: Central Nervous System Mechanisms of Obesity Hypertension
administering_ic: NHLBI
award_notice_date: 2008-02-15
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 090826
program_official: THRASHER, TERRY N
project_start_date: 2008-02-15
project_end_date: 2013-01-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 7258571
contact_pi: STOCKER, SEAN 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): Risk estimates from the Framingham Heart Study indicate that ~75% of essential hypertension in men and 65% of essential hypertension in women is largely attributed to excess body weight and obesity. Convincing evidence from both clinical studies and animal models demonstrates that elevated sympathetic outflow to the kidney and hindlimb vasculature plays a pivotal role in the pathogenesis of obesity-induced hypertension. Despite the important relationship between body weight or adiposity and activation of the sympathetic nervous system little is known regarding the neural pathways and cellular mechanisms that underlie the sustained increase in sympathetic outflow and arterial blood pressure during obesity. The long term goal of our laboratory is to identify the neural pathways and cellular mechanisms that increase sympathetic outflow and blood pressure in obesity. Two afferent signals to the brain postulated to mediate the elevated sympathetic outflow and blood pressure in obesity are hyperinsulinemia and hyperleptinemia. Our working hypothesis is that diet-induced obesity increases circulating insulin and leptin to activate a descending circuit from the arcuate nucleus to the hypothalamic paraventricular nucleus. Subsequent receptor activation in the hypothalamus increases the discharge of sympathetic neurons in the hypothalamic paraventricular nucleus to enhance excitatory drive to the brainstem and spinal cord. This enhanced excitatory drive increases sympathetic outflow and arterial blood pressure. In this application we will use state-or-the-art electrophysiological approaches to identify the central mechanisms that support obesity-induced hypertension. Specific aim 1 will identify the cellular mechanisms within the hypothalamic paraventricular nucleus by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 2 will identify the cellular mechanisms within the rostral ventrolateral medulla by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 3 will identify the mechanisms within the hypothalamic paraventricular nucleus and rostral ventrolateral medulla that support the elevated sympathetic outflow and blood pressure in a rodent model of diet-induced obesity. Our rationale for this project is that identification of the neural pathways and mechanisms that mediate the sympathoexcitatory actions of insulin and leptin and how these pathways ultimately contribute to obesity-induced hypertension will provide a framework for the development of novel therapeutic treatments.

project_terms:
Acute;Angiotensin II;Animal Model;Arts;Blood Pressure;Body Weight;Brain;Brain Stem;Chronic;Clinical Research;Data;Development;Diet;Elevation;Essential Hypertension;Framingham Heart Study;Glutamate Receptor;Glutamates;Goals;Hindlimb;Hormones;Human;Hyperinsulinism;Hypertension;Hypothalamic structure;Insulin;Kidney;Laboratories;Leptin;Mediating;Melanocortin 4 Receptor;Modeling;Nerve;Neural Pathways;Neuraxis;Neurons;Neurotransmitter Receptor;Neurotransmitters;Obesity;Pathogenesis;Pathway interactions;Phenotype;Plasma;Play;Publishing;Rattus;Receptor Activation;Receptor Angiotensin Type 1;Renin-Angiotensin System;Risk Estimate;Rodent;Rodent Model;Role;Science of neurochemistry;Signal Transduction;Spinal;Spinal Cord;Structure of nucleus infundibularis hypothalami;Structure of paraventricular nucleus;Sympathetic Nervous System;Synapses;Techniques;Woman;Work;in vivo;men;neuromechanism;neurotransmission;novel therapeutics;research study;response


application_id: 7348349
project_number: 5R01AG026711-02
project_title: Role of Neutral Sphingomyelinase-2 in aging
administering_ic: NIA
award_notice_date: 2008-02-14
application_type: 5
activity_code: R01
ic: AG
serial_number: 026711
program_official: FINKELSTEIN, DAVID B
project_start_date: 2007-02-15
project_end_date: 2012-01-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-02-15
project_terms:
Acute-Phase Proteins;Acute-Phase Reaction;Adenoviruses;Affect;Age;Age of Onset;Aging;Aging-Related Process;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bypass;CCAAT-Enhancer-Binding Proteins;Caloric Restriction;Cell Aging;Cell Line;Cells;Cellular Stress Response;Ceramides;Characteristics;Cytokine Signaling;Defect;Development;Doctor of Philosophy;Dose;Elderly;End Point;Endocrine;Exhibits;Figs - dietary;GW 4869;Gene Silencing;Genes;Glutathione;Glutathione Disulfide;Goals;Hepatocyte;IRAK1 gene;IRAK1 protein human;Immune system;In Vitro;Incidence;Inflammation;Inflammatory;Injection of therapeutic agent;Interleukin-10;Interleukins;Link;Liver;Longevity;MAPK8 gene;Macrophages Peritoneal;Measures;Mediating;Mediator of activation protein;Molecular;Mortality Vital Statistics;Neuroglia;Oligonucleotides;Organism;Oxidative Stress;Pattern;Pharmaceutical Preparations;Phenotype;Play;Process;Protein Overexpression;Protein Phosphatase 2A Regulatory Subunit PR53;Rate;Rattus;Research Personnel;Role;Signal Pathway;Sphingomyelinase;Stream;Stress;Testing;Transcriptional Activation;Ubiquitination;Up-Regulation (Physiology);adenoviral-mediated;aged;biological adaptation to stress;feeding;functional decline;immune function;in vivo;inhibitor/antagonist;juvenile animal;novel;practical application;prevent;programs;receptor;research study;response;scyphostatin


application_id: 7347262
project_number: 2P01AG005119-20A1
project_title: AB AND NADPH OXIDASE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 0012
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
4 hydroxynonenal;APP-PS1;Ablation;Affect;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Attenuated;Automobile Driving;Biochemical;Brain;Brain region;Cell Death;Cerebellum;Cessation of life;Characteristics;Clinical;Data;Dementia;Deposition;Diagnostic;Dose;Free Radicals;Frontotemporal Dementia;Future;Genetic;Genetic Techniques;Hippocampus (Brain);Histological Techniques;Human;Impairment;In Vitro;Inferior;Inflammation;Inflammatory;Injury;Knock-in Mouse;Link;Lobule;Measures;Mediating;Methods;Mice Transgenic;Microglia;Mitochondria;Modeling;Monitor;Mus;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neuroglia;Neuronal Injury;Neurons;Oxidases;Oxidation-Reduction;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Physiological;Population;Production;Proteins;RNA;Reactive Oxygen Species;Regulation;Respiratory Burst;Role;Senile Plaques;Signal Transduction;Societies;Specimen;Staging;Structure of middle temporal gyrus;Sum;System;Testing;Therapeutic Intervention;Time;Tissue Banks;Tissues;acetovanillone;age related;amyloidogenesis;attenuation;base;disorder control;in vivo;indexing;inhibitor/antagonist;innovation;mild cognitive impairment;mind control;mouse model;neuron loss;neuropsychological;neurotoxic;neurotoxicity;nitration;novel;novel strategies;oxidation;pre-clinical;research study;response


application_id: 7347261
project_number: 2P01AG005119-20A1
project_title: AB AND RAGE INTERACTIONS IN ALZHEIMER'S DIESEASE
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 0011
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Affinity;Alzheimer's Disease;Amyloid beta-Protein;Biology;Data;Deposition;Glycosylation End Products Advanced;Goals;Laboratories;Lead;Ligands;Mediating;Mus;Pathogenesis;Pilot Projects;Proteins;Reporting;Testing;Toxic effect;Transgenic Organisms;amyloidogenesis;in vivo;mouse model;neurotoxicity;novel therapeutics;receptor;receptor for advanced glycation endproducts


application_id: 7347260
project_number: 2P01AG005119-20A1
project_title: BRAIN PROTEIN OXIDATION IN AD MCI AND PCAD: ROLES OF AB AND PIN1
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 0010
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Accounting;Affect;Affinity;Age-Months;Alanine;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Autopsy;Binding (Molecular Function);Binding Sites;Biological Assay;Blotting Western;Brain;Brain region;Caenorhabditis elegans;Cerebellum;Cerebral cortex;Cessation of life;Codon Nucleotides;Collaborations;Cysteine;Data;Dementia;Dependovirus;Deposition;Depressed mood;Digestion;Disease;Electrospray Ionization;Elevation;Ensure;Environment;Event;Free Radicals;Functional disorder;Human;Hydrophobicity;In Vitro;Individual;Institutes;Isomerase;Knock-in Mouse;Laboratories;Lead;Length;Leucine;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Methionine;Methodology;Methods;Mice Transgenic;Microtubules;Modeling;Modification;Mus;Mutate;N-terminal;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Norleucine;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathology;Peptides;Peptidylprolyl Isomerase;Persons;Play;Positioning Attribute;Process;Production;Proline;Property;Protein Binding;Protein Biosynthesis;Protein Dephosphorylation;Proteins;Proteomics;Purpose;RNA;RNA Small Interfering;Recombinants;Reports Progress;Research;Research Personnel;Role;Senile Plaques;Series;Serine;Side;Site;Solubility;Source;Specificity;Staging;Tauopathies;Testing;Therapeutic Intervention;Thinking function;Threonine;Time;Toxic effect;Transgenic Organisms;Triose-Phosphate Isomerase;Wild Type Mouse;aging brain;aminoacid sequence of protein;base;disorder control;genetic regulatory protein;in vivo;in vivo Model;indexing;insight;knock-down;mild cognitive impairment;mind control;mutant;nervous system disorder;neurotoxic;neurotoxicity;novel;numb protein;oxidation;peptide A;pre-clinical;success;tandem mass spectrometry;tau Proteins;tau phosphorylation;therapeutic target


application_id: 7347259
project_number: 2P01AG005119-20A1
project_title: BETA AMYLOID-INDUCED RNA OXIDATION AS A MEDIATOR OF AD PATHOGENESIS
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 0009
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
APP-PS1;Acrolein;Affect;Age;Age-Months;Alzheimer's Disease;Amino Acid Substitution;Amyloid beta-Protein;Antibodies;Antioxidants;Attenuated;Autopsy;Biological Markers;Brain;Brain region;Cerebellum;Cerebral cortex;DNA;Data;Deposition;Development;Elevation;Enzymes;Event;Exhibits;Feasibility Studies;Free Radicals;Frontotemporal Dementia;Functional disorder;Guanine;Health;Hippocampus (Brain);Histone Deacetylase Inhibitor;Human;Immunohistochemistry;Impairment;In Vitro;Individual;Inferior;Injury;Ions;Knock-in Mouse;Knowledge;L-Selenomethionine;Link;Lipid Peroxidation;Lipids;Lobule;Manganese Superoxide Dismutase;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Methods;Mice Mutant Strains;Mice Transgenic;Microscopy Confocal;Mitochondria;Modification;Molecular Target;Monitor;Motor Cortex;Mus;NADPH Oxidase;Nerve Degeneration;Neuronal Injury;Neurons;Nuclear;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Pattern;Peptides;Phase;Play;Population;Preventive;Property;Protein Biosynthesis;Proteins;RNA;RNA Messenger;Range;Rate;Relative (related person);Ribosomal RNA;Rodent;Role;Rotenone;Secondary to;Selenomethionine;Specificity;Specimen;Staging;Standards of Weights and Measures;Structure of middle temporal gyrus;Study Section;Superoxide Dismutase;Testing;Therapeutic;Therapeutic Agents;Time;Toxin;Transfer RNA;Translations;United States;Wild Type Mouse;Yeasts;adduct;amyloidogenesis;base;copper zinc superoxide dismutase;disorder control;enzyme activity;glutathione peroxidase;in vivo;in vivo Model;indexing;inhibitor/antagonist;male;mild cognitive impairment;mind control;mouse model;neurotoxicity;novel therapeutics;oxidation;oxidative DNA damage;pre-clinical;prevent;programs;response;stressor;time use;usability


application_id: 7347258
project_number: 2P01AG005119-20A1
project_title: ANIMAL CORE
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 9005
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
APP-PS1;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Biochemical;Blotting Southern;Brain;Breeding;Cells;Clinical;Complex;Condition;Consultations;Crosses Genetic;Cultured Cells;Deposition;Development;Disease;Embryo;Ensure;Excision;Funding;Generations;Genes;Genetic;Genotype;Histologic;Histopathology;In Vitro;Individual;Infant Newborn;Knock-in Mouse;Knock-out;Leucine;Mediating;Methionine;Methods;Mice Transgenic;Microglia;Molecular;Monitor;Mus;Mutate;Mutation;NADP;NADPH Oxidase;Neurons;Numbers;Oxidative Stress;Pathologic;Phenotype;Polymerase Chain Reaction;Pregnancy;Primary Cell Cultures;Rattus;Research Design;Research Personnel;Rodent;Role;Schedule;Source;Staging;Support of Research;Techniques;Time;Transgenic Organisms;Wild Type Mouse;Work;animal data;base;brain cell;desire;postnatal;prevent;programs;pup;research study;success


application_id: 7347257
project_number: 2P01AG005119-20A1
project_title: BETA-AMYLOID CORE
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 9004
contact_pi_person_id: 8425703
contact_pi: MURPHY, PAUL M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
AP40;Adherence (attribute);Amyloid;Amyloid beta-Protein;Data;Deposition;End Point;Evaluation;Human;In Vitro;Individual;Laboratories;Maintenance;Measures;Methodology;Methods;Numbers;Peptides;Physiological;Preparation;Procedures;Property;Protocols documentation;Quality Control;Research;Research Personnel;Rodent;Science of neurochemistry;Senile Plaques;Solubility;Tissues;Toxic effect;in vivo;indexing;peptide A


application_id: 7347256
project_number: 2P01AG005119-20A1
project_title: ADMINISTRATIVE CORE
administering_ic: NIA
application_type: 2
activity_code: P01
ic: AG
serial_number: 005119
suffix: A1
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O4)]
subproject_number: 9003
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Advisory Committees;Alzheimer's Disease;Amyloid beta-Protein;Animal Welfare;Animals;Archives;Biometry;Clinical;Communication;Consensus;Consult;Consultations;Data;Databases;Endowment;Ensure;Equipment;Evaluation;Frontotemporal Dementia;Funding;Future;Goals;Guidelines;Individual;Kentucky;Knowledge;Lead;Leadership;Learning;Measures;Modeling;Names;Oxidative Stress;Pathogenesis;Patients;Prevention;Preventive;Program Reviews;Purpose;Reporting;Research;Research Design;Research Personnel;Role;Sample Size;Science of neurochemistry;Scientist;Specialist;Specimen;Structure;Supervision;Therapeutic;Universities;base;data management;disorder control;indexing;mild cognitive impairment;neuropathology;patient oriented;pre-clinical;programs


application_id: 7347007
project_number: 5R01CA119028-04
project_title: Mechanisms of As-Induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2008-01-23
application_type: 5
activity_code: R01
ic: CA
serial_number: 119028
program_official: POLAND, ALAN P
project_start_date: 2006-02-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-E(02)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-01-01
project_abstract:
DESCRIPTION (provided by applicant): Arsenic (As) is a well-documented human carcinogen. Environmental and occupational exposures to As-containing compounds are major public health issues. Understanding the mechanism of As-induced carcinogenesis is very important for early detection for risk assessment for establishment of an exposure standard and for development of intervention and prevention strategies. While increasing evidence has linked arsenic exposure and generation of reactive oxygen species (ROS) we do not clearly understand the exact nature of the specific reactive species the source and mechanism of ROS generation the sequence of formation of different reactive species and the specific species that are responsible for the arsenic-induced carcinogenesis. The goal of this proposal is to test the hypothesis that As-induced carcinogenesis is mediated by oxidative stress. To test this hypothesis we will: (a) identify the molecular mechanism of As-induced ROS generation in cells with emphasis on 02.- radical generation since this radical is a precursor of other reactive oxygen species; (b) develop and apply an in vivo electron spin resonance (ESR) method for detection and identification of As-induced free radical generation in living animals; (c) determine oxidative stress lipid peroxidation protein oxidation and oxidative DNA damage following As exposure in vivo; and (d) elucidate the role of oxidative stress in Cr(VI)-induced cell transformation and tumorigenesis. We will use As-treated HaCat cells to examine As-induced tumorigenesis in athymic nude mice and investigate the involvement of specific ROS species. We anticipate that As generates ROS which cause activation of NF-KB and activator protein (AP-1) leading to tumorigenesis in nude mice. The methods used in the proposal are multi-disciplinary representing a combination of physical chemical and molecular approaches. The results obtained from this proposal will provide a fundamental understanding concerning the role of ROS in As-induced carcinogenesis.

project_terms:
3-nitrotyrosine;Animal Model;Animals;Antioxidants;Arsenic;Biology;Carcinogens;Cells;Chemicals;Chronic;DNA Damage;Detection;Development;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental and Occupational Exposure;Exposure to;Free Radicals;Generations;Glutathione Disulfide;Goals;Health;Human;Hydroxyl Radical;Intervention;Kidney;Life;Link;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of urinary bladder;Measures;Mediating;Medicine;Methods;Mice Nude;Microscopy Confocal;Molecular;Nature;Not Defined;Oxidative Stress;Play;Prevention strategy;Protein Overexpression;Protein Processing Post-Translational;Proteins;Rate;Reaction;Reactive Oxygen Species;Research Personnel;Risk Assessment;Role;Signaling Protein;Skin;Skin Carcinogenesis;Source;Spin Trapping;Standards of Weights and Measures;Superoxide Dismutase;Superoxides;Techniques;Testing;Tumorigenicity;cancer risk;carcinogenesis;catalase;cell injury;cell transformation;chromium hexavalent ion;design;free radical oxygen;glutathione peroxidase;in vivo;inhibitor/antagonist;keratinocyte;oxidation;oxidative DNA damage;programs;public health medicine (field);response;therapy development;tumor;tumorigenesis


application_id: 7345483
project_number: 5U10HD045934-05
project_title: Center for Pediatric Clinical Pharmacology Research
administering_ic: NICHD
award_notice_date: 2007-12-20
opportunity_number: RFA-HD-03-001
application_type: 5
activity_code: U10
ic: HD
serial_number: 045934
program_official: GIACOIA, GEORGE
project_start_date: 2004-03-08
project_end_date: 2010-12-31
study_section: ZHD1-DSR-A(01)
contact_pi_person_id: 2311234
contact_pi: SULLIVAN, JANICE E
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):  This proposal is submitted in response to RFA HD-O3-O01 to obtain support for the KCPCRU Louisville KY as a sites in the NICHD PPRU Network. Long-term proqrammatic objectives of this proposal are: 1) To expand the active participation of the KCPCRU in multi-centered collaborative Clinical trials for the purpose of generating high-quality scientIfic and clinical data to support age-appropriate labeling of new currently marketed and off-patent pharmacologic agents in newborns infants and children 2) To further develop the interactive network of basic and clinical scientists at the University of Louisville dedicated to conducting translational research with a focus on characterizing the effect of human development on biologic targets key pathogenic mediators and physiologic surrogates of pharmacologic response in children 3) To fulfill the educational mission through the development of a multi-disciplinary training program in which physicians pharmacists and nurses can gain expertise in Pediatric Clinical Pharmacology. These objectives will be accomplished by the following specific aims: 1) To design and conduct collaborative clinical trials within the PPRU network NICI-ID NIH and FDA regarding pharmacokinetics pharmacodynamics safety and efficacy of new currently marketed and off-patent pharmacologic agents in preterm and term newborns infants children and adolescents Priority will be given to PPRU network studies 2) To develop an independent "mini-core" of the U of L Proteomics Laboratory that will serve as a complementary resource for network-sponsored trials and support the application of novel proteomic techniques in pediatric pharmacology studies 3) To apply proteomic techniques to identify develop validate andlor extrapolate from adult studies on biomarkers of diagnosis prognosis efficacy toxicity and disease activity 4) To characterize the effects of development disease and genetics on biologic targets key pathogenic mediators and physiologic surrogates of pharmacologic response in children using a translational science approach 5) To promote the development of students residents fellows and junior faculty in the discipline of Pediatric Clinical Pharmacology by providing a multi-faceted training experience encompassing clinical service research and didactic lectureship. The investigators and applicant institution are caoable of achieving these aims based upon: 1 )an excellent infrastructure to support the clinical and laboratory research components of our program 2)collective expertise in clinical and basic science aspects of pediatric clinical pharmacology research 3)previous and current research accomplishments including those resulting from collaborative investigations with existing PPRU network sites 4) the presence of a multi-disciplinary collaborative network of basic and clinical research scientists dedicated to the conduct of clinical pharmacology studies in children 5)presentation of 4 novel research proposals that speak directly to the program objectives and that are ideally suited for conduct within the PPRU network.

project_terms:
Address;Adolescent;Adult;Age;Basic Science;Biological Markers;Child;Childhood;Clinical;Clinical Data;Clinical Research;Clinical Services;Clinical Trials;Development;Diagnosis;Discipline;Disease;Drug Kinetics;Faculty;Forecast of outcome;Health Services Research;Hereditary Disease;Human Development;Infant Newborn;Institution;Investigation;Label;Laboratories;Legal patent;Marketing;Mediator of activation protein;Metabolism;Mission;National Institute of Child Health and Human Development;Nurses;Pharmacists;Pharmacodynamics;Pharmacology;Pharmacology Clinical;Physicians;Physiological;Process of absorption;Proteomics;Purpose;Research;Research Infrastructure;Research Personnel;Research Proposals;Research Laboratory;Resources;Safety;Scientist;Site;Students;Techniques;Toxic effect;Training;Training Programs;Translational Research;United States Food and Drug Administration;United States National Institutes of Health;Universities;base;design;experience;novel;pediatric pharmacology;programs;response


application_id: 7345464
project_number: 5R01AR049010-05
project_title: Prostaglandin E synthase in rheumatoid arthritis
administering_ic: NIAMS
award_notice_date: 2008-02-05
application_type: 5
activity_code: R01
ic: AR
serial_number: 049010
program_official: MANCINI, MARIE
project_start_date: 2004-12-01
project_end_date: 2009-11-30
study_section: Special Emphasis Panel[ZRG1-ACTS(01)Q]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
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: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant):   The effectiveness of non-steroidal anti-inflammatory drugs and specific cyclooxygenase (COX)-2 inhibitors for treatment of arthritis provides clinical evidence that increased prostaglandin (PG) production in joint tissues contributes to symptoms of pain swelling and stiffness. PG biosynthesis requires the sequential action of COX and PG synthase enzymes. After stimulation with pro-inflammatory cytokines there is a preferential increase in PGE2 in many different cell types including synovial fibroblasts. We demonstrated that increased PGE2 in response to pro-inflammatory cytokines in human primary synovial cells is due to induction of microsomal PGE synthase (mPGES)-1. The overall goal of this proposal is to characterize the role of mPGES-1 and other PGE synthases in eicosanoid biosynthesis in immune inflammatory arthritis. We hypothesize a requirement for mPGES-1 to achieve maximal PGE2 production and a role for mPGES-1-derived PGE2 in shaping the immune inflammatory response. We propose to determine the specific role of mPGES-1 relative to other synthetic enzymes for biosynthesis of PGE2 in human synovial fibroblasts using specific COX enzyme inhibitors and inhibitory RNA (RNAi). We will investigate eicosanoid production pathways in cells from mice deficient for COX-1 COX-2 or mPGES-1. Expression of the COX and PGES enzymes in synovial tissues from patients with arthritis or non-arthritic subjects and their relative subcellular localization will be determined. In addition we will examine the consequences of mPGES-1 deficiency for innate and acquired immunity in genetically null mice. We will determine eicosanoid and cytokine profiles of macrophages splenocytes and dendritic cells in mPGES-1 null mice. We will determine the impact of mPGES-1 deficiency on dendritic cell phenotype and function. We will determine the role of PGE2 on immune versus inflammatory mechanisms of arthritis using the collagen-induced arthritis and K/BxN serum models. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.

project_terms:
Adjuvant Arthritis;Anabolism;Ankylosing spondylitis;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Arthritis;Biological;Bone Marrow;CD4 Positive T Lymphocytes;Cardiovascular system;Cell Fractionation;Cell Line;Cell membrane;Cells;Chromatography High Pressure Liquid;Clinical;Collagen;Collagen Arthritis;Condition;Coxibs;Data;Degenerative polyarthritis;Dendritic Cells;Dinoprostone;Effectiveness;Eicosanoid Production;Eicosanoids;Embryo;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzyme-Linked Immunosorbent Assay;Enzymes;Epithelial;Epoprostenol;Event;Fatty Acids;Fatty Acids Nonesterified;Fibroblasts;Genotype;Glutathione;Goals;Helper-Inducer T-Lymphocyte;Human;Human Cell Line;Immune;Immune response;Immunization;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Interleukin-4;Interleukins;Joints;K/BxN model;Kidney;Localized;Macrophages Peritoneal;Measures;Mediating;Mice Knockout;Modeling;Monoclonal Antibody HuM291;Muromonab-CD3;Mus;Numbers;PGE synthase 1 mouse;Pain;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Principal Investigator;Production;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Prostaglandins E;Prostaglandins I;Protein Isoforms;RNA;RNA Interference;Rattus;Relative (related person);Reporting;Research Personnel;Resistance;Rheumatoid Arthritis;Risk;Role;Serum;Shapes;Site;Splenocyte;Staining method;Stains;Swelling;Symptoms;Synovial Cell;TNF protein human;Therapeutic Intervention;Time;Tissues;Toxic effect;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;acquired immunity;base;cell type;cyclooxygenase 1;cyclooxygenase 2;cytokine;eicosanoid metabolism;enzyme biosynthesis;gastrointestinal;in vivo;inhibitor/antagonist;macrophage;neutrophil;progesterone 11-hemisuccinate-(2-iodohistamine);programs;prostaglandin E synthase;response;synthetic enzyme


application_id: 7344837
project_number: 5R03AI068934-02
project_title: Rhabdovirus phosphoproteins: RNA silencing and complex formation
administering_ic: NIAID
award_notice_date: 2008-01-18
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AI
serial_number: 068934
program_official: CASSETTI, CRISTINA
project_start_date: 2007-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-G(90)S]
contact_pi_person_id: 8472940
contact_pi: GOODIN, MICHAEL M
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC 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: The family Rhabdoviridae has members that represent some of the greatest threats to human animal and plant health including Rabies virus of humans and animals Infectious hematopoietic necrosis virus offish and Rice yellow stunt virus of plants. By comparing the functions of proteins encoded by different rhabdoviruses we hope to fulfill our long-term goal which is to understand how new viral pathogens emerge via adaptive changes required for replication in different host cells. The proposed experiments will test the hypothesis that phosphorylated "P" proteins encoded by plant negative-strand RNA viruses have novel functions relative to the cognate proteins from animal viruses which are required for the successful infection of plant cells. My lab has provided experimental evidence that extends the multiple activities of P to include that of RNA silencing suppressor (RSS). We have also made the novel discovery that this activity can be regulated by its interaction with a second viral protein. The objective of this application is to elucidate the mechanism by which SYNV-P functions as an RSS and how this activity is moderated by interaction with other SYNV proteins. Specific Aim 1: To test the hypothesis that the RSS activity of SYNV-P is mediated via direct binding to RNA. Specific Aim 2: To test the hypothesis that RSS activity is conserved among rhabdovirus P proteins. Specific Aim 3: To test the hypothesis that the RSS activity of SYNV-P can be modulated via interactions with the nucleocapsid (N) or matrix (M) proteins. Additionally our expertise in purifying N and P protein complexes from insect and bacterial cells will enable us to take advantage of an NIH-funded project at the University of Kentucky that could determine the X-ray crystal structures for these proteins. To date the structures of the N and P proteins encoded by rhabdoviruses with animal hosts have not been determined. Therefore if successful the crystallization of any of these proteins in homo- or heterogeneous complexes would represent an important contribution valued by a large community of researchers from different disciplines. In sum this research is significant for its contribution to the basic understanding of the molecular and cell biology of rhabdoviruses particularly those of plants and has the potential to lead to the development of novel control strategies for a variety of diseases.

project_terms:
Affinity;Animals;Binding (Molecular Function);Cell Nucleus;Cells;Cellular biology;Communities;Complex;Crystallization;Data;Development;Discipline;Disease;Electrophoretic Mobility Shift Assay;Family;Fishes;Funding;Future;Genes;Glycine dehydrogenase (decarboxylating);Goals;Health;Human;In Vitro;Infection;Infectious hematopoietic necrosis virus;Insecta;Kentucky;Lasers;Lead;Length;M Protein multiple myeloma;Mediating;Methods;Microscope;Molecular;Nucleocapsid;Phosphoproteins;Plant Viruses;Plants;Play;Polymerase;Proteins;RNA;RNA Binding;RNA Interference;RNA Recognition Motif;RNA Viruses;RNA Double-Stranded;RNA Viral;RNA-Binding Proteins;Rabies virus;Reagent;Relative (related person);Replication-Associated Process;Research;Research Personnel;Rhabdoviridae;Rice;Roentgen Rays;Role;Scanning;Sonchus;Structure;Sum;System;Testing;Transcription Genetic;United States National Institutes of Health;Universities;Viral;Viral Proteins;Virus;Viruses Animal;base;in vivo;insight;member;mutant;novel;pathogen;protein function;protein structure;research study;transcription factor


application_id: 7344779
project_number: 5K23DE015298-03
project_title: Central Pain Processing in Chronic Face Pain:fMRI Study
administering_ic: NIDCR
award_notice_date: 2008-01-17
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015298
program_official: HARDWICK, KEVIN S
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7351795
contact_pi: DE LEEUW, RINSKJE
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal for a K23 "Mentored Patient-Oriented Research Career Development Award" will provide thecandidate with five years of continuous funding to gain a broad knowledge in the design and conduct ofcomplex clinical oral health trials. This training will enhance the research environment of the Orofacial PainCenter and mentoring capacity of the University of Kentucky College of Dentistry. The candidate earned aPhD in General Medicine from the University of Groningen and received three years of postgraduategraduate training in Orofacial Pain at the University of Kentucky. This award would allow the candidate toevolve to an independent investigator and would prepare the candidate to successfully mentor MS and PhDcandidates in orofacial pain research. The training program consists of two phases: a didactic componentemphasizing courses in research design biostatistics data analysis and epidemiology and a researchphase involving a neuroimaging investigation of central pain processing in patients with chronic face pain.Three specific aims are proposed in this training application: Specific Aim 1. To assess the presence of painaugmentation in patients with chronic masticatory myofascial pain; Specific Aim 2. To investigate differencesin location and extent of activation of brain regions involved in trigeminal pain processing between patientswith chronic masticatory muscle pain and pain-free volunteers; and Specific Aim 3. To investigate theinfluence of estrogen level on cerebral activation in response to an acute experimental pain stimulus inpatients with chronic masticatory muscle pain and pain-free volunteers. Dr. Charles Carlson PhD ProfessorDepartments of Psychology and Oral Health Science and research director of the Orofacial Pain Center andDr. Don Gash PhD Alumni Professor and Chair Department of Anatomy and Neurobiology and director ofthe Magnetic Resonance Imaging and Spectroscopy Center will mentor the candidate. There is limitedinformation on cerebral activation in response to stimulation of trigeminal structures in healthy pain-freevolunteers as well as in chronic face pain patients. The available data support that there are importantdifferences in the cerebral processing of pain in chronic pain patients compared to pain-free subjects.Moreover the existing data suggest that in chronic pain conditions the medial pain system the structuresassociated with the processing of the emotional-affective component of pain exhibits altered activity.Additionally there is a lack of information about the influence of estrogen on the central processing of pain.The available data suggest that estrogen may have an inhibitory / anxiolytic effect on the perception of painpossibly by modulating the endogenous opioid system. Because neuroimaging data on this topic are scarceand chronic pain conditions are predominant in women of reproductive age the role of estrogen on painshould be further explored.

project_terms:
Acute;Acute Pain;Address;Affect;Affective;Age;Age of Onset;Animals;Anterior;Anti-Anxiety Agents;Anxiety;Area;Award;Awareness;Behavioral;Biometry;Brain;Brain imaging;Brain region;Burn injury;Burning Mouth Syndrome;Cerebrum;Chronic;Clinical;Cognitive;Complex;Condition;Data;Data Analyses;Dentistry;Diagnosis;Distant;Doctor of Philosophy;Emotional;Endogenous Opiates;Environment;Epidemiology;Estrogens;Etiology;Exhibits;Facial Pain;Female;Female of child bearing age;Fibromyalgia;Funding;Gonadal Steroid Hormones;Head and neck structure;Human;Hyperalgesia;Hypersensitivity;Incidence;Intervention;Investigation;Irritable Bowel Syndrome;Kentucky;Knowledge;Life;Limbic System;Location;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Malignant Neoplasms;Mandible;Masticatory muscles;Measures;Medial;Medicine;Menstrual fluid;Menstruation;Mentored Patient-Oriented Research Career Development Award;Mentors;Migraine;Modality;Monitor;Mouth Diseases;Musculoskeletal Diseases;Musculoskeletal Pain;Myalgia;Neuraxis;Neurobiology;Neurons;Numbers;Opioid;Oral health;Outcome;Pain;Pain Clinics;Pain Disorder;Pain Research;Pain Threshold;Pain management;Pain Orofacial;Pain-Free;Participant;Pathology;Patients;Pattern;Perception;Peripheral;Personal Satisfaction;Persons;Phase;Physiological Processes;Play;Prefrontal Cortex;Pressure- physical agent;Prevalence;Principal Investigator;Process;Protocols documentation;Psychology;Puberty;Rate;Recurrent pain;Reporting;Research;Research Design;Research Personnel;Resistance;Role;Sample Size;Scanning;Science of Anatomy;Sensory;Serum;Signal Transduction;Site;Somatosensory Cortex;Spectrum Analysis;Stimulus;Stress;Structure;System;Temperature;Temporomandibular Joint Disorders;Testing;Thalamic structure;Training;Training Programs;Trigeminal Neuralgia;Trigeminal System;Trigeminal nerve structure;Universities;Woman;base;central pain;chronic neuropathic pain;chronic pain;cingulate cortex;cold temperature;college;concept;day;design;experience;health science research;human study;interdisciplinary approach;interest;male;masticatory myalgia;mechanical pressure;neuroimaging;orofacial;professor;programs;reproductive;response;volunteer


application_id: 7344745
project_number: 5R21CA123867-02
project_title: Phase I and Biological Studies of DB67 - A Blood Stable Camptothecin
administering_ic: NCI
award_notice_date: 2007-12-12
opportunity_number: PAR-04-155
application_type: 5
activity_code: R21
ic: CA
serial_number: 123867
program_official: XIE, HENG
project_start_date: 2007-01-26
project_end_date: 2008-12-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
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:
As a class the camptothecins have been widely recognized for their therapeutic potential which for manyreasons including the instability of the lipophilic lactone moiety has not been fully realized. DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog that was engineered to be bloodstable and highly potent on the basis of structure-activity relationship studies. The camptothecins have alabile a-hydroxy-5-lactone ring which hydrolyzes to yield the negatively charged carboxylate form.Compared to the uncharged lactone the negatively charged carboxylate is less likely to diffuse into cells andis often considered "inactive." Based on its blood stability and anti-tumor activity DB-67 was selected by theNCI for development through three cycles of the RAID program. Data from NCI studies and fromcollaborative efforts revealed impressive in vitro and in vivo anti-tumor activity particularly in glioma modelsbut also in melanoma and colon xenograft models. Currently DB-67 formulation and toxicology studies havebeen completed and clinical grade material is available through the NCI. Based on the extensive formulationtoxicology and pharmacokinetic profile observed in preclinical models and its potential to exert a potentanti-tumor effect in humans we hypothesize that DB-67 will be well-tolerated and efficacious in clinical trials.This grant application outlines the clinical studies and the correlative pharmacokinetic studies that will defineDB-67 disposition and toxicity in patients with refractory solid tumors. The following specific aims will beaccomplished: 1.1) To estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities(DLT) of intravenous DB-67 administered once daily for 5 days every 21 days to adults with recurrent orrefractory solid tumors in which standard therapies are not effective; 1.2) To characterize the plasmapharmacokinetics of DB-67 and metabolites after intravenous administration and relate DB-67pharmacokinetics and toxicity. Ultimately the objective is to use DB-67 as a single agent or in combinationwith other molecular-targeted therapies or cytotoxics in frontline therapy with the goal to improve overallpatient outcome.

project_terms:
Adult;Affinity;Biological;Biological Models;Blood;Blood Circulation;Camptothecin;Camptothecin Analogue;Cells;Charge;Class;Clinical;Clinical Research;Clinical Trials;Clinical Trials Phase I;Colon;Daily;Data;Development;Diffuse;Dose-Limiting;Drug Kinetics;Engineering;Enzymes;Formulations Drug;Generations;Genus Cola;Glioma;Goals;Grants Applications;Human;Hydrolysis;In Vitro;Intravenous;Lactones;Lipid Bilayers;Liver;Maximum Tolerated Dose;Mediating;Modeling;Molecular;Molecular Target;Noma;Outcome;Patients;Personal Satisfaction;Pharmaceutical Preparations;Pharmacogenetics;Phase;Plasma;Polymorphism Genetic;Pre-Clinical Model;Property;Proteins;Rapid Access to Intervention Development;Recurrence;Recurrent Malignant Neoplasm;Refractory;Serum Albumin;Solid Neoplasm;Standards of Weights and Measures;Structure;Structure-Activity Relationship;Therapeutic;Topotecan;Toxic effect;Toxicology;United States Food and Drug Administration;Water;Xenograft Model;Xenograft procedure;analog;aqueous;base;carboxylate;cytotoxic;day;drug metabolism;experience;improved;in vivo;intravenous administration;irinotecan;lipophilicity;melanoma;programs;tumor;uptake


application_id: 7344720
project_number: 5R01EY012974-06
project_title: The role of costimulatory molecules in uveitis
administering_ic: NEI
award_notice_date: 2007-11-30
application_type: 5
activity_code: R01
ic: EY
serial_number: 012974
program_official: SHEN, GRACE L
project_start_date: 2001-08-01
project_end_date: 2011-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
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: 2007-12-01
project_terms:
Acute;Animals;Anti-Inflammatory Agents;Antibodies;Autoimmune Diseases;Autoimmune Process;CTLA4-Ig;Cells;Chronic;Clinical Treatment;Combined Modality Therapy;Complex;Data;Development;Disease;Disease Progression;Disease model;Disease remission;Dose;Environmental Risk Factor;Eye;Generations;Genetic;Goals;Grant;Guanine Nucleotide Dissociation Inhibitors;Human;Immune response;Immunotherapy;Inflammation;Inflammatory;LTB4R gene;Laboratories;Leukotriene B4;Ligation;Lymphoid;MHC antigen;Mediating;Modeling;Molecular;Mus;Nature;Numbers;Onset of illness;Pathogenesis;Pathway interactions;Patients;Pattern;Phase;Protocols Treatment;Rattus;Reaction;Recruitment Activity;Recurrence;Regulation;Relapse;Research Personnel;Resistance;Rodent;Role;Signal Transduction;Study models;T memory cell;T-Cell Activation;T-Lymphocyte;Therapeutic;Therapeutic Effect;Time;Uveitis;Visit;Work;autoimmune uveitis;autoreactive T cell;cell motility;chemokine;cytokine;disorder control;human disease;insight;novel strategies;prevent;programs;protective effect;receptor;response;treatment effect;tumor


application_id: 7344680
project_number: 5R01GM077422-02
project_title: Targeting Nucleic Acids with an Integrated Vitural and Actual Screen
administering_ic: NIGMS
award_notice_date: 2008-02-28
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)]
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: 2008-02-01
project_abstract:
DESCRIPTION (provided by applicant): Nucleic acids are under-represented molecular targets for small molecule therapeutic agents even though recent research shows that unusual nucleic acid structures play a profound role in gene expression and DNA replication. We propose an innovative interdiscplinary high-throughput screening approach for the discovery of new nucleic acid-targeted therapeutic agents. Our approach integrates an actual experimental screening assay with a virtual screening assay. The former is a unique competition dialysis assay that we invented for the discovery of small molecules that target specific nucleic acid sequences or structures. In the competiton dialysis assay an array of designed nucleic acid structures and sequences are dialyzed against a common test ligand solution. At equilibirum more ligand accumulates in the dialysis cell that contains the preferred structure or sequence. The assay is thermodynamically rigorous and allows for quantitative measurement of ligand binding free energies. In our integrated approach an in silico virtual screening assay will be implemented that will contain an array of receptors that is identical to the actual array of nucleic acids used in the competiton dialysis assay. The virtual assay can easily screen millions of compounds for their selective binding to particular nucleic acid structures of functional significance. "Hits" from the virtual screen will be passed to the actual competition dialysis assay for validation. With proposed improvements the competiton dialysis can rapidly screen hundreds of compounds. Our strategy will be to identify libraries of compounds that selectively recognize particular structures with the virtual screen then to rigorously verify these "hits" by high-throughput competition dialysis. Specific plans for the development of the competition dialysis assay include : i) implementation of the assay in a 96-well plate format (facilitating automation) ii) reduction of sample volumes iii) expansion of the biologically significant nucleic acid array and iv) reduction of throughput time. The virtual and actual screens will be fully integrated by an iterative feedback loop to refine the scoring algorithm using actual data obtained from the first generation dialysis assay in which the interaction of 126 compounds with 13 nucleic acids structures was studied. Our approach matches the Road Map Initiative goals by its interdisciplinary approach and by its emphasis on expanding the toolbox available for the discovery of new therapeutics.

project_terms:
Adopted;Algorithms;Antineoplastic Agents;Automation;Base Sequence;Binding (Molecular Function);Biological Assay;Biological Factors;Cancer Biology;Cells;Clinical Trials Phase I;Computer Simulation;Computer software;DNA;DNA Binding;DNA biosynthesis;Data;Data Set;Development;Dialysis procedure;Diamidine;Docking;Drug Delivery Systems;Equilibrium;Feedback;Fluorescence;Free Energy;G-Quartets;Gene Expression;Generations;Goals;Hybrids;Intercalating Agents;Laboratories;Lead;Libraries;Ligand Binding;Ligands;Liquid substance;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Molecular;Molecular Target;Nucleic Acid Binding;Nucleic Acids;Nucleic acid sequencing;Numbers;Paste substance;Phase;Physical Dialysis;Plans Development;Play;Porphyrins;Publishing;Purpose;Research;Research Personnel;Role;Sampling;Score;Screening procedure;Site;Solutions;Specificity;Structure;System;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Transcription Genetic;Validation;Virtual Library;analytical method;cyanine dye;design;high throughput screening;innovation;intercalation;interdisciplinary approach;interest;novel;novel therapeutics;nucleic acid structure;programs;receptor;repository;small molecule;tool;virtual


application_id: 7343418
project_number: 7K08HL070304-06
project_title: Platelet Membrane Proteins in Thrombosis
administering_ic: NHLBI
award_notice_date: 2007-02-08
opportunity_number: PA-00-003
application_type: 7
activity_code: K08
ic: HL
serial_number: 070304
program_official: MONDORO, TRACI
project_start_date: 2001-08-01
project_end_date: 2007-05-31
study_section: ZHL1-CSR-M(M1)
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):                                                                                                                                    At the site of vascular injury platelet adhesion activation and aggregation      culminate in thrombus information the principle event underlying most acute        arterial thromboocculsive disorders.  Given that thrombosis is the leading          cause of death world-wide understanding the contribution of platelets to the       process is of particular importance.  Our novel observation of altered              platelet thrombus formation in mice deficient in P-selectin serves as the           basis of this proposal.  Until recently the primary function of P-selectin on      activated platelets and endothelial cells was thought to be promotion of the        initial interaction of these cells with leukocytes.  However P-selectin on         activated endothelial cells was implicated in recruitment of platelets and         our observations suggest that the protein may also play a role in promoting         platelet-platelet interactions.  Thus P-selectin and its ligand may be             involved in promoting the interactions of platelets with leukocytes                endothelial cells and with other platelets.  This proposal will determine the      role of platelet P-selectin in platelet-platelet interactions in vitro and          platelet thrombus formation in vivo.  This proposal tests the hypothesis that       P-selectin on activated platelets interacts with a specific platelet                counterreceptor and that this interaction affects platelet signaling and            influences platelet-platelet interactions mediated by alpha Ilbbeta3.              Complementary in vitro experiments will be conducted with human and mouse           platelets and mouse models of thrombosis will serve to define in vivo              function of P-selectin.  The Specific Aims are to: (1) establish an in vitro        assay of platelet adhesion to Pselectin to be used to identify the platelet         counter-receptor(s) for P-selectin (2) determine the role of P-selectin in         platelet-platelet interactions in vitro (3) determine the role of P-selectin       in models of thrombosis and (4) to delineate the contribution of platelet and      endothelial P-selectin to thrombosis and the arterial response to injury.           This work will identify a novel target for future antithrombotic strategies         and challenge the assumption that the beneficial effects of P-selectin              antagonists are exclusive to leukocytes.

project_terms:
arterioles;biological signal transduction;bone marrow transplantation;cell cell interaction;disease /disorder model;flow cytometry;genetically modified animals;hemostatics;human tissue;intravital microscopy;laboratory mouse;leukocyte adhesion molecules;ligands;membrane proteins;morphology;platelet activation;platelet aggregation;platelets;protein structure function;selectins;thrombosis;tissue /cell culture;vascular endothelium


application_id: 7343251
project_number: 5R01DE017138-03
project_title: Oral Immunity and Adjuvant Receptors
administering_ic: NIDCR
award_notice_date: 2008-02-19
application_type: 5
activity_code: R01
ic: DE
serial_number: 017138
program_official: LUNSFORD, DWAYNE
project_start_date: 2006-02-01
project_end_date: 2011-01-31
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: 2008-02-01
project_terms:
Address;Adhesins Bacterial;Adjuvant;Adjuvanticity;Agonist;Antibodies;Antigen-Presenting Cells;Antigens;Arts;Binding (Molecular Function);Biological Assay;CD4 Positive T Lymphocytes;Catalytic Domain;Cell Line;Cell Proliferation;Cell model;Cell physiology;Cholera Toxin;Class;Co-Immunoprecipitations;Complex;Data;Dendritic Cells;Engineering;Enterotoxins;Escherichia coli;Exhibits;Fluorescence Resonance Energy Transfer;Formulations Drug;Gangliosides;Genitourinary system;Human;Imaging Techniques;Immune response;Immunity;Immunity Mucosal;Immunization;Infection;Invaded;Investigation;Ligands;Lymphoid Cell;Mediating;Membrane Microdomains;Microscopy Fluorescence;Modeling;Molecular;Molecular Structure;Monitor;Mucosal Immune Responses;Mucous Membrane;Mus;Oral;Play;Point Mutation;Production;Proteins;Reagent;Research Personnel;Role;Route;Scanning;Signal Transduction;Specificity;Stimulus;Stomach;Streptococcus mutans;Structure;Structure-Activity Relationship;Surface;System;TLR2 gene;Techniques;Time;Toll-Like Receptor 2;Toll-like receptors;Toxic effect;Toxin;Up-Regulation (Physiology);Vaccines;base;cellular imaging;cytokine;ganglioside GD1a;improved;in vivo;interdisciplinary collaboration;interest;microbial;monocyte;mouse model;mutant;novel;novel vaccines;oral immunity;oral pathogen;pathogen;programs;receptor;receptor expression;respiratory;response;trafficking;transcription factor


application_id: 7343185
project_number: 5R01AA013561-05
project_title: Ethanol withdrawal and HIV-1 neurotoxicity
administering_ic: NIAAA
award_notice_date: 2008-01-31
opportunity_number: PA-02-039
application_type: 5
activity_code: R01
ic: AA
serial_number: 013561
program_official: SORENSEN, ROGER
project_start_date: 2004-02-10
project_end_date: 2009-01-31
study_section: AIDS Clinical Studies and Epidemiology Study Section[ACE]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK 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): Alcohol dependence or abuse is often observed in some populations of patients infected with human immunodeficiency virus type-1 (HIV-1). However the consequences of alcohol intake in those who are HIV- 1 infected with regard to function of the brain have been little studied. This is significant in that HIV-1 infection often results in motor and cognitive impairments collectively termed HIV-associated dementia (HAD). Long-term ethanol intake produces increased expression or sensitivity of N-methyl-D-aspartate type glutamate receptors (NMDAr). This effect may sensitize the brain to insult caused by excitotoxins such as the HIV-1 protein Tat a viral transcription factor thought to contribute to the development of HAD. In vitro and in vivo studies using Tat have shown that it causes NMDAr-mediated excitation Ca 2+ influx into neurons and neurotoxicity. Thus it was hypothesized that chronic ethanol exposure would sensitize the brain to the neurotoxic effects of Tat. The aims of these studies are to: 1. Determine if chronic ethanol ingestion sensitizes the NMDAr system to the detrimental effects of intra-hippocampal Tat injection on behavior and neuronal viability in rats; 2. Determine if Tat (1-72 and 1-86 amino acid forms) may directly interact with specific sites on the NMDAr using radioligand binding studies of rat hippocampus; 3. Determine the role of NMDAR polyamine-site over-activity and Ca 2v influx into neurons in the ability of chronic ethanol exposure to sensitize the hippocampus to Tat toxicity. These studies will employ fluorescent microscopy and immunohistoehemical methods in an organotypic slice-culture model derived from male rats; and 4. Evaluate the ability of novel synthetic NMDAr polyamine-site antagonists to attenuate the neurodegenerative and behavioral effects of ethanol and Tat exposure. In sum these studies are designed to elucidate the means by which ethanol intake sensitizes the brain to Tat toxicity and to identify potential therapeutic strategies that may be useful in reducing the incidence of neurological problems caused by HIV-1 infection in those who abuse alcohol or are alcohol-dependent.

project_terms:
AIDS Dementia Complex;Adult;Age;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcohols;Amino Acids;Animals;Attenuated;Behavior;Behavioral;Binding (Molecular Function);Binding Sites;Brain;Chronic;Cognitive deficits;Dementia;Development;End Point;Ethanol;Excitatory Neurotoxins;Exposure to;Generations;Glutamate Receptor;Glycine;Grant;HIV;HIV Seropositivity;HIV-1;Hippocampus (Brain);Impaired cognition;In Vitro;Incidence;Individual;Infection;Injection of therapeutic agent;Learning;Mediating;Memory Short-Term;Methods;Microscopy;Modeling;Motor;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Neurologic;Neurons;Patients;Pattern;Polyamines;Population;Rattus;Research Design;Role;Screening procedure;Seizures;Site;Slice;Sum;System;Therapeutic;Thinking function;Toxic effect;Viral;Withdrawal;Work;alcohol effect;alcohol exposure;cellular imaging;chronic alcohol ingestion;in vivo;male;neurotoxic;neurotoxicity;novel;radioligand;receptor binding;tat Protein;transcription factor


application_id: 7342631
project_number: 7R01NS039041-08
project_title: Neurogeneic Amplification of Pancreatitis Pain
administering_ic: NINDS
award_notice_date: 2007-06-13
application_type: 7
activity_code: R01
ic: NS
serial_number: 039041
program_official: PORTER, LINDA L
project_start_date: 2000-04-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-5(04)M]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_terms:
cancer pain;central neural pathway /tract;dorsal column;electrophysiology;functional magnetic resonance imaging;histology;laboratory rat;medulla oblongata;nociceptors;pancreas neoplasms;pancreatitis;thalamus


application_id: 7342486
project_number: 5R01CA105453-05
project_title: Novel Mechanisms of PTEN Gene Regulation
administering_ic: NCI
award_notice_date: 2008-01-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 105453
program_official: YASSIN, RIHAB R
project_start_date: 2004-02-05
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-CPA(05)M]
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: 2008-02-01
project_abstract:
DESCRIPTION (provided by applicant): The pro-apoptotic tumor suppressor gene PTEN (Phospatase and Tensin Homologue deleted from Chromosome 10) is a negative regulator of the PI-3 kinase/Akt dependent cell survival pathway. PTEN is located on chromosome 10q23 within a region that shows loss of heterozygosity in many human cancers and PTEN gene function is lost in diverse cancers either by mutation of PTEN or deletion of chromosome 10q23. However in several cancers such as non-small cell lung cancer and thyroid cancer the PTEN gene is intact and wild type but its expression is diminished. As haplo-insufficiency of PTEN is associated with tumorigenesis understanding the mechanism(s) involved in epigenetic down-regulation of PTEN is of both clinical and fundamental significance. Recent studies have shown that the PTEN pseudo-gene but not wild type PTEN gene is methylated indicating that DNA methylation is not a potential mechanism for silencing of the PTEN promoter leading to diminished PTEN gene expression. Our preliminary studies indicated that the anti-apoptotic transcriptional regulator NF-kappaB and oncogenic Ras which are over-expressed and activated in lung cancer down-regulate the expression of PTEN. Interestingly oncogenic Ras up-regulates the expression of the transcription factor Egr-1 which by itself suppresses PTEN gene expression.  The studies proposed here will address the mechanisms for down-regulation of PTEN gene expression that are functionally relevant; i.e. they result in elevated phospho-Akt levels and anti-apoptosis. We will determine the mechanisms of suppression of PTEN gene expression by NF-kappaB (Aim 1) and by oncogenic Ras (Aim 2) that confer apoptosis inhibition tumor progression and chemo- or radiation-resistance. Because these studies will elucidate novel mechanisms of PTEN tumor suppressor gene regulation by pro-survival and oncogenic factors most commonly encountered in lung cancer the findings may lead to the development of intervention strategies that can ablate the NF-kappaB or activated Ras-inducible anti-apoptotic pathways and thereby restore expression and the pro-apoptotic potential of PTEN.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Apoptosis;Apoptotic;Carcinoma Non-Small-Cell Lung;Casein Kinase 1 Alpha 1;Cell Survival;Chromosome Deletion;Chromosomes;Chromosomes Human Pair 10;Clinical;DNA Methylation;Development;Down-Regulation;EP300 gene;Epigenetic Process;Gene Expression;Gene Expression Regulation;Genes;Homologous Gene;Human;Inhibition of Apoptosis;Intervention;Ionizing radiation;Lead;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Mutation;NF-kappa B;Oncogenic;PTEN gene;Pathway interactions;Promotor (Genetics);Role;Signal Pathway;Thyroid carcinoma;Transcriptional Activation;Tumor Suppressor Genes;Up-Regulation (Physiology);chemotherapeutic agent;gene function;novel;radiation resistance;ras Oncogene;response;tensin;transcription factor;tumor;tumor progression;tumorigenesis


application_id: 7342467
project_number: 5R01NS040592-08
project_title: Axonal growth and guidance for nervous system repair
administering_ic: NINDS
award_notice_date: 2007-12-18
application_type: 5
activity_code: R01
ic: NS
serial_number: 040592
program_official: KLEITMAN, NAOMI
project_start_date: 2000-03-27
project_end_date: 2009-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(02)M]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-01-01
project_abstract:
DESCRIPTION (provided by applicant): Over 50000 peripheral nerve repair procedures are performed a year due to injury (National Center for Health Statistics 1995). These data do not include nerve injury due to tumor resection or prostatectomies. Even though the peripheral nerves regenerate well only 10 to 20% of patients that undergo surgery to repair traumatic nerve injuries show excellent to very good recovery of function. The high incidence of failed recovery is due to the misrouting of regenerating axons to their targets. This proposal is designed to better understand the potential mechanisms that direct this growth to increase functional recovery in adults. The studies will examine the role strategically expressed neurotrophins and chemorepulsive factors will have on directing the growth of sensory and motor axons into appropriate nerve branches or the spinal cord. All the experiments in this proposal will use bioreabsorbable implants to induce nerve repair and targeted gene expression of guidance factors. The first aim of these experiments will explore the use of the neurotrophins GDNF BDNF and NT-3 to induce the regeneration of sensory axon subsets across a 6mm dorsal root lesion gap and into the spinal cord. Behavioral analysis will examine recovery of mechanoreceptive and proprioceptive responses. The second to forth aim of experiments will use the femoral nerve model to examine peripheral nerve targeting after large excision lesions to that nerve. The femoral nerve contains both sensory and motor axons that normally segregate into a sensory branch (saphenous) and a motor branch (quadriceps femoris). After cut injury regeneration is mostly random in which each branch will contain a mixture of both cutanteous sensory and motor axons. The second aim will be to guide sensory axons into the saphenous branch and not the motor branch. In this study selective neurotrophins that are growth attractive for sensory axons will be expressed in the saphenous nerve and repulsive factors that are specifically inhibitory to sensory axons expressed in the motor branch. The third aim will examine neurotrophins and repulsive factors for the selective guidance of regenerating motor and proprioceptive axons into the motor branch and not the saphenous nerve. The forth aim is designed to incorporate the factors from aim 2 and 3 to optimize target directed regeneration to more normal like patterns. This aim will also develop and test clinically relevant bioreabsorbable nerve cuffs for slow release of guidance factors. This grant proposal is designed to better define the molecular mechanisms that influence axonal regeneration and guidance within the adult PNS with the ultimate goal of directing and organizing regeneration to more appropriate targets while discouraging aberrant connections.

project_terms:
Address;Adult;Axon;Back;Behavioral;Brain-Derived Neurotrophic Factor;Collaborations;Contracts;Coupled;Data;Development;Distal;Excision;Family;GDNF gene;Gene Expression;Goals;Grants Applications;Growth;Implant;Incidence;Individual;Injury;Lead;Legal patent;Lesion;Location;Modeling;Molecular;Motor;National Center for Health Statistics (U.S.);Natural regeneration;Nerve;Nerve Endings;Nerve Growth Factor 1;Nerve Growth Factor Pathway;Nerve Regeneration;Nervous system structure;Neuraxis;Neurons;Operative Surgical Procedures;Pathway interactions;Patients;Pattern;Peripheral Nerves;Peripheral Nervous System;Pharmaceutical Preparations;Play;Population;Posterior root of spinal nerve;Probability;Procedures;Prostatectomy;Protein Overexpression;Proteins;Receptor EphA1;Receptors Eph Family;Receptors Nerve Growth Factor;Recovery;Recovery of Function;Role;Semaphorin-3A;Semaphorins;Sensory;Sorting - Cell Movement;Spinal Cord;Structure of femoral nerve;Technology;Testing;Transplantation Autologous;Traumatic Nerve Injury;afferent nerve;axon growth;axon regeneration;clinically relevant;design;functional restoration;improved;nerve injury;neurotrophic factor;prevent;receptor;reconstruction;repaired;research study;response;tumor


application_id: 7342449
project_number: 5F31NS052012-03
project_title: Substance P and the tectothalamic pathway
administering_ic: NINDS
award_notice_date: 2008-01-30
application_type: 5
activity_code: F31
ic: NS
serial_number: 052012
program_official: GNADT, JAMES W
project_start_date: 2006-01-01
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-F02B(20)L]
contact_pi_person_id: 7390903
contact_pi: MASTERSON, SEAN P
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: 2008-01-01
project_abstract:
The long term goal of the proposed experiments is to determine the causes of attention impairment duringdisease. However it is first necessary to understand the organization of circuits that may contribute toattention mechanisms in the normal brain. Many studies have implicated the pulvinar nucleus as an area thatmay regulate visual attention. The rodent lateral posterior (LP) nucleus is a region comparable to inferiorregions of the primate pulvinar nucleus. The rodent LP nucleus is innervated by fibers which contain theneuropeptide substance P a neuromodulator known to facilitate neuronal firing properties. The LP nucleusreceives visual input from projection cells within an area of the superior colliculus that is substance P-immunoreactive. A combination of tract tracing immunocytochemistry electron microscopy and in vitroelectrophysiology will be used to examine the synaptic organization and functional properties of the tecto-thalamic pathway. Concomitant release of substance P with glutamate from tecto-thalamic terminals mightenhance and potentiate glutamatergic input from the superior colliculus. Because the LP nucleus projects tothe visual cortex the tecto-thalamic pathway could affect visual attention by modulating cortical circuitry.

project_terms:
Affect;Antibodies;Area;Attention;Biological Assay;Brain;Cell Nucleus;Cells;Corpora quadrigemina superior colliculus;Disease;Electric Stimulation;Electron Microscopy;Electrons;Electrophysiology (science);Fiber;Fire - disasters;Glutamates;Goals;Impairment;In Vitro;Inferior;Interneurons;Label;Lateral posterior nucleus of thalamus;Light;Microscopic;Microspheres;N-Methylaspartate;Neuromodulator;Neurons;Neuropeptides;Optics;Pathway interactions;Physiological;Potentials Synaptic;Preparation;Primates;Property;Pulvinar structure;Radiation;Rattus;Rodent;Series;Staining method;Stains;Stains Tissue;Substance P;Substance P Receptor;Synapses;Techniques;Tectum Mesencephali;Testing;Thalamic structure;Tissues;Visual;Visual Cortex;Visual attention;alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;amino 3 hydroxy 5 methylisoxazole 4 propionate;cell body (neuron);gamma-Aminobutyric Acid;immunocytochemistry;patch clamp;postsynaptic;research study;retrograde transport;vesicular glutamate transporter 1


application_id: 7341619
project_number: 5R01HL086644-02
project_title: Computer Modeling of Perlecan as a Vascular Regulator
administering_ic: NHLBI
award_notice_date: 2007-12-21
application_type: 5
activity_code: R01
ic: HL
serial_number: 086644
program_official: GOLDMAN, STEPHEN
project_start_date: 2007-01-19
project_end_date: 2010-12-31
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 1879706
contact_pi: FANNON, MICHAEL W
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-01-01
project_abstract:
Blood circulation is a complex system. At every moment a multitude of molecules are transportedsimultaneously and continuously to specific targets in the vasculature. The ability to regulate whole panelsof molecules by controlling the circulating concentration of a single moiety if discrete could provide apowerful tool to understand the causes prevention and treatment of cardiovascular disease and otherdisorders relating to blood vessels. Perlecan an important molecule in blood vessel and tumor growth couldbe such a molecule. Our hypothesis is that based on its high affinity for a number of growth factors that arecrucial to normal and pathological vascular growth and development circulating perlecan has the potential tosequester these growth factors in blood preventing their interactions with vascular surfaces. Because of thecomplexity of this system however it is difficult to characterize at a macro level using in vitro or in vivoapproaches alone. Computer modeling provides us with a powerful tool to test parameters and conditionssuch as multiple ligand interactions in solution and on vascular surfaces under flow which are crucialcomponents in developing an accurate understanding. A simulated vessel model under flow will be used totest the predictive value of the model using a variety of testable conditions. Our specific aims are to:1. Develop a model of endothelial cell binding based on the binding characteristics of three growth factorsand the proteoglycan perlecan2. Test the model using competitive binding assays with growth factors alone or in combination with otherfactors as a function of perlecan concentration3. Refine the model to mimic the interactions of the growth factors and perlecan under flow and adjust themodel to accommodate changes between what is observed in experimental assays and what is predictedbased on flow conditionsOur model will be the first step in attaining our long range goal of designing and testing Pharmaceuticals thatexploit similar regulatory characteristics. By using a systems biology approach the interrelatedness of theblood vessels and the components being transported through them will be characterized at the level of theorganism as a whole.

project_terms:
Address;Affinity;Binding (Molecular Function);Binding Sites;Binding Competitive;Biological Assay;Biological Availability;Bioreactors;Blood;Blood Circulation;Blood Vessels;Blood capillaries;Blood flow;Capillary Unspecified;Cardiovascular Diseases;Cell surface;Cells;Characteristics;Complex;Computer Simulation;Condition;Development;Disease;Elements;Endothelial Cells;Extracellular Matrix;Fibroblast Growth Factor;Goals;Growth Factor;Growth Factor Interaction;Growth and Development function;In Vitro;Kinetics;Lead;Ligands;Measures;Modeling;Neoplasms in Vascular Tissue;Numbers;Organ;Organism;Pharmacologic Substance;Predictive Value of Tests;Prevention;Proteoglycan;Pulsatile Flow;Pump;Range;Regulation;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Simulate;Site;Solutions;Surface;System;Systems Biology;Testing;Therapeutic;Tissues;Tube;base;design;in vitro Assay;in vivo;in vivo Model;novel;perlecan;prevent;programs;reaction rate;response;tool;tumor growth


application_id: 7340811
project_number: 3R01HL074185-04S1
project_title: Inhibitor ameliorates oxidative and proteolytic strees
administering_ic: NHLBI
award_notice_date: 2007-01-16
application_type: 3
activity_code: R01
ic: HL
serial_number: 074185
suffix: S1
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
project_abstract:
Endocardial endothelial (EE) dysfunction and accumulation of oxidized-matrix between endothelial and muscleare the hallmarks of congestive heart failure (CHF). The overall objective of this project is to understand themechanism of oxidized-matrix accumulation and EE dysfunction in CHF. Previous studies have suggested anassociation between induction of oxidative stress decrease in endothelial cell density activation of matrixmetalloproteinase (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 acentral hypothesis that oxidized-matrix accumulation and EE dysfunction are due to increased levels of MMPactivity and collagenolysis. These levels are associated with decreased levels of EE nitric oxide and CIMPin response to increased levels of reactive oxygen species (ROS) during protracted cycles ofischemia/reperfusion in volume overload. The increased levels of CIMP protects EE against oxidative andproteolytic stresses. We will test the central hypothesis by the following three specific aims: L Todetermine whether CIMP decreases oxidative stress by increasing EE nitric oxide concentration. Plasmaand left ventricle levels of nitric oxide ROS and nitrotyrosine will be measured in chronic volume overloadarteriovenous fistula mice treated with and without CIMP. 2_ To determine whether CIMP protein transferinhibits collagenolysis. MMP activity will be measured by in situ zymography. The levels of CIMP activitywill be measured by reverse zymography. Total collagen and its degradation fragments will be measured byWestern-blot analysis using anti-collagen antibody. 3-- To determine whether CIMP amelioratesendocardial endothelial dysfunction. Contractile responses to acetylcholine bradykinin and nitroprusside incardiac rings will be measured in a tissue myobath. These studies will enable us to determine whether CIMPimproves the hearts response to nitric oxide donors. Identification of major players involved in the control ofoxidative and proteolytic stresses will help to develop strategies to prevent CHF.

project_terms:
3-nitrotyrosine;Abbreviations;Acetylcholine;Acids;Antibodies;Antigens;Arginine;Arteriovenous fistula;Biochemical;Blotting Western;Bradykinin;CD31 Antigens;Cardiac;Cells;Chronic;Collagen;Complex;Congestive;Diastolic blood pressure;Disulfides;Endothelial Cells;Endothelium;Extracellular Matrix;Feedback;Functional disorder;Goals;Heart;Heart Failure Congestive;Heart failure;Hydroxyeicosatetraenoic Acids;Hypertrophy;In Situ;Ischemia;Left;Left ventricular structure;Matrix Metalloproteinases;Measures;Metalloproteases;Methods;Molecular;Mus;Muscle;Myocardial;NADH;NOS3 protein human;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitric Oxide Donors;Nitroprusside;Nuclear;Oxidases;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Oxides;Peroxisome Proliferator-Activated Receptors;Peroxonitrite;Physiological;Physiological reperfusion;Plasma;Poly(ADP-ribose) Polymerases;Principal Investigator;Prostaglandins;Protein Kinase C;Proteins;Purpose;Reactive Oxygen Species;Reperfusion Therapy;Reporting;Repression;Role;Stress;Sulfhydryl Compounds;Superoxide Dismutase;Techniques;Testing;Tissue Inhibitor of Metalloproteinases;Tissues;Tyrosine;Ventricular;arginine methyl ester;catalase;density;improved;inhibitor/antagonist;prevent;progesterone 11-hemisuccinate-(2-iodohistamine);programs;research study;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4


application_id: 7340800
project_number: 3R01HL074219-03S1
project_title: Integrin Signaling In Vascular Cells
administering_ic: NHLBI
award_notice_date: 2007-01-16
application_type: 3
activity_code: R01
ic: HL
serial_number: 074219
suffix: S1
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
project_abstract:
Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertensionatherosclerosis and restenosis. SMC function is controlled by complex regulatory mechanisms whichare governed in part by interactions with the extracellular matrix. Integrins the predominant receptors forthe extracellular matrix activate adhesion-dependent signaling pathways and cross-talk with growthfactor and G-protein coupled receptors to influence cellular functions. The objective of this application isto understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. Weobserved that wild-type mice treated with an antibody-inhibitor of beta3-integrins but notbeta3-integrin-deficient (beta3-/-) mice were protected from the development of intimal hyperplasia andhave found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for ourin vivo observations. Based on our preliminary data we hypothesize that integrin alphaVbeta3-dependent intracellular signaling positively and negatively regulates SMC growth and migration thorughdistinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize geneticpharmacologic and RNA interference techniques to target integrin alphaVbeta3 in well-characterizedcellular and animal models of SMC function. First we will identify alphaVbeta3-dependent pathways instimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch toregulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s)responsible for GTPase regulation. Second based on our preliminary data we have identified a role foralphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPKpathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMCquiescence. Third we will delineate the contribution of alphaVbeta3 to physiologic responses in culturedvessels and well-established mouse models of arterial injury. These results will provide specific insightsinto the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implicationsfor understanding alphaVbeta3 integrin function in angiogenesis osteoporosis and other disorders.

project_terms:
Ablation;Accounting;Address;Adhesions;Adhesives;Animal Model;Arterial Injury;Atherosclerosis;Basement membrane;Biology;Blood Vessels;Cardiovascular Diseases;Cell physiology;Cells;Cellular biology;Complement;Complex;Condition;Data;Development;Diagnosis;Disease;Down-Regulation;ECM receptor;Environment;Extracellular Matrix;Family;Focal Adhesions;Functional disorder;G-Protein-Coupled Receptors;Genetic;Goals;Grant;Growth;Growth Factor;Guanosine Triphosphate Phosphohydrolases;Human;Hyperplasia;Hypertension;Injury;Integrin alphaVbeta3;Integrin beta3;Integrins;Knowledge;MAP Kinase Gene;MAPK14 gene;Mediating;Modeling;Molecular;Mus;Myocytes Smooth Muscle;Osteoporosis;Outcome;Pathologic;Pathway interactions;Physiological;Play;Prevention;Proliferating;Property;RNA;RNA Interference;Reagent;Receptor Signaling;Regulation;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Stimulus;Techniques;Testing;Therapeutic;Thrombosis;Tumor Angiogenesis;Wild Type Mouse;Work;adhesion receptor;angiogenesis;antibody inhibitor;base;cell growth;improved;in vivo;innovation;insight;member;migration;mouse model;programs;receptor;receptor function;response;restenosis;rho;tool


application_id: 7340781
project_number: 5R01GM070559-04
project_title: Molecular Analysis of Juvenile Hormone Action
administering_ic: NIGMS
award_notice_date: 2008-06-27
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-TMP(99)]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: 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
budget_start_date: 2008-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Some insects compete with us for food and transmit human and livestock diseases but other insects are beneficial. Therefore there has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids are the major hormones that regulate molting metamorphosis and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding of the molecular basis of JH action. The main objective of this proposal is to identify genes that play critical roles in JH action. JH response elements (JHRE) identified in the promoter region of JH- and 20-hydroxyecdysone (20E)-responsive JH esterase (jhe) gene and ecdysone receptor (EcR) deficient Drosophila melanogaster cell line (L57) were used to develop a robust system that can be used for studying the molecular basis of JH action. In L57 cells a reporter gene placed under the control of JHRE is induced by JH and the JH induction was suppressed by 20E. The nuclear proteins isolated from L57 cells bind to JHRE and 20E in the presence of EcR can prevent this binding. In L57 cells EcR and DSP do not bind directly to JHRE and are not directly involved in JH induction of a reporter gene regulated by JHRE. Identification of proteins that bind to JHRE is critical for understanding JH action. The two specific aims of the proposal are: (1) to identify genes that play key roles in JH action; and (2) to determine the role of identified genes in JH action. The genes that are involved in JH induction of JHRE regulated reporter gene will be identified using RNAi and yeast assays. The identified gene will be characterized by studying the binding of expressed proteins to JHRE and labeled JH expression of their mRNA and proteins during D. melanogaster development and analysis of D. melanogaster mutants deficient in identified genes. JH analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents. The receptors can also be used in medicine by developing gene switches for various applications such as gene therapy drug discovery and therapeutic protein production.

project_terms:
Adult;Aedes (genus);Agonist;Alkaline Phosphatase;Base Pairing;Binding (Molecular Function);Binding Proteins;Biological;Biological Assay;Cell Line;Cells;Code;Collection;Complex;Culicidae;D Cells;DNA Complementary;Development;Disease;Disease Vectors;Displays mRNA Differential;Dose;Drosophila melanogaster;Ecdysone;Ecdysteroids;Ecdysterone;Elements;Esterase Gene;Event;Food;Gene Expression;Genes;Genes Reporter;Genes Switch;Hormone Receptor;Hormones;Human;Insect Control;Insecta;Intestines;Juvenile Hormones;Label;Lead;Length;Life Cycle Stages;Livestock;Luc Gene;Mediating;Medicine;Metamorphosis Biological;Methods;Molecular;Molecular Analysis;Molting;Mosquito Control;Nuclear Protein;Nuclear Proteins;Personal Satisfaction;Phosphorylation;Play;Production;Promoter Regions (Genetics);Protein Binding;Protein Dephosphorylation;Protein Kinase C;Proteins;RNA Interference;RNA chemical synthesis;RNA Double-Stranded;RNA Messenger;Repeats Direct;Reporter;Reproduction;Research;Research Personnel;Resistance development;Response Elements;Role;Screening procedure;Signal Transduction;System;Techniques;Time;Tissues;Vertebrates;Work;Yeasts;analog;base;drug discovery;ecdysone receptor;gene therapy;genome sequencing;hormone analog;hormone response element;insect disease;juvenile hormone esterase;mutant;prevent;programs;receptor;response;therapeutic protein;vector control


application_id: 7340767
project_number: 5R01DK067581-04
project_title: Histone Acetylation and Insulin Gene Expression
administering_ic: NIDDK
award_notice_date: 2008-02-01
opportunity_number: PA-02-100
application_type: 5
activity_code: R01
ic: DK
serial_number: 067581
program_official: SATO, SHERYL M
project_start_date: 2005-02-01
project_end_date: 2010-01-31
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 7875121
contact_pi: OZCAN, SABIRE
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Acetyltransferase;Address;Beta Cell;Binding (Molecular Function);Blood Glucose;Cell Line;Cells;Complex;DNA Binding;Data;Defect;Development;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Doctor of Philosophy;EP300 gene;Gene Expression;Genes;Glucose;Goals;HAT1 protein human;HNF-1alpha;HNF4A protein human;Histone Acetylation;Histone H4;Homeodomain Proteins;Huntington Disease;Hyperglycemia;Incidence;Insulin;Maintenance;Mediating;Mice Transgenic;Modification;Mus;Mutation;Pancreas;Pathogenesis;Patients;Play;Process;Production;Promotor (Genetics);RNA Small Interfering;Rattus;Recruitment Activity;Regulation;Research Personnel;Role;Structure of beta Cell of islet;Techniques;Testing;Transcription Genetic;Up-Regulation (Physiology);base;blood glucose regulation;histone acetyltransferase;in vivo;insulinoma;islet;programs;research study;response;transcription factor


application_id: 7340762
project_number: 5R01NS035377-13
project_title: Cholinergic Influences on Corticothalamic Transmission
administering_ic: NINDS
award_notice_date: 2007-11-29
application_type: 5
activity_code: R01
ic: NS
serial_number: 035377
program_official: GNADT, JAMES W
project_start_date: 1995-09-30
project_end_date: 2009-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-F(05)M]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
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: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of the proposed experiments is to determine the causes of attention impairment during disease. However it is first necessary to understand the organization of circuits that may contribute to attention mechanisms in the normal brain. Many studies have implicated the pulvinar nucleus as an area that may regulate visual attention. We propose to study the rodent lateral posterior (LP) nucleus a region comparable to inferior regions of the primate pulvinar nucleus. We will use a combination of tract tracing immunocytochemistry electron microscopy and in vitro electrophysiology to examine the synaptic organization and functional properties of LP neurons. We propose that the rat LP nucleus contains at least 2 subdivisions that are characterized by distinct synaptic inputs axonal projection patterns and cellular firing properties. Regular spiking cells in the caudal LP nucleus are predicted to receive tectal input and project to the striatum. The synaptic arrangements of tectothalamic terminals coupled with the linear firing properties of caudal LP neurons may serve to accurately transfer signals related to the movement of visual stimuli. This circuitry may underlie the coordination of visually guided movements. Clustered spiking cells in the rostral LP nucleus are predicted to receive input from layer 5 of the visual cortex and in turn project to cortical layer 1. The synaptic arrangements of layer 5 corticothalamic terminals coupled with the non-linear firing properties of rostral LP neurons may serve to amplify and synchronize cortical activity providing a substrate for the selective enhancement of visual signals. A thorough understanding of the firing characteristics of LP neurons and the organization and dynamic properties of their synaptic connections is necessary to begin to formulate reasonable hypotheses regarding the function of the rat LP nucleus and ultimately the human pulvinar nucleus.

project_terms:
Affect;Amygdaloid structure;Area;Attention;Axon;Brain;Calcium-Binding Proteins;Cell Nucleus;Cells;Cellular Morphology;Cerebral cortex;Characteristics;Cholinergic Agents;Complex;Corpora quadrigemina superior colliculus;Corpus striatum structure;Coupled;Disease;Electron Microscopy;Electrophysiology (science);Excitatory Amino Acid Antagonists;Felis catus;Fire - disasters;Glean;Glutamate Transporter;Goals;Human;Impairment;In Vitro;Individual;Inferior;Injection of therapeutic agent;Label;Lateral;Lateral posterior nucleus of thalamus;Location;Medial;Mediating;Morphology;Movement;Neurons;Nitric Oxide Synthase;Numbers;Optics;Pattern;Physiologic pulse;Physiological;Primates;Procedures;Property;Pulse taking;Pulvinar structure;Radiation;Rattus;Receptors Calcium-Sensing;Research Personnel;Rodent;Signal Transduction;Staining method;Stains;Stimulus;Substance P;Surface;Synapses;Synaptic Transmission;Techniques;Tectum Mesencephali;Testing;Thalamic Nuclei;Thalamic structure;Tracer;Training;Visual;Visual Cortex;Visual Perception;Visual attention;Whole-Cell Recordings;base;biocytin;biotinylated dextran amine;cholinergic;follow-up;immunocytochemistry;interest;postsynaptic;programs;receptor;research study;response;retrograde transport;transmission process;visual stimulus


application_id: 7340714
project_number: 5R21AI072170-02
project_title: Roles of host RNA binding proteins in virus replication
administering_ic: NIAID
award_notice_date: 2008-01-17
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AI
serial_number: 072170
program_official: PARK, EUN-CHUNG
project_start_date: 2007-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-G(90)S]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC 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: Plus-stranded RNA viruses which pose significant risks to human health and cause major losses for agriculture depend heavily on host factors to replicate in infected cells. The roles of the subverted host factors in virus replication are currently poorly understood due to the lack of tractable virus-host systems. To advance rapidly our understanding of virus-host interactions during viral replication the investigator has developed the powerful Tomato bushy stunt virus (TBSV)-yeast model system that led to the identification of numerous host factors affecting viral replication. This application is aimed at dissecting the roles of three RNA-binding host proteins: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) the p68 DEAD-box RNA helicase homolog Dpb2 and translation elongation factor EF-1alpha (Tef1/2p) all of which bind to TBSV RNA and also known to interact with Hepatitis C virus West Nile virus dengue 4 virus and hepatitis A virus RNAs suggesting that host factors might play similar roles in replication of these viruses. The advantages of tombusviruses for replication studies are numerous including (i) their simple genomes and robust replication; (ii) similarity of TBSV replicase proteins to proteins of important pathogens such as HCV West Nile virus and other flaviviruses and pestiviruses; (iii) availability of in vitro replication assays developed in the Investigator's laboratory; and (iv) the development by the investigator of an efficient yeast-based TBSV replication system. In addition a recent genome-wide screen including 95% of all yeast genes identified host genes that affected TBSV accumulation. Based on these advances TBSV is a premium model system to study the roles of host factors in virus replication in eukaryotic hosts. Due to the central role of virus replication in viral pathogenesis the proposed studies on host RNA-binding proteins involved in virus replication promise to advance our understanding of the viral replication process and to lead to identification of new antiviral targets. These and similar studies are needed urgently because our current knowledge on host factors involved in virus replication and in viral pathogenesis is incomplete. Knowledge of virus-host interactions and the roles of host RNA-binding proteins might reveal new drug targets and lead to development of novel antiviral strategies. The tractable in vitro and in vivo TBSV system developed by the investigator could prove beneficial to studies of other less amenable RNA viruses.

project_terms:
Affect;Agriculture;Animals;Antiviral Agents;Area;Binding (Molecular Function);Biological Assay;Biological Models;Boxing;Cataloging;Catalogs;Cells;Complex;Dengue;Dengue Virus;Development;Disease;Drug Delivery Systems;EF-1alpha;Factor Elongation;Flavivirus;Gene Delivery;Genes;Genome;Genomics;Glyceraldehyde-3-Phosphate Dehydrogenases;Health;Hepatitis A Virus;Hepatitis C virus;Homologous Gene;Human;In Vitro;Integration Host Factors;Knowledge;Laboratories;Lead;Oxidoreductase;Pestivirus;Plants;Play;Positioning Attribute;Proteins;Proteomics;RNA Binding;RNA Helicase;RNA Viruses;RNA replication;RNA Viral;RNA-Binding Proteins;RNA-Directed RNA Polymerase;Recombination Genetic;Replication-Associated Process;Research Personnel;Risk;Role;Site;System;Testing;Tomatoes;Tombusvirus;Translations;Viral;Viral Pathogenesis;Viral Physiology;Viral Vaccines;Virus;Virus Diseases;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;design;in vivo;inorganic phosphate;insight;novel;pathogen;replicase;research study;size;tomato bushy stunt virus;vector;virus host interaction


application_id: 7340690
project_number: 5R01NS046517-04
project_title: Estrogen androgen neprilysin and amyloid peptides.
administering_ic: NINDS
award_notice_date: 2007-12-04
application_type: 5
activity_code: R01
ic: NS
serial_number: 046517
program_official: CORRIVEAU, RODERICK A
project_start_date: 2004-12-01
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZRG1-CDIN(01)Q]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant): Model studies have shown that in mice ovariectomy increases amyloid B (AB) peptide levels while ovariectomy followed by estrogen replacement lowers the concentration of AB peptides to normal or below normal levels.  We recently found that ovariectomy in rats leads to a decrease in the activity of the peptidase neprilysin and that ovariectomy followed by estrogen replacement increases neprilysin gene transcription and neprilysin enzyme activity in the brain.  Neprilysin has been shown to be the major or one of the major enzymes involved in AB peptide clearance in the brain.  We thus postulate that the effect of the estrogen depletion in raising AB peptide levels and estrogen replacement in lowering AB peptide levels occurs at least in part as a result of estrogen effects on neprilysin activity.  Similarly it has recently been shown that gonadectomy increases AB peptide levels in rats and androgen replacement reverses this effect.  Since the neprilysin gene is also regulated by androgens we speculate that the effect of gonadectomy and androgen replacement on AB peptide levels is also mediated through effects on the neprilysin gene.  Two Specific Aims are proposed to test this hypothesis:  (1) we will compare the effect of estrogen in reducing AB peptide levels in mice expressing a mutant human amyloid precursor protein containing the Swedish and Indiana mutations (J20 mouse line) to the effect of estrogen in the J20 mouse crossed with a neprilysin knockout mouse and the J20 mouse crossed with an estrogen receptor knockout mouse.  These experiments will establish whether the estrogen dependent decreases in AB peptide levels is a result of the estrogen dependent increased in neprilysin activity and whether an estrogen receptor dependent mechanism is responsible for reported effect of androgen depletion increasing AB peptide levels and androgen replacement lowering AB peptide levels is due to androgen effects on neprilysin.  
  
Using mouse models we will determine whether steroid hormone mediated effects on AB peptide levels are a result of their affects on neprilysin activity and whether steroid hormones or their selective receptor modulators can serve as a target for the development of drugs for the prevention of Alzheimer's disease.

project_terms:
Affect;Alzheimer disease prevention;Amyloid;Amyloid beta-Protein Precursor;Androgen Receptor;Androgen Response Element;Androgens;Binding (Molecular Function);Brain;Dose;Enzymes;Estradiol;Estrogen Receptors;Estrogen Replacements;Estrogens;Genes;Glucocorticoid Receptor;Hormone Responsive;Human;Indiana;Knock-out;Laboratories;Mediating;Mice Knockout;Modeling;Mus;Mutation;Neprilysin;Ovariectomy;Peptide Hydrolases;Peptides;Progesterone;RNA Messenger;Rattus;Reporting;Rodent;Role;Study models;Testing;Transcription Genetic;Up-Regulation (Physiology);amyloid peptide;drug development;enzyme activity;mouse model;mutant;peptide A;peptide B;receptor;research study;response;steroid hormone


application_id: 7340657
project_number: 1R25ES016248-01
project_title: Summer Education Experience for Research
administering_ic: NIEHS
award_notice_date: 2008-01-07
opportunity_number: RFA-ES-06-009
application_type: 1
activity_code: R25
ic: ES
serial_number: 016248
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-01-01
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZES1 LKB-A (R5)]
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
project_terms:
Area;Biochemical;Cardiovascular system;DNA Repair;Decision Making;Educational aspects;Effectiveness;Environmental Health;Faculty;Goals;Grant;Hand;Interview;Joints;Kentucky;Laboratories;Medical Specialities;Mentors;Molecular;Mutagenesis;Oxidative Stress;Puerto Rico;Recruitment Activity;Research;Research Personnel;Research Project Grants;Schools;Series;Students;Time;Toxic effect;Toxicology;Training;Transcript;Universities;Week;Work;career;experience;interest;member;programs;satisfaction;skills;symposium;university student


application_id: 7340397
project_number: 5R01NS050311-04
project_title: Stem Cell Adaptability in Parkinson' Disease
administering_ic: NINDS
award_notice_date: 2007-12-04
opportunity_number: PAS-03-172
application_type: 5
activity_code: R01
ic: NS
serial_number: 050311
program_official: SUTHERLAND, MARGARET L
project_start_date: 2004-12-01
project_end_date: 2009-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Stem Cell Adaptibility in Parkinson's Disease   Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease (PD). Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. Recently it was demonstrated embryonic stem ceils (ESC) could be converted to dopamine neurons in culture and when implanted into animals with experimental Parkinson's disease produced a degree of functional recovery similar to implants of fetal dopamine neurons.  Because dopamine neurons derived from ESC are generated in cultures by manipulating various growth factors it still remains to be determine whether or not ESC-derived dopamine neurons have a similar phenotype as normal developing dopaminergic neurons. Moreover the dynamic microenvironment of the brain particularly the neurotrophic environment may alter the survival function and even the fate of transplanted ESC. The objective of the initial studies will determine whether or not ESC-derived dopamine neurons retain various cellular markers that are critical to the survival and maintenance of developing and mature dopamine neurons. In particular studies will focus on the identification of neurotrophic factors and neurotrophic factor receptors on ESC-derived dopamine neurons that are typically associated with normal dopamine neurons. We will then identify and measure various growth factors within the host brain that may influence the fate of transplanted ESC and assess how these factors change following a degenerative lesion of the nigrostriatal and/or during aging. Studies will be designed to vary the neurotrophic environment of the host brain in order to determine the adaptability of implanted ESC; conditions will be varied using various lesion models and gene therapy techniques to alter the expression of neurotrophic factors. The variable of host age on ESC-derived dopamine neuron adaptability will be studied.

project_terms:
Affect;Age;Aging;Animals;Brain;Brain-Derived Neurotrophic Factor;Cells;Characteristics;Clinical;Clinical Trials;Condition;Corpus striatum structure;DNA;Development;Dopamine;Embryo;Environment;ErbB4 gene;Experimental Parkinsonism;Fetus;Fiber;GDNF gene;Glial Growth Factor;Graft Survival;Growth Factor;Implant;In Situ Hybridization;In Vitro;Label;Lesion;Localized;Maintenance;Measures;Midbrain structure;Modeling;Neurites;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 3;Non-Viral Vector;Operative Surgical Procedures;Parkinson Disease;Patients;Phenotype;RNA Messenger;Rattus;Receptors Nerve Growth Factor;Recombinants;Recovery of Function;Relative (related person);Research Personnel;Site;Staging;Stem cells;Structure of blastomere;Symptoms;Techniques;Therapeutic;Time;Transplantation;Tyrosine 3-Monooxygenase;Viral Vector;design;dopaminergic neuron;embryonic stem cell;fetal;gene therapy;implantation;improved;in vivo;middle age;nanoparticle;neurotoxic;neurotrophic factor;nigrostriatal pathway;nigrostriatal system;receptor;reinnervation;stem;transgene expression;young adult


application_id: 7338308
project_number: 5R01NS053905-02
project_title: PLP alternative splicing and oligodendrocyte differentiation
administering_ic: NINDS
award_notice_date: 2008-02-03
application_type: 5
activity_code: R01
ic: NS
serial_number: 053905
program_official: UTZ, URSULA
project_start_date: 2007-01-03
project_end_date: 2011-12-31
study_section: Neurogenesis and Cell Fate Study Section[NCF]
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
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
budget_start_date: 2008-01-01
project_terms:
5' Splice Site;Alternative Splicing;Binding (Molecular Function);Biochemical;Brain;Cells;Coupled;Data;Demyelinating Diseases;Disease;Disruption;Elements;Enhancers;Equilibrium;Exons;Fibroblasts;Folch-Pi apoprotein;Future;Generations;Genes;Genetic;Genetic Diseases Inborn;Grant;Human;In Vitro;Inherited;L Cells (Cell Line);Maps;Mus;Mutation;Myelin;Myelin Proteolipid Protein;Nerve;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Nuclear;Numbers;Oligodendroglia;Patients;Protein Binding;Protein Isoforms;Proteins;RNA Interference;RNA Splicing;Regulation;Regulatory Element;Rest;Role;Scanning;Site;Testing;Tissues;Transcript;Transcriptional Activation;cell injury;in vivo;innovation;knock-down;nervous system disorder;novel;progenitor


application_id: 7338250
project_number: 3R01CA034627-22S1
project_title: Pharmacogenetics of drug and carcinogen metabolism
administering_ic: NCI
award_notice_date: 2007-08-09
application_type: 3
activity_code: R01
ic: CA
serial_number: 034627
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 1989-09-01
project_end_date: 2009-06-30
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
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:
Genetic susceptibility to breast cancer is determined by an interaction of genes and environment butremains poorly understood. In this revised competing renewal of our investigation into the role ofpharmacogenetic polymorphisms in carcinogen metabolism on genetic predisposition to cancer wehypothes ze that aromatic amine carcinogens such as 4-aminobiphenyl (ABP) present in tobacco smoke andheterocyclic amine carcinogens such as 2-amino-3-methylimidazo [45-f]pyridine (IQ) present in deep-friedwell-done meats are more likely to initiate breast cancer in those individuals with rapid and/or slow acetylatorN-acetyltransferase- 1 (NAT1) and - 2 (NAT2) acetylator genotypes. We hypothesize that breast cancerfrequency will be higher in tobacco smokers with very slow NAT2 acetylator / rapid NAT1 acetylatorgenotypes and in individuals who eat deep-fried well-done meats and are rapid for both NAT1 and NAT2acetylator genotypes. To test this hypothesis we propose to determine the effect of single nucleotidepolymorphisms (SNPs) in human NAT1 and NAT2 on ABP and IQ genotoxicity through stable transfection ofhuman NAT1 or NAT2 variant alleles into Chinese hamster ovary cells transfected with human CYP1A1 orCYP1B1; determine the relative level of NAT1 and NAT2 expression in normal human mammary tissue as afunction of genotype; construct and characterize rapid and slow acetylator rat strains congenic at the NAT2locus to determine the frequency of breast tumors in female rapid and slow acetylator congenic ratsadministered ABP or IQ; determine quantity stability and regulatory effects of ABP or iQ on NAT1- andNAT2-specific mRNA protein and catalytic activity; and determine the metabolism and genotoxicity of ABPand IQ in primary mammary cell cultures derived from rapid and slow acetylator congenic rats. We also willassess the effect of NAT1 and NAT2 genotypes in breast cancer risk through participation in ongoingmolecular epidemiology investigations of breast cancer in Shanghai China and in Nashville Tennessee.

project_terms:
2-Amino-1-Methyl-6-Phenylimidazo[45-b]pyridine;4-biphenylamine;Acetylation;Affinity;Alleles;Aromatic Amines;Breast;CYP1A1 gene;Carcinogen Metabolism;Carcinogens;China;Chinese Hamster Ovary Cell;Cultured Cells;DNA;DNA Adducts;DNA Repair;DNA Repair Gene;Data;Depth;Eating;Environmental Exposure;Enzymes;Epidemiology Molecular;Epithelial Cells;Female;Frequencies (time pattern);Genes;Genetic;Genetic Predisposition to Disease;Genotype;Health;Heterocyclic Amines;Human;Individual;Investigation;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Neoplasms;Mammary gland;Meat;Metabolism;N-acetyltransferase 1;NADPH-Ferrihemoprotein Reductase;NAT1 protein human;NAT2 protein human;Pharmaceutical Preparations;Pharmacogenetics;Phase;Polymorphism Genetic;Population;Predisposition;Proteins;RNA Messenger;Rat Strains;Rattus;Relative (related person);Role;Sampling;Single Nucleotide Polymorphism;Smoker;Tennessee;Testing;Tissue Sample;Tissues;Tobacco;Tobacco smoke;Transfection;Variant;cancer risk;carcinogenicity;chemical carcinogen;congenic;cytochrome P-450 CYP1B1;cytotoxicity;gene environment interaction;genotoxicity;heterocyclic aromatic amines;protein expression;pyridine


application_id: 7338230
project_number: 3R01CA102285-04S1
project_title: Role of MIF in Rb inactivation and Tumorigenesis
administering_ic: NCI
award_notice_date: 2007-04-13
application_type: 3
activity_code: R01
ic: CA
serial_number: 102285
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2004-07-01
project_end_date: 2009-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT 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:
Many human cancers require the production of soluble growth factors for tumor initiation promotion andsurvival. These extracellular factors contribute to and promote most stages of tumor development. Forexample tumors of the mammary gland are strongly influenced by the activity of epidermal growth factor(EGF) receptor family members. EGF binding to its cognate receptor is thought to contribute to breastcancer cell cycle regulation by activating signaling pathways that facilitate cyclin D1 expression cyclin-dependent kinase 4 or 6 (Cdk4t6) activation and ultimately retinoblastoma (Rb) inactivation. While Rbinactivation is critically important for oncogene-induced malignancies the nature of the signals induced byoncogenes to facilitate this are incompletely understood. We recently discovered that the pro-inflammatorycytokine migration inhibitory factor (MIF) is both necessary and sufficient for mitogen and oncogene-inducedcyclin D1 transcription Cdk4 activity and Rb inactivation. Moreover our results reveal that MIF is stronglyinduced by tumor promoting oncogenes and cells from MIF-deficient mice are resistant to oncogene-inducedmalignant transformation. Despite these findings more work is needed to investigate in detail the influencemechanism and effectors of MIFs contribution to Rb inactivation malignant growth properties and de novotumorigenesis. We hypothesize that MIF promotes both normal and neoplastic cell growth by stimulatingRhoA GTPase activity that leads to the activation of the canonical MAP kinase pathway and resulting incyclin D1 transcription and Rb inactivation. To test the fundamentals of our hypothesis and fulfill the statedobjectives of this application the following specific aims are proposed: 1) Examine the regulatory andeffector requirements for MIF in cyclin D1 transcription focusing on Rho GTPase activated pathways; 2) Testthe requirements for MIF in human breast carcinoma Rho activation cyclin D1 expression and Rbinactivation and; 3) Investigate the contribution and functional requirements for MIF in de novo mammarytumorigenesis. This work should contribute to a greater understanding of the physiologic and pathologicimportance of soluble growth factors to cell cycle regulation and neoplastic processes and may reveal anovel target for future cancer therapies.

project_terms:
Accounting;Agar;Binding (Molecular Function);Breast;Breast Cancer Cell;Breast Carcinoma;Cell Cycle Regulation;Cell Line;Cells;Cyclin D1;Cyclin-Dependent Kinase 4;Cyclins;Data;Development;Diagnostic Neoplasm Staging;Disease;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Epithelial Cells;Family;Family member;Fibroblasts;Future;Growth;Growth Factor;Growth Factor Receptors;Guanosine Triphosphate Phosphohydrolases;Human;Human Mammary Carcinoma;In-Migration;Inflammatory;Knowledge;Laboratories;Lead;Link;MCF7 cell;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Neoplasms;Mammary Tumor Virus Mouse;Mammary Tumorigenesis;Mammary gland;Mediating;Mediator of activation protein;Mesenchymal;Migration Inhibitory Factor;Mitogen-Activated Protein Kinases;Mitogens;Mus;Mutation;Nature;Neoplasms;Neoplastic Processes;Normal Cell;Oncogenes;Oncogenic;Pathologic;Pathway interactions;Phosphorylation;Physiological;Production;Property;Protein Overexpression;Proto-Oncogenes;Publishing;RNA Interference;Relative (related person);Resistance;Retinoblastoma;Role;Signal Pathway;Signal Transduction;TP53 gene;Testing;Thinking function;Transcription Genetic;Tumor Suppressor Proteins;Tumor stage;Viral Oncogene;Work;Xenograft procedure;autocrine;base;cancer cell;cancer therapy;cell growth;cell motility;cell transformation;cytokine;extracellular;in vivo;insight;mouse model;neoplastic;neoplastic cell;novel;paracrine;prognostic;receptor;research study;rho;rho GTP-Binding Proteins;therapeutic target;tumor;tumor growth;tumor initiation;tumorigenesis


application_id: 7336341
project_number: 5R01AI064421-03
project_title: Analyzing and modulating immunoregulatory defects in autoimmune disease.
administering_ic: NIAID
award_notice_date: 2008-01-22
application_type: 5
activity_code: R01
ic: AI
serial_number: 064421
program_official: ESCH, THOMAS R
project_start_date: 2006-01-01
project_end_date: 2010-12-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-01-01
project_abstract:
Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimrnunity.Although the thymus appears to be a major site of CD4+CD25+ T cell development it is stillunclear whether there are also peripheral sites of development. We have found recently thatCD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in theperiphery. Conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells may be a veryimportant mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenanceand a defect in this process could contribute to autoimmune disease development. We havefound that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in thethymus but a significantly lower percentage in the periphery. Furthermore NOD CD4+CD25"Tcells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function stronglysuggesting that NOD mice may have a defect in this conversion process and may therefore beunable to maintain this regulatory population. The central hypothesis of this proposal is thatenhanced conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD micecan prevent diabetes. We will test this hypothesis by studying the mechanisms and defects inconversion in NOD mice determinewhether this process can be restored and whether restorationis associated with amelioration of disease. By understanding the defects in conversion ofCD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice it may be possible todevise strategies to overcome these defects andthereby develop therapies to prevent or treatautoimmune disease.

project_terms:
Address;Antigens;Appendix;Autoimmune Diseases;Autoimmunity;Cells;Condition;Defect;Development;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Disease;Exposure to;Goals;Homeostasis;Maintenance;Mice Inbred NOD;Mus;Numbers;Organ;Peripheral;Phenotype;Population;Process;Range;Site;T-Cell Development;T-Lymphocyte;Testing;Thymus Gland;in vivo;prevent;reconstitution;response;restoration


application_id: 7334617
project_number: 3U01CA114622-03S3
project_title: Understanding Cancer Information Needs of Appalachian Cancer Survivors/Providers
administering_ic: NCI
award_notice_date: 2007-09-26
opportunity_number: RFA-CA-07-501
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S3
program_official: COOPER, LESLIE
project_start_date: 2005-05-06
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZCA1 RPRB-G (M1)]
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
project_abstract:
DESCRIPTION (provided by applicant): Due to the advances in cancer screening diagnosis and treatment and an aging population cancer survivorship has become a focal cancer control and health communications research area. Both adult and childhood cancer patients are treated with modalities that are accompanied with immediate and late- appearing complications. Moreover there are multiple psychosocial and economic consequences associated with a cancer diagnosis. Consequently information and communication are essential for patients and providers to manage these complications and long-term health issues. All of the abovementioned challenges may be magnified in Appalachia where cultural barriers lower SES co-morbidities and high-risk health behaviors and limited access to health services and insurance are often present. Reliance on primary care providers for survivorship care and information may be especially high in the Appalachian region since many cancer survivors may have received their primary treatment in a distant urban setting or from one of a limited number of oncologists practicing in the area. The extent to which the information needs of Appalachian cancer survivors are being met by their primary care providers is currently unknown. In addition we are unaware of the strategies used and challenges faced by Appalachian primary care providers in providing survivorship-oriented care and information. In collaboration with community-based partners and primary care providers in Appalachian Kentucky and Virginia we will conduct formative research using focus groups and in-depth interviews. The broad long-term goal of the project is to improve understanding of the dynamics of communication and information sharing between Appalachian cancer survivors and their primary care providers. Reaching this goal will help improve patient-provider communication reduce cancer morbidity and mortality and improve quality of life and ultimately impact cancer disparities in Appalachia. The study's 3 specific aims are to: 1) Identify the cancer information and communication needs of Appalachian cancer survivors and their primary care providers; 2) Determine Appalachian cancer survivors' experiences with and perceptions of their primary care provider in providing cancer survivorship care and information; and 3) Identify the strategies used and challenges faced by Appalachian primary care providers in managing the care and information needs of cancer survivors in their practices.

project_terms:
Adult;Amputation;Anxiety;Appalachian Region;Area;Cancer Control;Cancer Patient;Cancer Survivor;Cancer Survivorship;Cardiac;Care Managed;Caring;Collaborations;Communication;Communication Research;Communities;Condition;County;Data;Depth;Diagnosis;Distant;Economics;Educational aspects;Elderly;Employment;Ensure;Family Caregiver;Focus Groups;Fright;Goals;Health;Health Communication;Health Services Accessibility;Health behavior;Huntington Disease;Infertility;Information and Communication Theory;Insurance;Interview;Kentucky;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Mental Depression;Minor;Minority;Modality;Morbidity - disease rate;Mortality Vital Statistics;Numbers;Nurse Practitioners;Oncologist;Participation Community;Patients;Perception;Phase;Physician Assistants;Population;Practice based research;Prevalence;Primary Care Physician;Primary Health Care;Provider;Quality of life;Range;Reliance;Research;Research Personnel;Risk;Rural;Screening for cancer;Second Primary Cancers;Stress;Survivors;United States;Virginia;Work;aging population;base;cancer diagnosis;cancer health disparity;cancer therapy;coping;experience;improved;intimate behavior;medically underserved;neoplasm registry;programs;psychosocial;social;survivorship


application_id: 7334527
project_number: 3U01CA114622-03S2
project_title: Increasing Colorctal Cancer Screening by Primary Care Physicians-Appalachia PA
administering_ic: NCI
award_notice_date: 2007-09-21
opportunity_number: RFA-CA-07-501
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S2
program_official: COOPER, LESLIE
project_start_date: 2005-05-06
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZCA1 RPRB-G (M1)]
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
project_abstract:
DESCRIPTION (provided by applicant): Screening rates for colorectal cancer in Pennsylvania lag behind national fates and rates for the Appalachian regions in this state are even lower. Data from the Centers for Disease Control and Prevention's (CDC) Behavioral Risk Factor surveillance System (BRFSS) indicate that the percentage of respondents who reported use of screening tests for colorectal cancer (fecal occult blood test (FOBT) flexible sigmoidoscopy (FS) or colonoscopy) in accordance with guidelines of U.S. Preventive Services Task Force was 53%" nationwide. The figures for Pennsylvania were 49% whereas those for Appalachian Pennsylvania were 44.4%. According to a national survey by the American Cancer Society (ACS) a reason frequently given for low screening rates is "it was not recommended by my doctor." The long-range goal of this project is to determine the feasibility of conducting a community-based full-scale dissemination trial of a physician education intervention in multiple locations and under varying practice settings. The objective of this application is to do a collaborative one-year pilot project focusing on the challenge of increasing screening for colorectal cancer in four primary care practice sites through physician education. The central hypothesis is that development and implementation of this intervention delivered by trained staff of two networks in Appalachia Pennsylvania ACTION Health Cancer Task Force and Penn State Ambulatory Research Network (PSARN) will be a feasible way to increase colorectal cancer screening. Specific aims include: 1. Better understand current barriers to colorectal cancer screening by qualitative methodology. 2. Implement a tailored multi-phase intervention in four clinics in the ACTION Health Cancer Task Force and PSARN based on pre-intervention qualitative evaluation. 3. Assess the fates of colorectal cancer screening before and after intervention through medical record review. Our rational for this research is that with better understanding of successful physician education that improves cancer screening a full-scale implementation can be conducted. We are prepared to conduct this research because of the strong networks participating and experience of the research team. At the completion of this work our expectation is to have better understanding of barriers to colorectal cancer screening in this population and how this intervention had impact. These findings will be translated into improved physician education to improve screening efforts.

project_terms:
Address;Advisory Committees;Age-Years;Ambulatory Care;American Cancer Society;Appalachian Region;Behavioral Risk Factor Surveillance System;Centers for Disease Control and Prevention (U.S.);Clinic;Clinical;Colonoscopy;Colorectal Cancer;Communities;County;Data;Development;Educational Intervention;Educational aspects;Fecal occult blood;Feedback;Flexible fiberoptic sigmoidoscopy;Future;Goals;Guidelines;Health;Intervention;Lead;Location;Malignant Neoplasms;Medical Records;Medicine;Methodology;Network-based;Pennsylvania;Phase;Physicians;Pilot Projects;Population Intervention;Preventive;Primary Care Physician;Primary Health Care;Qualitative Evaluations;Range;Rate;Reporting;Research;Research Personnel;Respondent;Rural;Screening for Colorectal Cancer;Screening for cancer;Screening procedure;Self Assessment (Psychology);Services;Site;Surveys;Testing;Training;Translating;Universities;Work;base;cancer prevention;college;dissemination trial;expectation;experience;improved


application_id: 7334221
project_number: 5R01DK073586-03
project_title: Prolonged Diabetic Damage to Cardiac Mitochondria
administering_ic: NIDDK
award_notice_date: 2008-02-01
opportunity_number: RFA-DK-05-001
application_type: 5
activity_code: R01
ic: DK
serial_number: 073586
program_official: JONES, TERESA L Z
project_start_date: 2006-01-15
project_end_date: 2009-12-31
study_section: ZDK1-GRB-N(O1)S
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
project_abstract:
In diabetic patients complications such as cardiomyopathy develop over many years of hyperglycemia. Weare proposing that the prolonged time course stems from the gradual accumulation of damage tomitochondrial DNA caused by increased mitochondrial generation of reactive oxygen species (ROS) andreactive nitrogen species (RNS). For several reasons mitochondrial DNA is especially vulnerable to damageand some types of damage are poorly repaired. We hypothesize that mitochondrial DNA damage is causal forcellular and organ dysfunction in the diabetic state. Our laboratory developed the OVE26 mouse model ofType I diabetes optimal for following chronic development of complications. Cardiac mitochondria fromlong-term diabetic OVE26 mice exhibit morophological degeneration decreased glutathione content andincreased DNA damage. Transgenic mice with increased activity of the mitochondrial antioxidant MnSODtargeted to the heart when crossed onto the OVE26 background show less contractile dysfunction improvedmitochondrial morphology and a significant improvement in mitochondrial respiration. We propose thatMnSOD overexpression suppresses damage to the mitochondrial genome and that this accounts for improvedcardiomyocyte function. To test the hypothesis that progressive mitochondrial DNA damage by ROS or RNScontributes to the development of diabetic cardiomyopathy we will carry out the following Specific Aims:Aim 1: Evaluate mutations and deletions in mitochondrial DNA and correlate these changes withmitochondrial respiratory function electron transport chain complex activities cellular and mitochondrialROS generation and cardiomyocyte contractility. Aim 2: Determine if there is a cause and effect relationshipbetween mitochondrial DNA damage and diabetic cardiomyopathy. On the OVE26 diabetic backgroundmitochondrial DNA will be protected by cardiac overexpression of MnSOD and mitochondrial targetedOGG1. We will also determine whether both DNA damage and diabetic cardiomyopathy are exacerbated bycrossing existing OGG1 knockout animals to our diabetic mice. Aim 3: Assess whether systemic therapywith agents that bind free transition metals can prevent superoxide from forming more reactive species thatdamage mitochondrial DNA. Results of these investigations may be directly applicable to the development ofnew therapies which minimize or absolutely prevent certain diabetic complications.

project_terms:
8-Oxoguanine DNA Glycosylase;Accounting;Age;Animal Model;Animals;Antioxidants;Binding (Molecular Function);Cardiac;Cardiomyopathies;Cell Nucleus;Chronic;Complex;Complications of Diabetes Mellitus;DNA Damage;DNA Repair;DNA Repair Enzymes;DNA Mitochondrial;Data;Deletion Mutation;Development;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Diabetic mouse;Elderly;Electron Transport;Enzymes;Exhibits;Functional disorder;Generations;Glutathione;Heart;Histones;Human;Hydroxyl Radical;Hyperglycemia;Individual;Investigation;Laboratories;Life;Lyase;Mice Transgenic;Mitochondria;Morphology;Mus;Myocytes Cardiac;OGG1 gene;Organ;Pathology;Patients;Peroxonitrite;Personal Satisfaction;Process;Production;Protein Overexpression;Proteins;Publishing;Rate;Reactive Nitrogen Species;Reactive Oxygen Species;Research Personnel;Respiration;Respiratory physiology;Sampling;Source;Superoxides;Systemic Therapy;Testing;Time;Transition Elements;Week;Work;cell type;diabetic;diabetic cardiomyopathy;improved;knockout animal;mitochondrial genome;mouse model;prevent;programs;repaired;stem


application_id: 7331523
project_number: 5R01HL055477-12
project_title: Toxicity and Detoxification of 4Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2008-02-04
application_type: 5
activity_code: R01
ic: HL
serial_number: 055477
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2010-12-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-01-01
project_abstract:
Although several studies suggest that myocardial injury during ischemia/reperfusion is in part due to reactiveoxygen species the mechanisms by which these oxidants injure the heart and those by which the heartprotects itself from their effects are not known. We propose that the myocardial effects of oxidative stressare mediated in part by 4-hydroxyalkenals such as 4-hydroxy-trans-2-nonenal (HNE) which are derived fromoxidation of lipoproteins and membrane lipids. Our previous work has led to the identification of the majorbiochemical pathways of HNE detoxification in cardiovascular tissues. These results suggest that aldosereductase (AR)-catalyzed reduction of HNE and its glutathione conjugate is a particularly critical step in thismetabolism because inhibition of AR increases HNE accumulation in the ischemic heart and abolishes thecardioprotective effects associated with the late phase of ischemic preconditioning (PC). Based on theseobservations and our preliminary data we now plan to test how the ischemic heart metabolizes HNE andwhether this is facilitated by the activation of AR due to nitric oxide (NO) generated during ischemia. Usingboth ex vivo and in situ murine models of myocardial ischemia-reperfusion injury we will identify ischemicchanges in AR and HNE metabolism and identify the chemical nature of AR modification and the oxidantsand triggers that induce it (Aim 1). In addition we will determine the role of endothelial and inducible NOsynthases (NOS) in activating AR and increasing HNE detoxification in the ischemic heart using micedeficient in individual NOS isoforms or overexpressing inducible NO synthase in the heart (Aim 2). Tounderstand the mechanisms of AR-mediated cardioprotection we will examine changes in the mitochondriaand myocardial survival signaling (Aim 3) and elucidate how pharmacologic inhibition of AR or cardiospecificoverexpression of AR (or its murine homolog FR-1) affects ischemia-reperfusion-induced mitochondrialpermeability transition and NF-kappaB activation (Aim 3). Successful completion of this project will lead to a better understanding of mechanisms of cardioprotection due to ischemic PC and NO and could form the basis of new clinical approaches to limit myocardial infarction. Delineation of the contribution of specific enzymes to HNE metabolism in the ischemic heart will be useful in identifying population subgroups that may be highly susceptible to oxidative stress caused by cardiovascular disease.

project_terms:
Affect;Aldehyde Reductase;Aldehyde dehydrogenase (NAD+);Aldehydes;Atherosclerosis;Attenuated;Biochemical Pathway;Biochemical Process;Cardiac;Cardiovascular Diseases;Cardiovascular system;Cell Survival;Chemicals;Chronic;Clinical;Data;Development;Enzymes;Excision;Glutathione;Glutathione S-Transferase;Heart;Heart failure;Homologous Gene;In Situ;Individual;Injury;Ischemia;Ischemic Preconditioning;Kinetics;Lead;Lipid Peroxidation;Lipoproteins;Mediating;Mediator of activation protein;Membrane Lipids;Metabolic Detoxication Drug;Metabolism;Mice Knockout;Mitochondria;Mitochondria Heart;Modeling;Modification;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;NF-kappa B;NOS2A protein human;Nature;Nitric Oxide;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Oxidative Stress;Permeability;Phase;Physiological reperfusion;Population;Process;Protein Isoforms;Protein Overexpression;Proteins;Reactive Oxygen Species;Regulation;Reperfusion Injury;Reperfusion Therapy;Role;Signal Transduction;Spectrum Analysis Mass;Subgroup;Testing;Tissues;Toxic effect;Work;aldehyde dehydrogenases;base;gain of function;injured;insight;loss of function;novel;oxidation;preconditioning;prevent;research study;response


application_id: 7331459
project_number: 5R01GM072756-03
project_title: Dissection and Reconstitution of Human Mismatch Repair
administering_ic: NIGMS
award_notice_date: 2007-12-10
application_type: 5
activity_code: R01
ic: GM
serial_number: 072756
program_official: PORTNOY, MATTHEW
project_start_date: 2006-01-01
project_end_date: 2009-12-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
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: 2008-01-01
project_abstract:
The long-term goal of this project is to understand the molecular mechanism of human mismatch repair(MMR) and its impact on human health and disease. The importance of MMR is underscored by the fact thatdefects in MMR genes lead to genomic instability and eventually to cancer predisposition. Despite the factthat the excision-step of the human MMR reaction has been recently reconstituted using purified proteinsincluding MutS alpha MutL alpha EXO1 and RPA many fundamental questions in MMR still remainunanswered. For example how mismatch-provoked excision initiates and terminates and what role MutLalpha plays in MMR are unknown. Through the reconstitution of the 5' nick-directed human MMR reactionwe found that MutL alpha negatively regulates mismatch-provoked EXO1-catalyzed excision and terminatesit immediately upon mismatch removal. Given the dependency of the EXO1-catalyzed mismatch excision onMutS alpha and physical interactions among EXO1 MutS alpha and MutL alpha we hypothesize thatmismatch-provoked excision is precisely regulated through interactions among these proteins. Specifically inthe presence of a mismatch MutS alpha preferentially interacts with EX01 to promote excision; but theremoval of the mismatch by EXO1 allows EXO1 to preferentially interact with MutL alpha which thenterminates the excision. To test this hypothesis a series of EXO1 MutS alpha MutL alpha mutant proteinsthat disrupt the interaction of EXO1 with one Mut protein but not the other will be constructed expressed andpurified. These mutant proteins will be tested in an in vitro reconstitution system for their ability to performmismatch-provoked excision at the initiation and at the termination. Analysis of the excision intermediates ineach reaction will reveal how the interactions among MutS alpha and MutL alpha and EXO1 regulate aparticular step of the excision reaction. Finally to understand how efficiently the MMR system terminatesmismatch-provoked excision the excision termination sites for heteroduplexes with differentsequencecontents and distances separating the mismatch and the strand break will be precisely determined. Inaddition to revealing the molecular mechanism of mismatch-provoked excision this study will provideimportant clues to understand many puzzling phenomena in mlhl null mutants regarding 5' directed MMRmeiotic cell apoptosis and anti-recombination.

project_terms:
Affect;Apoptosis;Cells;DNA Sequence;Defect;Dependency (Psychology);Disease;Dissection;EXO1 gene;Excision;Fluorescence;Genes;Genome Stability;Genomic Instability;Goals;HMGB1 gene;Health;Hereditary Nonpolyposis Colorectal Neoplasms;Human;In Vitro;Individual;Insecta;Lead;Location;Malignant Neoplasms;Meiosis;Mismatch Repair;Molecular;Monitor;Mutagenesis Site-Directed;Nucleotides;Play;Predisposition;Process;Proteins;Reaction;Recombination Genetic;Repair Excision;Reporter;Research Personnel;Role;Series;Site;Syndrome;System;Testing;Work;base;design;desire;mutant;programs;reconstitution;research study;southern hybridization


application_id: 7327838
project_number: 1R43NS060471-01
project_title: Small Molecule Drug Therapy for Stroke
administering_ic: NINDS
award_notice_date: 2007-09-28
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: NS
serial_number: 060471
program_official: GOLANOV, EUGENE V
project_start_date: 2007-09-30
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (11)]
contact_pi_person_id: 8726051
contact_pi: CHAUDHARY, NILABH
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 803410831
duns_number: 803410831
fips: US
organization_id: 10010204
organization_name: NEOCYTEX BIOPHARMA, INC.
organization_city: Covington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-30
budget_end_date: 2008-08-31
project_abstract:
DESCRIPTION (provided by applicant): There is an urgent and unmet need for effective treatment methods for stroke patients who have suffered debilitating loss of nervous tissue and neural function. Development of neuroregeneration therapy is an important goal because neurological disorders such as stroke disable and kill millions of people worldwide each year yet a viable therapeutic option is not available. Discovery of neural stem cells (NSCs) in the aging brain and in stroke patients has sparked interest in the development of new approaches to boost the body's natural ability to create healthy new cells from endogenous stem cells. Recently we made the serendipitous discovery that a small molecule heterocyclic pyrimidine derivative can speed up the growth of human neural stem cells grown in culture. Subsequent preliminary analysis in rodents suggested that the molecule can accelerate neurogenesis in animals as well apparently without any ill effects. Based on these early observations we are hypothesizing that administration of the compound will stimulate new brain cell formation leading to improved neural function. To test this we are proposing to conduct a series of quantitative cell culture assays and animal studies to determine whether: (a) the compound can accelerate the growth of human neural stem cell without adversely affecting other cell types or increasing tumor cell growth (b) the newly formed cells are fully capable of differentiating into neurons and other cell types that typically populate the brain (c) when injected in normal adult mice the compounds will induce normal neurogenesis in a dose dependent manner and (d) when injected in a mouse model of stroke there will be a significant rise in neurogenesis with potential for improvement of neural function. Immunohistological assays growth assays and behavioral tests will be used to quantify the compound's activity. Upon the completion of these experiments we expect to confirm the feasibility of using the pyrimidine derivative to promote dose dependent neurogenesis in cell and animal models without inducing obviously deleterious effects. In Phase II we will conduct detailed safety distribution and efficacy studies on the molecule in preparation for carrying out IND- enabling studies during Phase III. This project is innovative because our test compound offers a novel approach for inducing new brain cell growth in patients with neurodegenerative diseases. We are proposing to test a new small molecule drug candidate that can boost the body's natural ability to regenerate brain cells from endogenous neural stem cells. When successful our drug candidate will offer a new treatment alternative for patients with neurodegenerative diseases such as stroke Alzheimer's disease Parkinson's and ALS.

project_terms:
A Mouse;Abnormal Cell;Adult;Adverse effects;Affect;Alzheimer's Disease;American;Amyotrophic Lateral Sclerosis;Animal Model;Animals;Behavior;Behavior Animal;Biological Assay;Blood flow;Brain;Bromodeoxyuridine;Caring;Cause of Death;Cell Line Tumor;Cell Proliferation;Cell Transplantation;Cells;Cellular Morphology;Cellular biology;Cerebrum;Cessation of life;Clinical Trials;Clinical Trials Phase I;Cognitive deficits;Condition;Cultured Cells;Daily;Data;Development;Disease;Disruption;Dose;Drug Industry;Drug Monitoring;Forelimb;Formulations Drug;Funding;Future;Goals;Grant;Growth;Healed;Histology;Human;Immunohistochemistry;Injection of therapeutic agent;Injury;Killings;Label;Lead;Licensing;Life;Maleates;Marketing;Measurable;Measurement;Measures;Mesenchymal Stem Cells;Metabolic;Methods;Microscopy;Modeling;Molecular Target;Monitor;Motor;Mus;Myron (drug combination);Natural regeneration;Nerve Tissue;Nervous System Physiology;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Neurons;Neurophysiology - biologic function;Numbers;Oligodendroglia;Other Resources;Pathology;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Population;Preparation;Primates;Proliferating;Property;Pyrimidine;Pyrimidines;Range;Rate;Recovery;Recovery of Function;Reflex action;Rehabilitation therapy;Research;Research Personnel;Rodent;Rose Bengal;Safety;Science of Chemistry;Sensory;Series;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Speed (motion);Staging;Stem cells;Testing;Therapeutic;Tissues;Toxic effect;United States;Week;Work;aged;aging brain;base;behavior test;brain cell;cancer cell;cell growth;cell type;commercialization;cost;day;design;disability;experience;healing;improved;in vivo;innovation;interest;mouse model;neoplastic cell;nerve stem cell;nervous system disorder;neurogenesis;novel;novel strategies;relating to nervous system;research and development;research study;restoration;size;small molecule;stroke;success;tool


application_id: 7327536
project_number: 1R43CA130543-01
project_title: Novel Peptide Libraries for Early Cancer Detection
administering_ic: NCI
award_notice_date: 2007-09-10
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: CA
serial_number: 130543
program_official: WANG, WENDY
project_start_date: 2007-09-10
project_end_date: 2009-09-09
study_section: Special Emphasis Panel[ZRG1 BCMB-L (11)]
contact_pi_person_id: 8838612
contact_pi: DARLAK, KRZYSZTOF
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 106895766
primary_uei: R2GLRKJGMVP8
duns_number: 106895766
uei: R2GLRKJGMVP8
fips: US
organization_id: 2235101
organization_name: PEPTIDES INTERNATIONAL, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402993861
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Global cancer rates are predicted to increase by 50% to 15 million by 2020. Treatments depend on early detection and identification to select the most effective therapies to end the suffering and loss of life. Biomarkers offer tremendous potential for early detection though few exist today. Biomarkers of early stage disease are likely to be at very low concentrations in highly complex biological samples containing abundant proteins. Dramatic improvements in technology would be needed for better detection and identification of these specific but trace biomarkers. No bioseparation method exists today to accomplish this goal in a simple cost-effective manner while utilizing existing sample collection and analytical platforms. Thus new robust and sensitive processing technology is urgently needed for early detection of biomarkers. In 2001 solid-phase peptide combinatorial libraries were developed at the American Red Cross (ARC) and produced by Peptides International (PI) to generate leads in biomarker discovery and drug development. ARC demonstrated that the libraries could be used to concentrate trace analytes in complex biological mixtures. PI now proposes a more powerful approach for identification of cancer-specific biomarkers with emphasis on protein tyrosine kinases (PTK) which are key regulators of cellular growth and differentiation processes in immune endocrine and nervous system physiology and are of critical importance in the development of many cancers. This requires the selective concentration of classes of proteins e.g. PTKs using Targeted Combinatorial Peptide Library (TCPL) technology. We propose a new sample preparation device comprising a novel peptide library for the selective enrichment of class specific proteins initially targeted for PTKs. The Specific Aims of this Phase I feasibility study will be the synthesis and evaluation of the following: (i) a control Combinatorial Peptide Library (CPL); (ii) a tyrosine-enriched TTCPL; (iii) a phosphotyrosine-enriched TCPL and (iv) a phosphate analog-enriched TCPL. The criterion for advancement to Phase II studies is the targeted library that yields at least a10-fold enhancement of PTK detection over the existing unmodified control library which itself is anticipated to improve detection of trace proteins by = 10 fold. Upon demonstrated success of this feasibility study we envision a successful Phase II/III commercialization path to produce Targeted Peptide Libraries for early cancer detection for research organizations and diagnostic companies. This novel device would be a quantum leap in improvement over existing techniques which currently offer no such commercial product. This project seeks to develop a novel approach to biomarker discovery and detection for the early diagnosis of cancer. It addresses the problem of enrichment and selective identification of classes of trace proteins in disease-related biopsy samples. The project focuses on achieving early and more reliable detection of protein tyrosine kinases (PTKs) that are important in the diagnosis of cancer. It achieves this by using novel targeted peptide libraries that will allow patients to receive earlier therapy. While focused on cancer this technology has broad application to many other disease states.

project_terms:
Address;American;Amino Acids;Binding (Molecular Function);Binding Proteins;Biological;Biological Markers;Biological Products;Biopsy Specimen;Businesses;Cells;Chemicals;Chromatography Affinity;Class;Clinical Trials Phase II;Combinatorial Synthesis;Complex;Complex Mixtures;Condition;Contracts;Cysteine;Cytolysis;Cytoplasmic Protein;Detection;Development;Devices;Diagnostic;Diagnostics Research;Disease;Early Diagnosis;Endocrine;Endopeptidases;Enzyme Stability;Enzymes;Evaluation;Excision;Feasibility Studies;Funding;Generations;Goals;Immune;Individual;International;Lead;Libraries;Licensing;Life;Ligands;Location;Malignant Neoplasms;Methionine;Methods;N-terminal;Nervous System Physiology;Numbers;Patients;Peptide Hydrolases;Peptide Library;Peptide Synthesis;Peptides;Performance;Phase;Phenylalanine;Phosphate-Binding Proteins;Phosphoric Monoester Hydrolases;Phosphotransferases;Phosphotyrosine;Plasma;Positioning Attribute;Preparation;Prions;Process;Protein Tyrosine Kinase;Proteins;Proteomics;Protocols documentation;Randomized;Rate;Receptor Protein-Tyrosine Kinases;Red Cross;Research;Research Personnel;Resins Plant;Saline;Sampling;Screening for cancer;Side;Sites Active;Solid;Specificity;Spectrum Analysis Mass;Staging;Structure;Synthetic Peptide Libraries;Techniques;Technology;Testing;Therapeutic Uses;Time;Today;Tyrosine;Validation;Work;analog;base;cancer diagnosis;cell growth;combinatorial;combinatorial chemistry;commercialization;cost;design;drug development;experience;gel electrophoresis;improved;innovation;inorganic phosphate;manufacturing process;novel;novel strategies;numb protein;pathogen;peptide structure;protein purification;quantum;sample collection;success


application_id: 7326239
project_number: 1R41CA121665-01A2
project_title: ApoVax-SVN as a Novel Vaccine for Cancer Immunotherapy
administering_ic: NCI
award_notice_date: 2007-09-06
opportunity_number: PA-06-121
application_type: 1
activity_code: R41
ic: CA
serial_number: 121665
suffix: A2
program_official: WELCH, ANTHONY R
project_start_date: 2007-09-06
project_end_date: 2009-03-05
study_section: Special Emphasis Panel[ZRG1 ONC-L (12)]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
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: 2007-09-06
project_abstract:
DESCRIPTION (provided by applicant): The main objective of this proposal is to develop a novel cancer vaccine ApoVax-SVN(tm) based on the use of a proprietary costimulatory chimeric ligand 4-1BBL designed to specifically deliver survivin a tumor associated antigen (TAA) to professional antigen-presenting cells (APCs) and activate them for the generation of an effective anti-tumor immune response with therapeutic efficacy for cancer immunotherapy. Therapeutic vaccines represent an attractive treatment modality for the management of cancer primarily due to their specificity and ability to induce long lasting immunological memory that may prevent against recurrences. However their therapeutic potential remains to be realized partially due to the complex nature of interactions taking place between the immune system and cancer cells in the course of tumor progression. These interactions are primarily regulated by two opposing forces; immune mechanisms that target the tumor for destruction and tumor-mediated counter-mechanisms that enable the tumor to evade the immune system. As such to be effective tumor vaccines must be capable of generating a potent anti-tumor immune response as well as overcoming immune evasive mechanisms for a therapeutic effect. Various cancer vaccine approaches based on the use of TAAs have been developed and shown effective in preclinical models. However the therapeutic efficacy of these vaccines has been limited in clinical trial settings. Although the reasons for their clinical inefficacy remain unknown the lack of a strong adjuvant effect ineffective delivery of TAAs to professional APCs and/or the presence of significant immunoinhibitory immune evasion mechanisms may contribute to this effect. To overcome some of these difficulties a novel technology designated as ProtEx(tm) has recently been developed by the Principle Investigator of this application. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin modification of the cell membrane with biotin and decoration with chimeric proteins. There are three distinct advantages to this technology. First chimeric ligands exist as tetramers and higher structures and as such effectively crosslink their receptors on immune cells for potent signal transduction. Second chimeric proteins can be displayed singly or in a combination on the surface of any biotinylated cell at desired levels in a rapid (< 2 hrs) efficient (100% of the targeted cells) and durable (t1/2= days to weeks) manner without compromising the function of the protein or the cell. Third chimeric proteins can be conjugated to biotinylated molecules of interest via streptavidin/biotin interaction and used as vehicles to deliver such molecules to cells of interest expressing receptors for the chimeric proteins. The Principle Investigator of this application recently developed a novel proprietary potential cancer vaccine approach based on the use of 4-1BBL chimeric molecule conjugated to biotinylated TAA antigens. In preliminary studies this novel vaccine showed potent stimulatory activity on the innate as well as adaptive arms of the immune system and inhibitory activity on T regulatory cells implicated in tumor growth. More importantly since the last submission of this grant we have demonstrated that immunization with SA-4-1BBL plus a synthetic peptide representing the CD8+ T cell epitope of E7 was effective in eradicating established tumors in a cervical cancer animal model. Therefore the objectives of this proposal are to test and determine in vivo conditions required for protective as well as therapeutic effects of ApoVax-SVN(tm) vaccine using a B cell lymphoma transplantable model expressing survivin as a TAA. Proof-of-principle confirmation in experimental cancer models will pave the way for testing this novel concept in human clinical trials. Immune system-based treatment of cancer represents an alternative therapeutic approach to classic chemotherapy and radiation treatment and promises to yield a more definitive solution based on a true molecular approach to cancer. ApoImmune's novel immune system-based therapy ApoVax104 vaccine is a new innovative approach to treating cancer and malignant neoplastic diseases.

project_terms:
Activated Lymphocyte;Acute;Adjuvant;Adverse effects;Animal Model;Animals;Antibody Formation;Antigen Presentation;Antigen Presentation Pathway;Antigen-Presenting Cells;Antigens;B-Cell Lymphomas;Binding (Molecular Function);Biotin;CD8B1 gene;Cancer Model;Cancer Patient;Cancer Vaccines;Cause of Death;Cell Differentiation process;Cell membrane;Cells;Chimeric Proteins;Clinical;Clinical Trials;Clinical Trials Phase I;Complex;Condition;Dendritic Cells;Dendritic cell activation;Developed Countries;Developing Countries;Development;Disease;Dose;Effectiveness;Enzyme-Linked Immunosorbent Assay;Epitopes T-Lymphocyte;Extracellular Domain;Figs - dietary;Generations;Goals;Grant;Grants Applications;Human;Immune;Immune Targeting;Immune response;Immune system;Immunization;Immunologic Memory;Immunotherapy;In Vitro;Injection of therapeutic agent;Life;Ligands;Lymphocyte antigen;Maintenance;Major Histocompatibility Complex;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Marketing;Mediating;Mice Inbred BALB C;Modality;Modeling;Modification;Molecular;Mus;Natural Killer Cells;Nature;Operative Surgical Procedures;Patients;Peptides;Phase;Play;Pre-Clinical Model;Prevention;Protein Isoforms;Protocols Treatment;Radiation;Radiation therapy;Recurrence;Research Personnel;Role;Series;Signal Transduction;Small Business Technology Transfer Research;Solutions;Specificity;Staining method;Stains;Streptavidin;Structure;Surface;Survivin Antigen;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Tumor Antigens;United States;Upper arm;Vaccinated;Vaccines;Week;Work;base;cancer cell;cancer immunotherapy;cancer prevention;cancer therapy;cell mediated immune response;chemotherapy;concept;crosslink;cytokine;day;design;desire;in vivo;innovation;interest;macrophage;mouse model;neoplastic;new technology;novel;novel vaccines;prevent;prophylactic;protein function;receptor;response;size;success;survivin;synthetic peptide;therapeutic effectiveness;therapeutic vaccine;tumor;tumor growth;tumor progression;vaccine efficacy


application_id: 7325809
project_number: 8R01HD058299-26
project_title: Hepatic Drug Elimination in Pregnancy
administering_ic: NICHD
award_notice_date: 2008-01-03
application_type: 8
activity_code: R01
ic: HD
serial_number: 058299
program_official: ZAJICEK, ANNE
project_start_date: 1979-09-30
project_end_date: 2010-11-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
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: 2007-12-01
project_abstract:
This proposal focuses on the function and expression of MRP2 (ABCC2) the ABC transporter that mediatesthe biliary excretion of glucuronide and glutathione conjugates from the hepatocyte into bile. The proposalbuilds on our findings that 1) MRP2 transports tauroursodeoxycholate (TUDC) a bile acid used for thetreatment of cholestatic liver disease including intrahepatic cholestasis of pregnancy (ICP) 2) estradiol-17[3-D-glucuronide (E217G) causes increased permeability of the hepatocellular tight junction that coincides withendocytic retrieval of MRP2 and the bile salt export pump (BSEP) from the canalicular membrane anddecreased bile flow and 3) identification of upstream open reading frames (uORF) in the 5' leadersequences of rathuman and mouse MRP2. Aim 1 will characterize MRP2-mediated transport of hydrophilicbile acids including TUDC (3-muricholicacid and tetrahydroxy bile acids and the importance of heterotropicand homotropic activation in their transport. We will also examine the ability of MRP2 variants to transportthese bile acids. We will use an MRP2 baculovirus expression system in Sf9 cells to characterize transport.Aim 2 will determine the role of protein kinase C (PKC) and tight junction permeability in E217G-inducedcholestasis. We will test the hypothesis that E217G disrupts hepatocyte tight junctions in a PKC-dependentmanner that coincides with endocytic retrieval of key transporters MRP2 and BSEP from the canalicularmembrane leading to cholestasis. We will use 4 model systems to test this hypothesis: in vivo studies in therat the isolated perfused rat liver isolated rat hepatocyte couplets and HepG2 cells coupled with confocalfluorescence and electron microscopy to monitor the localization of transporters and tight junction proteinsafter treatment with E217G and in the presence and absence of PKC inhibitors. Aim 3 will characterize theimportance of the uORF in rathuman and mouse MRP2 mRNA on the translational regulation of MRP2protein. We will characterize the differential tissue expression of MRP2 mRNA transcripts expressing theuORF and use site-directed mutagenesis to disrupt the uORF coupled with in vitro translation assays toinvestigate the importance of leaky scanning and the sequence of the peptide encoded by the uORF inregulating translation of Mrp2/MRP2. We will also determine whether the peptide encoded by the rat uORFis expressed in vivo. Significance: MRP2 is critical for elimination of polar metabolites from liver and kidneyas well decreasing the intestinal absorption of dietary carcinogensand its expression in liver is decreasedinpregnancy. Characterization of mechanisms of regulation of the activity localization and expression ofMRP2 can lead to improved drug therapy for women in pregnancy and development of therapeutic measuresto increase MRP2 function in cholestatic liver disease particularly in ICP.

project_terms:
5' Untranslated Regions;ATP-Binding Cassette Transporters;Acids Bile;Aftercare;Amniotic Fluid;Animals Laboratory;Baculovirus Expression System;Bile fluid;Biliary;Biological Models;Cells;Cholestasis;Codon Initiator;Coupled;Data;Development;Electron Microscopy;Estradiol;Estrogens;Excretory function;Fluorescence;Generations;Glucuronides;Glutathione;Glycine;Hepatic;Hepatocyte;Human;In Vitro;Intestinal Absorption;Kidney;Kinetics;Laboratories;Lead;Liver;Liver diseases;Measures;Mediating;Membrane;Microtubules;Monitor;Multidrug Resistance-Associated Proteins;Mus;Mutagenesis Site-Directed;Nucleotides;Open Reading Frames;Patients;Peptides;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Pregnancy;Protein Isoforms;Protein Kinase C;Protein Kinase C Inhibitor;Proteins;Pump;RNA Messenger;Rattus;Recovery;Regulation;Retrieval;Role;Salts Bile;Scanning;Single Nucleotide Polymorphism;Sulfates Inorganic;Sulfates Unspecified or Sulfate Ion;Taurine;Testing;Therapeutic;Tight Junctions;Tissues;Transcript;Translational Regulation;Translations;Treatment Efficacy;Urine;Variant;Woman;aminoacid sequence of protein;base;citrate carrier;estradiol-3-glucuronide;glucuronide;hydroxyl group;improved;in vivo;intrahepatic cholestasis of pregnancy;muricholic acid;prevent;protein expression;translation assay;ursodeoxycholate


application_id: 7325641
project_number: 1R43CA130228-01
project_title: A novel biotherapeutic treatment for prostate cancer
administering_ic: NCI
award_notice_date: 2007-08-31
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: CA
serial_number: 130228
program_official: LOU, XING-JIAN
project_start_date: 2007-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1 ONC-L (14)]
contact_pi_person_id: 8717940
contact_pi: XU, KEVIN
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 782233501
primary_uei: HJPDQTK95NS8
duns_number: 782233501
uei: HJPDQTK95NS8
fips: US
organization_id: 10010035
organization_name: BEXION PHARMACEUTICALS, INC.
organization_city: Covington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The American Cancer Society estimated a total of 1372910 new cancer cases and 570280 cancer deaths in the U. S. in 2005. The National Cancer Institute solicits research proposals to develop cancer treatments via the Small Business Innovation Research funding mechanism. The long-term objective of Bexion Pharmaceutical Inc's research and development program is to evaluate the clinical benefits of Bexion's proprietary first-in-class biotherapeutic agent in treating common primary and metastasized cancers including prostate cancer. The incident rate of 232090 cases of prostate cancer is the highest among all cancers in men and it is the second leading cause of death resulting in 30350 deaths in the U.S. in men in the U.S. in 2005. The objective of the proposed research is to conduct pre-clinical proof-of-principle studies to show that the treatment agent is efficacious in reducing the size of primary as well as metastasized prostate cancer. In the specific aims of this project we propose to evaluate the preclinical benefit of Bexion's treatment agent on (1) orthotopic and (2) metastasized prostate tumors in male athymic mice. To achieve these objectives we will utilize the Caliper Life Sciences' bioluminescent prostate cancer cell line (PC-3M-luc-6M) to generate orthotopic and metastasized prostate cancer in athymic mice and use Caliper's in vivo non-invasive imaging system to quantify the real-time effects of Bexion's treatment agent on the size of these tumors before during and after treatment in individual mice. Prostate cancer is the leading cancer disease and is the second leading cause of cancer death in men. However treatment options for the disease are limited. Bexion Pharmaceuticals Inc. is developing a first-in-class cancer biotherapeutics that has the potential for the treatment of both primary and metastasized prostate cancer.

project_terms:
Aftercare;American Cancer Society;Animal Model;Animals;Apoptosis;Biological Products;Biological Response Modifier Therapy;Biological Sciences;Bioluminescence;Bulla;Cancer Etiology;Cancer cell line;Cause of Death;Cells;Ceramides;Cessation of life;Class;Clinical;DNA Fragmentation;Development;Disease;Dose;Elevation;Funding Mechanisms;Goals;Growth;Human;Image;In Vitro;Individual;Injection of therapeutic agent;Invasive;Left ventricular structure;Luciferases;Malignant Neoplasms;Malignant neoplasm of prostate;Mice Nude;Monitor;Mus;National Cancer Institute;Neoplasm Metastasis;Numbers;PC3 cell line;Personal Satisfaction;Pharmacologic Substance;Photons;Plasmids;Primary Neoplasm;Prostate;Prostatic Neoplasms;Protocols Treatment;Rate;Research;Research Proposals;Serine;Small Business Innovation Research Grant;System;Tail;Time;VP6 protein Rotavirus;Veins;Week;Xenograft procedure;beta-Glucosidase Stimulating Protein;cancer cell;cancer therapy;caspase;clinical efficacy;design;implantation;in vivo;male;men;mouse model;neoplastic;neoplastic cell;novel;pre-clinical;programs;proteoliposomes;research and development;size;subcutaneous;tumor


application_id: 7325628
project_number: 1R43DK079394-01
project_title: ApoFasL: a Novel Immunotherapeutic for T1D
administering_ic: NIDDK
award_notice_date: 2007-08-06
opportunity_number: PA-06-121
application_type: 1
activity_code: R43
ic: DK
serial_number: 079394
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2007-08-06
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1 EMNR-E (10)]
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: 2007-08-06
budget_end_date: 2009-01-31
project_abstract:
DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease that targets insulin secreting pancreatic beta cells for destruction and remains a major cause of morbidity and mortality in over 1% of the population worldwide. Although insulin therapy and islet transplantation are currently the most effective treatments both of these approaches suffer from major limitations including the inability of insulin therapy to totally prevent diabetes- associated complications the limited availability of human islets for transplantation and the rejection of islet allografts irrespective of the use of immunosuppressive drugs. Therefore the use of islets from a different species such as pigs and induction of tolerance without the chronic use of immunosuppressive drugs will be important therapeutic advancements required for the efficient treatment of T1D in the clinic. The main objective of this proposal is to establish proof-of-principle for a novel safe and practical approach designated as ApoFasL to induce transplantation tolerance to xenogeneic pancreatic islets as a therapeutic intervention for the treatment of Type 1 diabetes Given the important role played by Fas/FasL system in immune tolerance to self antigens immune privilege and lymphocyte homeostasis and the extensive use of FasL to induce allograft tolerance in various settings the Principle Investigator of this grant Dr. Haval Shirwan developed a novel form of FasL with potent apoptotic activity using ApoImmune's ProtEx(tm) technology. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin modification of a cell membrane with biotin and decoration of biotinylated membrane with chimeric proteins. Preliminary data have demonstrated that the display of FasL on pancreatic islets (ApoFasL therapy) using ProtEx(tm) resulted in the prevention of graft rejection and treatment of chemically-induced diabetes in an allogeneic transplant model. Expanding on these data the focus of this proposal is to develop proof-of-principle for an effective clinically applicable approach to induce immune tolerance to xenogeneic islet grafts in a rat-to-mouse model for the treatment of diabetes. FasL will be displayed on rat donor islets for transplantation into both chemically-induced diabetic mice and spontaneously diabetic non-obese diabetic (NOD) mice which exhibit destructive autoimmune pancreatic insulitis. Transplants will be done in the presence of rapamycin a pharmaceutical agent used in the clinic for the prevention of graft rejection. We hypothesize that islets decorated with FasL will induce tolerance by eliminating xenoreactive lymphocytes via apoptosis and expanding T regulatory cells. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells thereby creating donor specific immune tolerance leading to the survival of transplanted islets. Proof-of-principle will be followed by a Phase II STTR application to further develop ApoFasL into a lead product by testing its efficacy in a pig-to-nonhuman primate xenograft model. Tolerance to xenogeneic islets will serve as the first step towards the translation of this novel approach to the clinic for the treatment of T1D. If proven effective ApoFasL may improve the quality of life of millions of individuals worldwide with an economic impact in billions of dollars. Xenograft islet transplantation represents an alternative therapeutic approach for Type 1 diabetes over classic allogeneic islet transplantation and insulin treatment therapies and promises to yield a more definitive solution. The ApoFasL approach when successful will ensure a pathway to the treatment of Type 1 diabetes.

project_terms:
Allogenic;Animal Model;Apoptosis;Apoptotic;Atypical lymphocyte;Autoantigens;Autoimmune Diseases;Autoimmune Process;Biotin;C57BL/6 Mouse;Cell membrane;Cells;Chimeric Proteins;Chronic;Clinic;Clinical;Clinical Treatment;Clinical Trials;Condition;Data;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Diabetic mouse;Disease;Economics;Effector Cell;Engineering;Ensure;Environment;Exhibits;Extracellular Domain;Family suidae;Figs - dietary;Generations;Goals;Graft Rejection;Graft Survival;Grant;Histocompatibility Antigens;Homeostasis;Human;Immune;Immune Tolerance;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Individual;Injection of therapeutic agent;Insulin;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Ligands;Localized;Lymphocyte;Maintenance;Membrane;Mice Inbred NOD;Modeling;Modification;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neoadjuvant Therapy;Non obese;Organ;Pancreas;Pathway interactions;Peripheral;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiological;Play;Population;Prevention;Quality of life;Rats Inbred WF;Rattus;Replacement Therapy;Research Personnel;Rodent Model;Role;Role playing therapy;Signal Transduction;Sirolimus;Small Business Technology Transfer Research;Solid;Solutions;Streptavidin;Streptozocin;Structure;Structure of beta Cell of islet;Surface;Sus scrofa;System;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Intervention;Tolerance Allograft;Translations;Transplantation;Transplantation Tolerance;Tumor Necrosis Factor Ligand Superfamily Member 6;Week;Work;Xenograft Model;Xenograft procedure;base;crosslink;day;design;desire;diabetic;improved;interest;islet;islet allograft;islet xenograft;mouse model;nonhuman primate;novel;novel strategies;novel therapeutics;prevent;protein function;receptor;response


application_id: 7324811
project_number: 5R01HL075241-05
project_title: Regulation of Ras Signaling by Rlf In Hypertrophy
administering_ic: NHLBI
award_notice_date: 2007-11-28
application_type: 5
activity_code: R01
ic: HL
serial_number: 075241
program_official: BUXTON, DENIS B
project_start_date: 2003-12-01
project_end_date: 2009-02-28
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 7875399
contact_pi: POST, STEVEN
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: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant): Important recent advances derived from experimental models of cardiac hypertrophy suggest that distinct signaling pathways regulate compensated hypertrophy and decompensated heart failure. Ras is a small GTP binding protein that signals through multiple effectors including the Raf-MEK-ERK pathway PI3 kinase (PI3K) guanine exchange factors for Ral (RalGEFs) and cJun N-terminal kinase (JNK). In transgenic mice V12Ras-mediated hypertrophy is associated with JNK activation and depressed cardiac function. However certain Ras-dependent signaling cascades including ERK and PI3K activate compensatory hypertrophic responses that preserve contractile activity. To identify novel Ras effectors we screened a human heart cDNA library using Ras as bait and isolated Ral guanine nucleotide exchange factor-like factor (RIf). To examine the functional consequence of the Ras-RIf interaction we expressed V12Ras in concert with RIf in neonatal ventricular rat myocytes (NRVM). Expression of RIf suppressed V12Ras-induced JNK activity and ANF expression but not other Ras effectors. RIf also inhibited sorbitol-induced JNK activation indicating that RIf expression negatively regulates JNK activation in response to multiple stimuli. These results demonstrate that RIf suppresses an effector pathway suggested to mediate depressed function of myocardial cells. We will test the hypothesis that RIf negatively regulates JNK activation and that function inhibits the development of hypertrophic cardiomyopathy in vivo. The signaling pathways that couple Ras to JNK activation are not known but may involve MEKK1 (MAPWERK kinase kinase 1) a Ras binding protein that preferentially activates JNK. In aim #1 we will define the role of MEKK1-JKK-JNK in RIf-mediated inhibition of V12Ras- and stress- signaling. In aims #2 and #3 the pathophysiological implications of RIf function will be investigated in transgenic mice that overexpress RIf. We will test the potential protective role of RIf on the pathogenesis of cardiac hypertrophy in response to pressure overload isoproterenol infusion and V12Ras overexpression and investigate the signaling cascades involved. Elucidation of the mechanisms by which RIf regulates hypertrophic signaling pathways may lead the development of novel therapeutic approaches to prevent cardiac dysfunction.

project_terms:
1-Phosphatidylinositol 3-Kinase;Age;Americas;Atrial Natriuretic Factor;Binding Proteins;Cardiac;Cells;Cellular Stress;Chronic;Depressed mood;Development;Diagnosis;Exhibits;Family;Fibrosis;Forecast of outcome;Functional disorder;GTP-Binding Proteins;Genetic;Guanine;Guanine Nucleotide Exchange Factors;HRAS gene;Heart;Heart Diseases;Heart Failure Congestive;Heart Hypertrophy;Heart failure;Human;Hypertrophic Cardiomyopathy;Hypertrophy;Infusion procedures;Isoproterenol;JNK-activating protein kinase;Lead;MAPK8 gene;MEKs;Mediating;Mice Transgenic;Modeling;Models Experimental;Mus;Muscle Cells;Myocardial;Myocardium;Myosin Heavy Chains;N-terminal;Neonatal;Nucleotides;Oligonucleotides Antisense;Pathogenesis;Pathway interactions;Phenotype;Phosphoinositide-3-Kinase Catalytic Gamma Polypeptide;Phosphotransferases;Pressure- physical agent;Promotor (Genetics);Protein Overexpression;Rattus;Regulation;Research Personnel;Risk;Role;Severities;Signal Pathway;Signal Transduction;Sorbitol;Stimulus;Stress;Survival Rate;Testing;Transgenic Organisms;Ventricular;Week;Work;cDNA Library;in vivo;interstitial;member;mouse model;novel;novel therapeutics;prevent;programs;response


application_id: 7322977
project_number: 1R43HL090055-01
project_title: Development of a Personalized Medicine Interface for the Safe and Effective Treat
administering_ic: NHLBI
award_notice_date: 2007-08-14
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: HL
serial_number: 090055
program_official: LINK, REBECCA P
project_start_date: 2007-08-16
project_end_date: 2008-02-15
study_section: Special Emphasis Panel[ZRG1 GGG-J (10)]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-16
budget_end_date: 2008-02-15
project_abstract:
DESCRIPTION (provided by applicant):  PGXL Laboratories has access to a unique computational tool that can significantly reduce the morbidity and mortality associated with warfarin anticoagulation therapy. This project will yield a web-based software tool that will for the first time allow physicians to incorporate their patients' genetic and physical characteristics into individualized treatment plans. The long-term objective of this proposal is to create a software interface which generates customizable treatment plans for individual patients based on their genotypic and physical traits. Within the scope of this Phase I application the applicants propose the development of a software tool for use with individuals undergoing warfarin therapy. The project goal is to develop a novel computational model that: (1) accurately estimates the plasma warfarin concentration following every warfarin dose while (2) providing a visual representation of the time required to achieve steady state; and (3) accurately predicts the most appropriate warfarin maintenance dose. Completion of these aims will establish that the model can provide clinicians with the three crucial elements of information they need to develop the most effective treatment strategy for each individual patient. Patient genotypes at two loci CYP2C9 and VKORC1 will be utilized as variants of these genes are closely associated with the reduced effectiveness of warfarin. Physical characteristics including age gender and weight will also be incorporated as well as steady-state plasma warfarin concentrations and prothrombin time to "train" the software through a series of regression analyses. Once the software has been satisfactorily trained Phase II of the project will take the software live incorporating data from patients as they begin warfarin therapy. As cooperating physicians follow their patients the model will be tested to determine how closely it predicts real-world results. At the same time the software package will be under development to turn it into a Windows-based user-friendly interface. The costs involved in the current methods of warfarin therapy management are great including frequent office visits testing dosing adjustments and hospital stays as the result of adverse drug reactions. The greatest costs of all are the risks involved inappropriate dosing. By incorporating genetic testing into standard warfarin therapy practices almost 100000 people could be saved from bleeding or stroke events annually and as much as $2 billion a year could be saved. . Personalized medicine is a new approach by which the genetic and physical characteristics of a patient are combined to produce an individualized treatment plan. Simple tools which allow physicians to easily practice personalized medicine hold great promise for the future of safe effective and efficient patient therapy. Proposed here is a software interface which will generate a unique customizable and dynamic model which not only will predict the optimal dose of warfarin required by a given patient but will also guide the physician throughout the patient's course of therapy.

project_terms:
Accident and Emergency department;Accounting;Adverse event;Age;Anticoagulants;Anticoagulation;Blood;Blood Tests;Characteristics;Complex;Computer Simulation;Computer software;Cost Savings;Cytochromes;Data;Data Analyses;Development;Dose;Effectiveness;Elements;Event;Future;Gender;Genes;Genetic;Genetic screening method;Genotype;Goals;Health;Health Care Costs;Hemorrhage;Individual;Laboratories;Length of Stay;Life;Maintenance;Maintenance Therapy;Marketing;Medicine;Methods;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Names;Office Visits;Online Systems;Oral;Overdose;Patients;Pharmaceutical Preparations;Pharmacogenetics;Phase;Physicians;Plasma;Polymorphism Genetic;Prevention;Proteins;Prothrombin time assay;Range;Rate;Reaction;Regression Analysis;Risk;Safety;Series;Standards of Weights and Measures;Testing;Therapeutic;Time;Tools Software;Toxic effect;Training;Translating;Treatment outcome;United States;Update;Variation (Genetics);Visual;Waran;Warfarin;Weight;Writing;base;caN protocol;clinical application;computerized tools;cost;dosage;experience;improved;novel;novel strategies;patient safety;pharmacogenetic testing;predictive modeling;prescription document;prescription procedure;stroke;tool;trait;treatment planning;user-friendly;vitamin K epoxide reductase


application_id: 7319658
project_number: 5F31MH074245-03
project_title: Comparing Personality Disorder Models: FFM and DSM-IV
administering_ic: NIMH
award_notice_date: 2007-10-18
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: MH
serial_number: 074245
program_official: RUBIO, MERCEDES
project_start_date: 2005-12-17
project_end_date: 2008-12-16
study_section: Special Emphasis Panel[ZRG1-F12B(20)L]
contact_pi_person_id: 8087519
contact_pi: SAMUEL, DOUGLAS B
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 proposed study will allow the current DSM-IV categorical model of personality disorders to be compared directly to the Five-Factor model (FFM) of personality on the basis of temporal stability within a clinical setting convergent and discriminant validity and clinical utility. The FFM is the most heavily researched of the dimensional models that have been proposed as an alternative for the current DSM-IV system. The DSM- IV and FFM ratings will be assessed in a group of 75 self-referred individuals who are currently receiving outpatient psychotherapy for a personality disorder using the four primary methods of assessment used in clinical practice: unstructured clinical interview by the client's therapist semi-structured interview by a trained researcher self-report inventory and informant report. Additionally the same participants will be assessed again after six months to examine the temporal stability of each model. Finally the therapists who are treating these clients and providing the unstructured clinical interview ratings will also provide feedback on the clinical utility of each model. It is hoped that this research will help to better conceptualize personality difficulties and ultimately a more coherent and useful diagnostic system.

project_terms:
American;Biological Models;Categories;Client;Clinical;DSM-IV;DSM-V;Diagnostic;Diagnostic and Statistical Manual;Dimensions;Disadvantaged;Disease;Disease model;Emotional;Equipment and supply inventories;Feedback;Individual;Interview;Introversion (Psychology);Link;Methodology;Methods;Modeling;Neurotic Disorders;Nomenclature;Outpatients;Participant;Patient Self-Report;Personality;Personality Disorders;Population;Psychotherapy;Publishing;Rate;Reporting;Research;Research Personnel;Structure;Syndrome;System;Training;Work;Writing;base;design;experience;trait


application_id: 7317306
project_number: 1R01AI072683-01A1
project_title: Characterization of Anaplasma phagocytophilum adhesins
administering_ic: NIAID
award_notice_date: 2007-07-12
application_type: 1
activity_code: R01
ic: AI
serial_number: 072683
suffix: A1
program_official: PERDUE, SAMUEL S
project_start_date: 2007-07-15
project_end_date: 2007-10-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
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 fatal disease and the second most common tick-borne infection in the United States. The etiologic agent is Anaplasma phagocytophilum an obligate intracellular bacterium that displays a unique tropism for neutrophils and neutrophil precursors. A. phagocytophilum adhesion to neutrophil surfaces involves recognition of P-selectin glycoprotein ligand-1 (PSGL-1) and sialyl Lewis x (sLex) a tetrasaccharide that modifies the N-terminus of PSGL-1 and other selectin ligands. Specifically this recognition requires interactions with a PSGL-1 N-terminal peptide and alpha 23-linked sialic acid and alpha 13-linked fucose of sLex. We hypothesize that A. phagocytophilum uses multiple adhesins that cooperatively bind these determinants. Studies of A. phagocytophilum and other Anaplasmataceae family members suggest the A. phagocytophilum PSGL-1/ sLex-targeting adhesins are induced late in development and may require glycosylation and multimerization into adhesin complexes-for proper function. The objective of this proposal is to identify and characterize the individual adhesins that recognize PSGL-1 sialic acid and fucose. The specific aims are: (1) identify candidate adhesins using affinity-based approaches; (2) identify adhesin candidates as upregulated or glycosylated outer membrane proteins; (3) test binding of putative adhesins to PSGL-1/ sLex glycoconjugates and cell surfaces. We have selected for an A. phagocytophilum adhesin variant the adhesion of which is PSGL-1- and sialic acid-independent but remains fucose-dependent. This variant will simplify identification of the fucose-specific adhesin and will aid adhesin hunting assays by circumventing the reliance of wild-type A. phagocytophilum on cooperative binding. Accomplishing these goals will shed light onto novel themes of bacteria-host cell interactions and will identify targets for treating or preventing HGA. Furthermore these studies may lead to the development of new treatments for inhibiting cellular adhesion events associated with inflammatory disorders.

project_terms:
Adherence (attribute);Adhesins Bacterial;Adhesions;Affinity;Amino Acid Sequence;Anaplasma phagocytophilum;Anaplasmataceae;Appendix;Bacteria;Bacterial Adhesion;Binding (Molecular Function);Biological Assay;Bovine Anaplasmosis;Cell Adhesion;Cell Communication;Cell surface;Cells;Complex;Cytolysis;Dependency (Psychology);Development;Disease;Electrospray Ionization;Epitopes;Event;Family member;Fostering;Fucose;Genome;Glycoconjugates;Goals;HL-60 Cells;Human;Immune Sera;Individual;Infections Tick-Borne;Inflammatory;Knowledge;Lead;Ligands;Light;Link;Mammals;Membrane Proteins;Microspheres;Modeling;N-terminal;Organism;P-selectin ligand protein;Paper;Pathogenesis;Peptides;Polysaccharides;Proteome;Recombinant Proteins;Recombinants;Reliance;Research;Selectins;Sialic Acids;Surface;Testing;Ticks;Transcript;Tropism;United States;Variant;Work;base;glycosylation;human granulocytic ehrlichiosis;inhibitor/antagonist;liquid chromatography mass spectroscopy;member;neutrophil;novel;pathogen;prevent;sialyl Lewis x


application_id: 7313615
project_number: 1R01NS054708-01A2
project_title: Genetic approaches to functional remyelination after SCI
administering_ic: NINDS
award_notice_date: 2007-12-26
opportunity_number: PAS-05-092
application_type: 1
activity_code: R01
ic: NS
serial_number: 054708
suffix: A2
program_official: KLEITMAN, NAOMI
project_start_date: 2008-01-01
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1 BDCN-J (05)]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Adult;Animals;Axon;Behavioral;Biological;Brain-Derived Neurotrophic Factor;Cells;Chest;Ciliary Neurotrophic Factor;Contusions;Data;Demyelinations;Dominant-Negative Mutation;Engraftment;Environment;Evoked Potentials Motor;Failure (biologic function);Functional disorder;Gene Deletion;Genetic;Heterozygote;Hindlimb;Impairment;In Vitro;Injury;Intervention;Lentivirus Vector;Lesion;Locomotor Recovery;Magnetism;Measures;Methods;Modeling;Modification;Molecular Genetics;Monitor;Mus;NRG1 gene;Natural regeneration;Neuregulin 1;Neuregulins;Notch Signaling Pathway;Numbers;Oligodendroglia;PLAB Protein;Play;Publications;Publishing;RNA Small Interfering;Rattus;Recovery;Recovery of Function;Research Personnel;Retroviridae;Role;Score;Signal Pathway;Signal Transduction;Spinal Cord;Spinal cord damage;Spinal cord injury;Stem cells;Work;cell type;clinically relevant;combinatorial;functional restoration;human embryonic stem cell;in vivo;injury prevention;insight;mouse model;myelination;neurotrophic factor;nicastrin protein;notch protein;partial recovery;precursor cell;response;success;vector;white matter


application_id: 7312847
project_number: 5P30NS051220-02
project_title: Core--Pharmacokinetics and Biomarker
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9005
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
budget_end_date: 2007-04-30
funding_mechanism: Research Centers
project_terms:
analytical chemistry;biomarker;biomedical facility;brain injury;enzyme linked immunosorbent assay;gas chromatography mass spectrometry;lipid peroxides;neuroprotectants;pharmacokinetics;spectrin;spinal cord injury


application_id: 7312846
project_number: 5P30NS051220-02
project_title: Core--Microscopy Image Analysis and Stereology
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9004
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
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: 2006-05-01
budget_end_date: 2007-04-30
funding_mechanism: Research Centers
project_terms:
bioimaging /biomedical imaging;biomedical facility;brain injury;digital imaging;fluorescence microscopy;image processing;microscopy;neuroimaging;spinal cord injury;video microscopy


application_id: 7312845
project_number: 5P30NS051220-02
project_title: Core-Behavioral Testing
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9003
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
budget_end_date: 2007-04-30
funding_mechanism: Research Centers
project_terms:
Rodentias;behavior test;behavioral /social science research tag;biomedical facility;brain injury;spinal cord injury


application_id: 7312844
project_number: 5P30NS051220-02
project_title: Core--Animal surgery and TBI /SCI model
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9002
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
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: 2006-05-01
budget_end_date: 2007-04-30
funding_mechanism: Research Centers
project_terms:
analgesia;biomedical facility;brain injury;disease /disorder model;laboratory mouse;laboratory rat;postoperative state;spinal cord injury;trauma;veterinary science


application_id: 7312620
project_number: 5P01HL078825-02
project_title: CORE--Pathology Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2006-04-01
project_end_date: 2010-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9003
contact_pi_person_id: 1880936
contact_pi: ANVERSA, PIERO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
project_terms:
biomedical facility;cardiovascular imaging /visualization;confocal scanning microscopy;fluorescence microscopy;immunocytochemistry;morphometry;pathology;terminal nick end labeling


application_id: 7312617
project_number: 5P01HL078825-02
project_title: Metabolic Basis of Preconditioning
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0004
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Adenoviridae;cytoprotection;electron spin resonance spectroscopy;free radicals;gene expression;genetically modified animals;heme oxygenase;ischemic preconditioning;laboratory mouse;metabolism;mitochondria;nitric oxide synthase;oxidative stress;protein localization;recombinant virus;reperfusion


application_id: 7312616
project_number: 5P01HL078825-02
project_title: Delayed Cardioprotection Induced by NO and CO
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 1964532
contact_pi: XUAN, YU-TING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
apoptosis;carbon monoxide;cytoprotection;genetically modified animals;ischemic preconditioning;laboratory mouse;mitogen activated protein kinase;nitric oxide;reperfusion;terminal nick end labeling;transcription factor


application_id: 7312615
project_number: 5P01HL078825-02
project_title: Cardioprotective Genes and Postinfarction Left Ventricular Remodeling
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
apoptosis;cytoprotection;echocardiography;enzyme induction /repression;enzyme mechanism;gene expression;gene therapy;genetically modified animals;heart failure;heme oxygenase;immunocytochemistry;ischemic preconditioning;laboratory mouse;nitric oxide synthase;oxidative stress;polymerase chain reaction;superoxide dismutase;western blottings


application_id: 7312614
project_number: 5P01HL078825-02
project_title: Gene Therapy to Achieve Permanent Cardioprotection
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
cardiovascular disorder prevention;cytoprotection;gene therapy;genetically modified animals;immunocytochemistry;ischemic preconditioning;laboratory mouse;myocardial infarction;nitric oxide;nitric oxide synthase;polymerase chain reaction;transcription factor


application_id: 7311936
project_number: 5P42ES007380-10
project_title: Core--Research Support
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9005
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The proposed Research Support Core (Core B) of the Superfund Basic Research Program at the University of Kentucky (SBRP) will perform the vital role of supporting the research activities of multiple investigators involved in our SBRP. The main objective of this Core is to provide a central facility that will enhance and develop the research capabilities of our SBRP particularly in the areas of proteomics bioinformatics and PCB analysis. Statistical consultations an integral part of all projects also reside within the Core. Establishment of a coordinated effort in the form of the Research Support Core will maximize both the research and cost effectiveness of our SBRP investigators. This Core will be divided into 3 major components directed by an expert in each area: 1. Proteomics Component - coordinated by Dr. Zhu 2. Bioinformatics Component - coordinated by Dr. Lodder 3. PCB Analysis Component - coordinated by Dr. Gavalas4. Biostatistical Component - coordinated by Dr. Mahfound. The overall activity of the Research Support Core will be managed by Dr. Toborek in close collaboration with the coordinators of individual Components Dr. Hennig (the Director of our SBRP) Administrative Core and the Project Leaders of all individual grants. The Specific Aims of the Research Support Core are to provide laboratory and statistical services equipment technical support facilitate access to new technology (particularly in the areas of proteomics and bioinformatics) and quality control for multiple SBRP investigators by: Establishing and implementing a variety of state-of-the-art proteomics bioinformatics and PCB analysis procedures that are required by all investigators of our SBRP to address the PCB-mediated regulatory mechanisms in the context of the effects of nutrition on PCB toxicity and diverse disease processes. Providing biostatistical consultations and help to develop proteomics and bioinformatics procedure as required by investigators of the University of Kentucky SBRP. Rigorous quality control of all aspects of the performed research.

project_terms:
analytical chemistry;bioinformatics;biomedical facility;environmental toxicology;proteomics;statistics /biometry


application_id: 7311935
project_number: 5P42ES007380-10
project_title: Core--Research Translation
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9004
contact_pi_person_id: 8022353
contact_pi: ORMSBEE, LINDELL
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The University of Kentucky Basic Superfund Research Program will focus on the environmental health impacts of chlorinated organics with and a more specific focus on PCBs and TCE. The Program will include five separate biomedical research projects that will seek to better understand the biochemical and cellular mechanisms associated with exposure to such chemicals as well as the associated impacts on such diseases as cancer diabetes hypertension and cardiovascular disease i.e. diseases common in Kentucky. One of the unique aspects of the research program will be the investigation of the role of nutrition in mitigating the impacts associated with such exposures. In addition separate projects will examine the use ofnanotechnologies and biosensors in detecting such chemicals in the environment and explore novel techniques for remediation with a particular focus on groundwater contaminated by TCE. The latter project will have a specific potential for application as a result of ongoing remediation studies associated with the Gaseous Diffusion Plant in Paducah Kentucky. The Research Translation Core of the project will seek to translate the Program research to five targeted audiences: Government Industry Broad Audiences Health Professionals and Academia. Consistent with the guidelines of the RFA the specific aims of the Research Translation Core are summarized as follows:1. Communicate important research outcomes to appropriate audiences to ensure the accurate and timely use of the data generated by individual research projects.2. Develop and implement a mechanism for receiving feedback from the designated target audiences so as to confirm the utility and appropriateness of the communication tools selected.3. Ensure that research results are being appropriately applied to immediate environmental and health issues through the use of partnerships and other communication tools.

project_terms:
biomedical facility;environmental health;environmental toxicology;information dissemination;nutrition education


application_id: 7311934
project_number: 5P42ES007380-10
project_title: Core--Superfund Inter-Disciplinary Training
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9003
contact_pi_person_id: 8650958
contact_pi: DEO, SAPNA K.
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The environmental challenges posed by Superfund chemicals are higly significant and affect several aspects of human life. The aim of the University of Kentucky Superfund Program is to study the effects of nutrition as a modulator of toxicity of Superfund chemicals the detection of these chemicals and their remediation. Environmental problems such as those present at Superfund sites are complex and require an interdisciplinary approach to address them. Therefore we are establishing a training program to educate the next generation of scientists and engineers in a way that does not only promote strong disciplinary training but also encourages them to become interdisciplinary thinkers and be effective communicators. The goals of the Traininig Core are (i) to provide thorough training of students in their specific field (ii) to instill basic knowledge about socioeconomic law scientific and ethical aspects and (iii)to enhance the ability of students to communicate with other scientists and the general public. The latter will be accomplished in coordination with the Community Outreach and Research Translation Cores. The Training Core builts on successful collaborations among the Superfund faculty who will serve as research mentors of the trainees through one of the seven research projects of the SBRP program. In addition to interdisciplinary research the trainees will be expected to fulfill coursework requirements in their home departments which will be supplemented with a series of couses in Environmental Systems a course on ethics and a course in Nutritional Sciences. The Training Core will fund three student traineeships duringeach calendar year. It will also provide travel funds to student trainees and postdoctoral scholars to present their research at scientific conferences. Emphasis will be placed on identifying and recruiting motivated individuals from underrepresented groups through brochures web pages and presentations at minority institutions. The effectiveness of the Training Core activities will be measured through a regular evaluation process.

project_terms:
biomedical facility;environmental toxicology;interdisciplinary collaboration;nutrition education;nutrition related tag;training


application_id: 7311933
project_number: 5P42ES007380-10
project_title: Core--Community Outreach
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9002
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Since 2000 UK's SBRP Community Outreach Core has provided support and guidance through critical information on nutrition and health-related issues to meet the needs of individuals and communities affected by environmental contaminants. This purpose is underscored through its new title Superfund Community Action through Nutrition (SCAN). During previous funding SCAN established a close collaboration with a community group in Kentucky and SCAN programs endorsed by this community group provided a new service resource for nutrition and scientific information. The aim of SCAN is to empower affected individuals and communities to take proactive steps toward their own health by drawing on the strength of the nutritionrelatedresearch from UK's SBRP. The specific aims of SCAN include: 1) further develop and present SCAN nutrition and environmental health programs through a series of Science Seminars for both new and previously established community constituents; 2) develop nutrition education tools that emphasize diets high in anti-oxidants and fiber and low in fat which may reduce the toxicity of PCB's and related compounds as reported by UK SBRP's researchers; 3) evaluate the outcomes of SCAN programs as to improved knowledge and attitudes of health risks associated with exposure to environmental contaminants and the influence of nutrition on these risks using pre- and post-test surveys and questionnaires; and 4) evaluate the effectiveness of SCAN programs on changes in nutrition and health-related behavior (e.g. increased intake of anti-oxidant-rich foods decreased intake of certain fats increased physical activity) using pre- and posttest nutrition assessments including anthropometries body composition metabolic rate and food and exercise records. Results of SCAN programs will be used to design new nutrition education and diet strategies for individuals families and communities to enable them to optimize their health in the face of exposure to Superfund contaminants.

project_terms:
biomedical facility;clinical research;education evaluation /planning;environmental toxicology;health education;human subject;information dissemination;nutrition education;nutrition related tag;nutritional epidemiology


application_id: 7311932
project_number: 5P42ES007380-10
project_title: Impact of Obesity on PCB Toxicity
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0008
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Obesity is at epidemic proportions in the US with 64.5% of the adult population considered overweight. Kentucky a state with numerous superfund sites on the national priority list has the 4th highest prevalence of obesity in the nation. Obesity predisposes to cardiovascular diseases such as hypertension. Polychlorinated Biphenyls (PCBs) highly lipophilic superfund chemicals that concentrate in adipose tissue have also been linked to hypertension. When exposed to PCBs obese individuals have higher adipose accumulation that lean subjects; however the impact of sequestration of PCBs in the excess lipid pools of adipocytes with obesity is unknown. During weight loss reductions in fat mass result in release of PCBs into the bloodstream and at the adipocyte. Preliminary data demonstrates effects of co-planar and noncoplanar PCBs to increase the expression of adipocyte differentiation factors (PPARgamma) and adipokines involved in obesity-related hypertension (angiotensinogen). The working hypothesis of thisproposal is that the effect of PCBs to regulate adipocyte differentiation and the adipocyte renin-angiotensin system is influenced by obesity and weight loss culminating in adverse consequences of PCBs on adipocyte function and blood pressure control. In specific aim 1 the effect of PCBs differing in lipophilicity structure and receptor affinities on adipose differentiation and the adipocyte renin-angiotensin system will be examined. These studies will determine if sequestration of PCBs in the lipid pools of adipocytes impacts their ability to interact with receptor targets and influence adipocyte function. In specific aim 2 a rat model of diet-induced obesity will be used to determine the in vitro and in vivo effect of PCB exposure on the development of obesity and hypertension. Hypertrophied adipocytes from obese rats are anticipated to sequester large amounts of PCBs potentially impacting the development of obesity and the subsequent hypertension that develops in obese rats. In specific aim 3 we will determine the effect of prior PCB exposure on adipocyte differentiation the adipocyte renin-angiotensin system and blood pressure during weight loss in a rat model of diet-induced obesity and hypertension. Release of PCBs from the large lipid pools of obese rats with weight loss is anticipated to increase PCB toxicity. Results from these studies will increase our understanding of adipose PCB accumulation and disease.

project_terms:
adipocytes;adipose tissue;angiotensin /renin /aldosterone hypertension;angiotensinogen;bioaccumulation;cell differentiation;chemical structure function;environmental exposure;environmental toxicology;halobiphenyl /halotriphenyl compound;hydropathy;hypertension;laboratory rat;nutrient interaction;nutrition related tag;obesity;peroxisome proliferator activated receptor;renin angiotensin system;toxicant interaction


application_id: 7311931
project_number: 5P42ES007380-10
project_title: Vascular Mechanisms of PCB-Induced Brain Metastases
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0007
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Polychlorinated biphenyls (PCBs) are industrial chemicals mass produced and sold on a large scale in the U.S. for approximately 50 years. Evidence indicates that PCBs have both tumor promoting and vascular effects. However very little is known about the influence of specific PCBs on cancer metastasis formation and in particular on the development of brain metastatic disease. Brain metastases belong to most common forms of metastases and their development dramatically worsens the prognosis and survival of cancer patients. We have evidence that selected coplanar and non-coplanar PCB congeners with multiple rtho-chlorine-substituents stimulate metastatic events such as disruption of endothelial cell integrity tumor cell adhesion to the endothelium and transendothelial migration. Based on these data we propose a novel hypothesis that specific PCBs can induce endothelial cell activation disrupt the blood-brain barrier (BBB) and thus stimulate the development of brain metastases. In addition wehypothesize that nutritional intervention can protect against PCB-mediated metastases formation. To study these hypotheses this research proposal will focus on the effects of specific PCBs on critical events in the development of brain metastases such as: a) alterations of cellular redox status and overexpression of prometastatic/proinflammatory genes; b) overexpression of matrixmetalloproteinases (MMPs); and c) alterations of expression of junctional proteins anddisturbances of endothelial barrier function. The proposed research combines elements of clinical approaches (brain metastases) environmental toxicology with molecular and vascular biology. In addition it is based on a variety of model systems such as cultures of endothelial cells Transwell systems to study permeability across the model of brain endothelium and animal studies. The long-term goals of this proposal are to determine the mechanisms which are responsible for PCB-induced injury to brain endothelial cells disruption of the BBB and the development of brain metastases. Data arising from this proposal will be critical for a better understanding of the molecular mechanisms of brain metastasis formation. In a broader aspect this proposal will contribute to better knowledge on how air pollution contributes to cancer biology and the development of metastases.

project_terms:
athymic mouse;blood brain barrier;brain neoplasms;cell migration;cellular respiration;chemical carcinogenesis;environmental toxicology;halobiphenyl /halotriphenyl compound;human tissue;metalloendopeptidases;metastasis;molecular oncology;nutrition related neoplasm /cancer;nutrition related tag;oxidative stress;vascular endothelium;vascular endothelium permeability


application_id: 7311930
project_number: 5P42ES007380-10
project_title: Chloro-Organic Degradation by Nanosized Metallic Systems
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0005
contact_pi_person_id: 6656295
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Versatile technologies are required for the development of effective dechlorination techniques of hazardous organics utilizing both oxidative and reductive pathways. Chlorinated organics range from chloroethylenes (such as the degreasing solvent trichloroethylene TCE) chlorophenols polychlorinated biphenyls (RGBs) etc. Many chlorinated organics are toxic even at low concentrations and exert a cumulative deleterious effect on the environment. The overall objective of this proposal is to develop iron-based oxidative (with Fe(ll) chelates) and reductive (zero valent Fe with dopants such as Ni Pd) platforms suitable for highly effective remediation strategies for selected chloro-organic detoxification (PCB's and TCE). Our recent research work has shown the benefits of chelate-modified hydroxyl radical-based oxidative reaction andnanosized zero valent metals for reductive dechlorination. The fundamental understanding of these reactive systems is critical for sustainable use involving remediation. For the oxidative systems the proposed research will examine in-situ generation of hydrogen peroxide by enzymes immobilization of polychelates (such as poly-acrylic acid) on inert particles for controlled release of Fe(ll) which is needed for hydroxyl radical formation and control of dechlorination rates. The reductive platform will examine synthesis of nanosized Fe/Ni and Fe/Pd bimetallic systems using chemical reductants (such as borohydride) and by a novel particle formation method using electrochemical technique within conducting polymers. The proposedresearch will require several studies involving development of materials reagent immobilization techniques quantification of surface morphology parent compound and intermediates analysis for establishing reaction rates and carbon balance closure and reaction kinetic parameters for remediation needs. Since hazardous waste and Superfund sites often contain mixture of organics the simultaneous development of both oxidative and reductive remediation techniques should provide more flexibility and tractable approaches.

project_terms:
chelating agents;chemical reaction;chlorination;detoxification;electrochemistry;environmental contamination;environmental protection;halobiphenyl /halotriphenyl compound;hydrogen peroxide;hydroxyl radical;nanotechnology;oxidation reduction reaction;trichloroethylene;waste treatment


application_id: 7311929
project_number: 5P42ES007380-10
project_title: Sensing Superfund Chemicals with Recombinant Systems
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0004
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
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
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Detection of Superfund chemicals is a first step towards eliminating them from the environment or studying their effect on biological processes. To that end we propose to develop molecular tools for the highly sensitive and direct detection of Superfund chemicals such as PCBs. These molecular tools will include whole cell- and protein-based optical sensing systems. For that we propose to utilize naturally available operons induced in the presence PCBs and the catabolic enzymes involved in their degradation. We plan to modify these operons by incorporating the gene for the reporter which will allow us to monitor their induction in the presence of PCBs. Catabolic enzymes involved in the degradation of PCBs in particular the enzyme biphenyl dioxygenase (BphAt) will be isolated and labeled with signal transduction moieties for the analysis of these compounds. In addition to improve the selectivity of these catabolic enzymestowards PCB congeners mutagenesis studies aimed at modifying the active site of the enzyme are proposed. In order to make these biosensing systems amenable to field studies and high throughput sample analysis we propose to incorporate them into a microfluidics platform. This miniaturized analytical platform should find applications in the on-site monitoring of Superfund chemicals. Specifically we plan to adapt our biosensing systems for PCBs to a compact disc centrifugal microfluidics platform. The advantages of our proposed biosensing systems include sensitivity portability and the feasibility of analysis of PCBs in different matrices such as soil water and biological samples.

project_terms:
DVD /CD ROM;biohazard detection;biosensor device;biotechnology;environmental toxicology;halobiphenyl /halotriphenyl compound;high throughput technology;microfluidics;molecular /cellular imaging;operon;oxygenases;reporter genes;technology /technique development;toxin metabolism


application_id: 7311928
project_number: 5P42ES007380-10
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfu
administering_ic: NIEHS
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0002
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
budget_end_date: 2007-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Atherosclerosis a chronic inflammatory disease is still the number one cause of death in the United States. Numerous risk factors for the development of atherosclerosis have been identified including obesity and hypertriglyceridemia. Superfund chemicals such as PHAs and PCBs also have been shown to increase the risk and incidence of cardiovascular diseases. Most of all we have evidence that both selected PCBs and fatty acids can induce endothelial cell dysfunction and inflammation critical events in the early pathology of atherosclerosis. Little is known about mechanisms and regulation of cellular uptake trafficking and initiationof proinflammatory pathways by both PCBs and fatty acids. Membrane lipid rafts such as caveolae are particularly abundant in endothelial cells where they are believed to play a major role in the regulation of endothelial vesicular trafficking. Thus we hypothesize that caveolae are critical in the cellular uptake of fatty acids and lipophilic environmental contaminants such as PCBs. More recently caveolae have also been implicated in the regulation of cell signal transductions. Thus we hypothesize that PCBs and certain fatty acids interact with caveolae and trigger distinct proatherogenic signaling pathways leading to endothelial cell dysfunction. We also hypothesize that these signaling pathways can be down-regulated by antioxidantnutrients and related bioactive compounds as well as by ligands of antiatherogenic nuclear receptors (PPARs). These hypotheses will be tested in vitro as well as in vivo by studying the interactions of PCBs with dietary compounds such as fatty acids and antioxidants. Importantly we will use cell and mouse models lacking the caveolin gene to determine the involvement of caveolae in the PCB and fatty acid uptake and toxicity. We propose to explore mechanisms of nutrient-mediated modulation of PCB toxicity and the outocome of our proposed study may lead to novel nutritional recommendations and therapeutic interventions in population exposed to Superfund chemicals.

project_terms:
antiatherogenic agent;antioxidants;atherosclerotic plaque;biological signal transduction;carbopolycyclic compound;caveolas;caveolins;dietary constituent;environmental toxicology;fatty acid transport;halobiphenyl /halotriphenyl compound;human tissue;inflammation;laboratory mouse;nutrient interaction;nutrition related tag;pathologic process;peroxisome proliferator activated receptor;tissue /cell culture;toxicant interaction;vascular endothelium


application_id: 7304728
project_number: 2R15DA015351-02A1
project_title: Mechanisms of Amphetamine Withdrawal and Recovery
administering_ic: NIDA
award_notice_date: 2007-08-17
opportunity_number: PA-06-042
application_type: 2
activity_code: R15
ic: DA
serial_number: 015351
suffix: A1
program_official: THOMAS, DAVID A
project_start_date: 2002-07-15
project_end_date: 2011-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1885629
contact_pi: WHITE, WESLEY O
other_pis: Not Applicable
congressional_district: 05
department: PSYCHOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed research will evaluate whether dopaminergic mechanisms play a role in the elicitation of symptoms of amphetamine-induced acute withdrawal. This will be done using an animal model approach. Rats will be housed in stations where behavior can be monitored for extended periods of time they will receive control and drug treatments and the effects of these treatments on activity and food intake will be monitored. In rats moderate doses of amphetamine produce hypoactivity and hypophagia 18 to 24 hours later suggesting that an acute withdrawal is present during that time. The hypoactivity can be produced by moderate doses of the nonselective dopamine agonist apomorphine and by moderate doses of D1 and D2 agonists given together but not alone. We want to know if these same treatments can produce hypophagia. The results would not only show the degree of dependence of these symptoms on dopaminergic mechanisms but would also begin to reveal how symptoms of acute withdrawal are organized: If different symptoms are similarly responsive to the same treatments then mediation of these symptoms by a common mechanism would be indicated. Otherwise distributed mechanisms would be indicated. In addition to these manipulations we also want to see to see whether blocking either dopamine receptor subtype prior to amphetamine administration can prevent the hypoactivity. This result would confirm that amphetamine produces hypoactivity by promoting an interaction of D1 and D2 receptors in the short term. Finally we will begin to determine whether the expression of amphetamine-induced hypoactivity and hypophagia are due to a change in dopamine D1 or D2 receptor number. To do this we will see how genes for D1 and D2 receptors are expressed in different brain areas at different times after saline and amphetamine treatment using real time PCR. Acute withdrawal is associated with personal distress decreased productivity and increased risk of drug relapse: Consequently preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical well controlled and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments.

project_terms:
Acute;Affect;Aftercare;Agonist;Amphetamines;Animal Model;Apomorphine;Area;Behavior;Brain;Circadian Rhythms;Corpus striatum structure;Dependence;Distress;Dopamine;Dopamine Agonists;Dopamine D1 Receptor;Dopamine D2 Receptor;Dopamine Receptor;Dorsal;Dose;Drug Controls;Eating;Event;Gene Expression;Genes;Hour;Housing;Mediation;Midbrain structure;Monitor;Nucleus Accumbens;Numbers;Pattern;Play;Polymerase Chain Reaction;Prefrontal Cortex;Productivity;Rattus;Receptor Gene;Recovery;Research;Risk;Role;Saline;Symptoms;Time;Withdrawal;drug relapse;prevent;receptor;research study;response;treatment effect


application_id: 7302632
project_number: 7R01ES015375-02
project_title: Apple Peel Extract Protects UV-Induced Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2007-03-02
application_type: 7
activity_code: R01
ic: ES
serial_number: 015375
program_official: HUMBLE, MICHAEL C
project_start_date: 2006-09-28
project_end_date: 2011-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-30
project_terms:
AP1 protein;DNA damage;antioxidants;apoptosis;cancer prevention;carcinogenesis inhibitor;cell proliferation;chemoprevention;electron spin resonance spectroscopy;environmental exposure;free radicals;gene expression;genetically modified animals;high performance liquid chromatography;laboratory mouse;nuclear factor kappa beta;nutrition aspect of cancer;nutrition related tag;oxidation;oxidative stress;peroxidation;phenols;plant extracts;radiation carcinogenesis;ultraviolet radiation


application_id: 7302230
project_number: 1R01AI075212-01
project_title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome
administering_ic: NIAID
award_notice_date: 2008-08-06
application_type: 1
activity_code: R01
ic: AI
serial_number: 075212
program_official: DONG, GANG
project_start_date: 2008-08-08
project_end_date: 2012-07-31
study_section: Erythrocyte and Leukocyte Biology Study Section[ELB]
contact_pi_person_id: 6799635
contact_pi: RANE, MADHAVI 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: 2008-08-08
project_terms:
Address;Antigen-Antibody Complex;Apoptosis;Apoptotic;Bacteria;Binding (Molecular Function);Biological Assay;Blotting Western;Cell Fractionation;Cell Survival;Cessation of life;Chimeric Proteins;Complex;DNA Complementary;Data;Disease;Disruption;Excision;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Heat Shock Protein 27;IL8 gene;Immune system;In Vitro;Infection;Infection Control;Infectious Agent;Inflammatory;Injury;Killings;Laboratories;Lead;Leukotriene B4;Lipopolysaccharides;MAP Kinase Gene;MAPK14 gene;MAPK8 gene;Mediating;Microscopy Confocal;Mutagenesis Site-Directed;Neutrophil Activation;Organ failure;Pathway interactions;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Protein Kinase;Protein Processing Post-Translational;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Rate;Regulation;Reperfusion Injury;Reporting;Role;Scaffolding Protein;Sepsis;Signal Pathway;Signal Transduction;Site;System;Testing;Time;Tissues;Transfection;Ubiquitin;Ubiquitination;Work;base;chemokine;cytokine;fighting;intracellular protein transport;member;multicatalytic endopeptidase complex;neutrophil;novel;novel strategies;novel therapeutics;pathogen;prevent;protein localization location;protein protein interaction;research study;response


application_id: 7301839
project_number: 5F31MH077450-02
project_title: Determinants of Reward Value
administering_ic: NIMH
award_notice_date: 2007-08-22
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: MH
serial_number: 077450
program_official: PINARD, COURTNEY ROSE
project_start_date: 2006-09-29
project_end_date: 2008-09-28
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8194588
contact_pi: SINGER, REBECCA 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 proposed experiments will examine an effect reported by Clement Feltus Kaiser and Zentall (2000) in which a preference was found for stimuli that followed greater effort over those that followed less effort. When such effects are found in humans they are attributed to cognitive dissonance the discrepancy between beliefs and behavior. Clement et al. interpreted this behavior as a form of contrast in which stimuli that follow greater effort appear to have more value when compared to the aversive event that preceded it. However their design does not rule out an account based on delay to reinforcement. The first set of proposed experiments will distinguish experimentally between contrast and delay reduction accounts. The next proposed experiment will examine whether a shift in food preference can result from requiring greater effort to obtain it an application that could be used in treating eating disorders such as obesity. A final experiment will examine whether a direct manipulation of hedonic state can produce a similar effect. Autism centers in the United States are applying this research to behavior management plans (how effort and subject reward value are related). This model is also used to study risk-taking and gambling behavior.

project_terms:
Accounting;Affect;Autistic Disorder;Behavior;Behavior Therapy;Belief;Cognitive Dissonance;Eating Disorders;Event;Food Preferences;Gambling;Human;Modeling;Obesity;Psychological reinforcement;Reporting;Research;Rewards;Risk-Taking;Stimulus;United States;base;design;hedonic;novel;preference;research study;theories


application_id: 7296119
project_number: 5R21NR009916-02
project_title: Building Bridges to Hospice and Rural Appalachia
administering_ic: NINR
award_notice_date: 2007-08-02
opportunity_number: PAR-05-026
application_type: 5
activity_code: R21
ic: NR
serial_number: 009916
program_official: BOYINGTON, JOSEPHINE
project_start_date: 2006-09-18
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-HOP-S(50)R]
contact_pi_person_id: 8435397
contact_pi: KIRSH, KENNETH L.
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): Palliative care and specifically the management of pain issues is an important and understudied issue in rural Appalachian Kentucky. Despite attempts to increase awareness on this issue pain continues to be under-treated for chronic pain patients including those with advanced disease and at end-of-life. This will only worsen as fears grow concerning prescription medication abuse and diversion. The application is designed to create a fully functioning community-based participatory research (CBPR) entity between the University of Kentucky (UK) and Hospice of the Bluegrass (HOB). One major outcome of this relationship is to conduct a formal needs-based assessment of frontline care workers (i.e. nurses CNAs social workers) who have to manage pain issues in a rural population noted for issues with prescription drug abuse and diversion. Data will be used for the purpose of identifying barriers to effective treatment and to gather initial data for a future interventional study. The needs assessment will be conducted through focus groups key informant interviews and assessment of frontline care workers at HOB. Specific attention will be paid to deficits in the knowledge base of providers regarding the appropriate use of opioid analgesics. To meet this end assessment instruments will include worker demographics a survey of their knowledge base and attitudes about pain management a job satisfaction survey and a measure of general self-efficacy. An additional survey on opioid knowledge and fear of use along with a case vignette will be developed to further round out the assessment package. As a final step the study will conclude the needs-based assessment by conducting an agency wide survey at HOB to target future areas for applied research that address the application of clinical research needs pertinent to HOB and their patient population.

project_terms:
Address;Analgesics Opioid;Appalachian Region;Applied Research;Area;Attention;Attitude;Awareness;Cancer Patient;Caring;Clinical Research;Collaborations;Communities;Consent;Data;Data Collection;Dedications;Disease;End of Life Care;Ethics Committees Research;Evidence based intervention;Family;Focus Groups;Fright;Future;Goals;Grant;Health Personnel;Home environment;Hospice Care;Institutes;Intervention;Interview;Job Satisfaction;Kentucky;Knowledge;Leadership;Left;Measures;National Cancer Institute;National Institute for Occupational Safety and Health;Needs Assessment;Nurses;Nursing Research;Occupational;Opioid;Outcome;Pain;Pain management;Palliative Care;Participation Community;Patients;Pharmaceutical Preparations;Pilot Projects;Poa plant;Policies;Population;Process;Protocols documentation;Provider;Purpose;Reporting;Research;Research Infrastructure;Research Personnel;Risk;Rural;Rural Community;Rural Population;Sampling;Self Efficacy;Series;Services;State Interests;Surveys;Time;Universities;Workers Social;Workplace;base;chronic pain;community based participatory research;community organizations;cost effective;demographics;design;end of life;forging;health disparity;hospice environment;instrument;interest;knowledge base;medically underserved;novel;outreach;point of care;prescription document;prescription drug abuse;prescription procedure;programs;research study;social


application_id: 7295816
project_number: 5R21DK077643-02
project_title: Fetal Adiponectin Expression /Obesity of Gestational Diabetes Mellitus Offspring
administering_ic: NIDDK
award_notice_date: 2007-08-17
opportunity_number: RFA-DK-05-014
application_type: 5
activity_code: R21
ic: DK
serial_number: 077643
program_official: CASTLE, ARTHUR
project_start_date: 2006-09-15
project_end_date: 2009-09-14
study_section: ZDK1-GRB-N(O1)S
contact_pi_person_id: 8333955
contact_pi: SHAO, JIANHUA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Over the last two decades the prevalence of obesity has increased to epidemic proportions in the general population of the US. Gestational diabetes mellitus (GDM) increases the neonate birth weight which closely associates with the development of adolescent and adult obesity. Therefore the intrauterine GDM environment predisposes a high risk of obesity in GDM offspring. Our long-term goal is to investigate the underlying mechanisms that increase birth weight and the susceptibility of obesity in GDM offspring. Adiponectin is an adipose-derived hormone and plays an important role in regulating glucose and lipid metabolism. Recent studies revealed that fetal and neonatal serum adiponectin concentrations are 4-7 fold higher than those in adults. Serum adiponectin levels positively correlate with gestational age and body weight which indicates that adiponectin may regulate fetal development and growth. Furthermore most recent studies demonstrated that the overexpression of adiponectin promotes obese phenotype in mice and adiponectin enhances adipocyte differentiation and lipid accumulation. Our preliminary studies demonstrated that newborn mice from mothers with GDM exhibit a high birth weight elevated adiponectin expression and serum adiponectin protein levels. High fat feeding also induces more weight gain in the GDM offspring. We hypothesize that the GDM intrauterine environment increases fetal adiponectin expression which predisposes high birth weight and susceptibility of obesity in GDM offspring. In Specific Aim 1 we will determine the effect of the GDM intrauterine environment on adiponectin gene expression from fetus to adult using a well established GDM mouse model (db/+). The relationship of maternal or fetal energy metabolism and fetal adiponectin gene expression will be evaluated. In Specific Aim 2 the role of adiponectin in GDM- induced high birth weight and subsequent development of obesity will be studied by cross-mating db/+ and adiponectin gene deficient mice. The results of this project will not only determine the role of adiponectin in GDM-associated high birth weight and the subsequent development of obesity but also provide very useful information regarding fetal adiponectin gene expression and the involvement of adiponectin in regulating fetal development and growth under normal gestational condition. These results will lead to a new strategy for obesity prevention.

project_terms:
A Mouse;Adipocytes;Adipose tissue;Adolescent;Adolescent Development;Adult;Birth;Birth Weight;Body Weight;Caucasians;Caucasoid Race;Child;Childhood;Clinical Research;Collaborations;Condition;Data;Development;Diabetes Gestational;Diet;Elevation;Energy Metabolism;Environment;Epidemic;Exhibits;Exposure to;Fatty Acids Nonesterified;Fatty acid glycerol esters;Fetal development of the mammalian embryo or fetus;Fetus;Gene Expression;General Population;Genes;Gestational Age;Glucose;Goals;Growth;Growth and Development function;Growth Fetal;Homeostasis;Hormones;Human;Infant;Infant Newborn;Insulin;Lead;Length;Lipids;Mediating;Metabolic syndrome;Modeling;Molecular Profiling;Mothers;Mus;Neonatal;Obesity;Partner in relationship;Personal Satisfaction;Phenotype;Plasma;Play;Predisposition;Prevalence;Protein Overexpression;Proteins;Reporting;Risk;Role;Series;Serum;Single Nucleotide Polymorphism;Skin;Smooth muscle (tissue);Tissues Fetal;Transgenic Organisms;Umbilical Cord Blood;Vascular Diseases;Weight Gain;Work;adipocyte differentiation;adiponectin;feeding;fetal;human study;insulin sensitivity;lipid metabolism;mouse model;neonate;obesity prevention;obesity risk;prevent;research study;response


application_id: 7295763
project_number: 5R21DA021199-02
project_title: Prenatal Nicotine Behavioral Teratogenicity and Dopamine
administering_ic: NIDA
award_notice_date: 2007-08-22
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: DA
serial_number: 021199
program_official: HOFFMAN, ALLISON
project_start_date: 2006-09-25
project_end_date: 2009-08-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1883820
contact_pi: PAULY, JAMES 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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Neuropsychological development is frequently impaired in children exposed to prenatal tobacco smoke even after adjusting for other possible genetic and environmental confounds. Although the causative agents in tobacco smoke that lead to altered development are not known accumulating evidence from animal studies suggests that nicotine may play a crucial role. However in most animal studies nicotine has been administered acutely to naive dams leading to significant fetal hypoxia and increased levels of stress hormones which could contribute to an unfavorable fetal environment. Our previous studies have shown that oral nicotine exposure is a stress free and effective method for delivery of nicotine to pregnant mice. Oral nicotine delivery to pregnant mice causes persistent gender-dependent changes in baseline behavior and sensitivity to nicotine in the progeny. In this proposal we will study one possible neurochemical mechanism that may underlie behavioral teratogenicity produced by developmental nicotine exposure. We propose a thorough and systematic evaluation of changes in structure/function of dopaminergic and nicotinic cholinergic neuronal systems following prenatal nicotine administration. The underlying hypothesis of this proposal is that prenatal nicotine exposure changes the temporal and anatomical patterns of apoptotic cell death in the developing mouse nervous system. Inhibition of apoptotic cell death in the CNS may cause permanent molecular cellular or neurochemical changes that predispose animals to have altered sensitivity to drugs and/or susceptibility to drug seeking and relapse. These studies will provide a thorough assessment of changes in cholinergic and dopaminergic neurotransmission following prenatal nicotine exposure. In light of consistent evidence that enhancement of dopamine (DA) neurotransmission may be important for nicotine reinforcement/addiction we believe that evaluation of dopaminergic function is the most relevant target for mechanistic studies to unravel the causes of nicotine induced behavioral teratogenicity. These studies are relevant to public health since nicotine replacement therapy is commonly prescribed for women that are pregnant and wish to stop smoking tobacco. We believe that nicotine plays a significant role in the negative outcomes that have been frequently associated with in utero tobacco smoke exposure.

project_terms:
Acute;Administration Oral;Amphetamines;Animals;Antibodies;Apoptotic;Autoradiography;Basal Ganglia;Behavior;Behavioral;Body Temperature;Brain;Cancer Biology;Cell Count;Cell Death;Child;Cholinergic Agents;Chronic;Classification;Cocaine;Corpus striatum structure;Development;Devices;Dopamine;Environment;Evaluation;Female;Foundations;Gender;Genetic;Home environment;Hormones;Immunohistochemistry;Implant;Lead;Light;Measures;Medial;Mediating;Methods;Methylphenidate;Molecular;Motor Activity;Mus;Nervous system structure;Neurons;Nicotine;Nicotinic Receptors;Oral;Outcome;Patient currently pregnant;Pattern;Pharmaceutical Preparations;Play;Predisposition;Prefrontal Cortex;Pregnant Women;Promoters Tumor;Property;Psychological reinforcement;Publishing;Relapse;Research Personnel;Role;Science of neurochemistry;Signal Transduction;Slice;Stress;Structure;System;Telemetry;Testing;Thinking function;Tobacco;Tobacco smoke;Work;addiction;cancer cell;caspase-3;cholinergic;dopamine transporter;dopaminergic neuron;drug of abuse;fetal;fetal tobacco exposure;fetus hypoxia;in utero;male;neuropsychological;neurotransmission;nicotine replacement;prenatal;prenatal exposure;programs;public health medicine (field);receptor;research study;response;smoking cessation


application_id: 7292138
project_number: 3P42ES007380-10S1
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2006-09-27
opportunity_number: RFA-ES-04-001
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: 2008-03-31
study_section: ZES1
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
project_abstract:
DESCRIPTION (provided by applicant)    The University of Kentucky being a land grant and comprehensive institution has a tradition of excellence in interdisciplinary research.  Such an academic environment will allow study for the overall theme of our SBRP research which focuses on the toxicology of Superfund chemicals and how health effects of exposure can be modulated by both intrinsic and extrinsic factors namely genetics and nutrition respectively.  The investigators will integrate five biomedical and two non-biomedical projects to concentrate on chlorinated organics (e.g. polychlorinated biphenyls trichloroethylene) as model toxins.  Chlorinated organics are prevalent in most Superfund sites including those found in Kentucky.  The preliminary findings suggest that nutrition and dietary habits can markedly influence mechanisms of toxicity of the above-mentioned Superfund chemicals.  Thus a major objective of our SBRP is to explore the paradigm that nutrition can modify Superfund chemical toxicity.  The investigators hypothesize that highly refined diets i.e. diets high in fats or calories and low in fruits and vegetables (antioxidants) are associated with an observed national epidemic in chronic diseases and that populations associated with such dietary habits are more prone to Superfund chemical insult.  Biomedical projects will focus on chronic diseases such as cardiovascular disease cancer obesity hypertension and diabetes.  In addition non-biomedical projects will explore novel techniques for both remediation (detoxification) and biosensors associated with PCBs and other chlorinated organics.  Results from the interdisciplinary research will be utilized for informative/educational technology transfer training policy and translational purposes as part of the objectives of the Research Translation Community Outreach and Training Cores.  Nutrition may be the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults.  Thus the research may lead to novel dietary recommendations at the national level for populations at risk i.e. people residing near Superfund sites.

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


application_id: 7291035
project_number: 5R25MH079332-02
project_title: Mechanisms of Neurologic Disease Course
administering_ic: NIMH
award_notice_date: 2007-08-15
opportunity_number: RFA-MH-06-006
application_type: 5
activity_code: R25
ic: MH
serial_number: 079332
program_official: DESMOND, NANCY L
project_start_date: 2006-09-25
project_end_date: 2010-08-31
study_section: ZMH1-ERB-Y(04)
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
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):  This R25 proposal is to support the development and implementation of a new graduate course Mechanisms of Neurologic Disease at the University of Kentucky (UK). UK has a strong program in neuroscience research. Our local chapter of the Society for Neuroscience includes 96 faculty 105 graduate students and 41 postdoctoral fellows. There are three Neuroscience T32 programs at UK focusing on the biology of aging sensory systems and oxidative stress. This proposal reflects our efforts to develop a new course on the neurobiology of disease that meets and exceed the expectations outlined in the RFA and the NIH Neuroscience Blueprint. Mechanisms of Neurologic Disease is organized into 8 major themes including disorders of cell migration and signaling channelopathies metabolic and mitochondrial disorders neuroimmune and transmissible disorders neurodegenerative disorders and protein aggregation triplet repeat disorders acute CNS insults and drug abuse and addiction. Mechanistic links among disorders will be emphasized. In addition one module will focus on state-of-the-art and emerging methods in neurobiology of disease research such as biosensors. The course will consist of didactic presentations by basic and clinical neuroscientists in addition to "journal club" format discussions of recent primary literature focusing on disease mechanisms or translational research. Outside experts will also be invited to lecture and meet with the students. In addition to the lectures and journal club discussions students must attend a consensus conference on the clinico-pathological diagnosis of Alzheimer's disease and related disorders offered monthly in the Sanders-Brown Center on Aging and attend a brain cutting session offered weekly by Pathology/Neuropathology. Additionally the students and faculty will organize a one day conference on translational research in one of the thematic areas. Program evaluation will include short and long term questionnaires. Dissemination of course materials will be through a course-specific web page and a multimedia CD. The course will be required for neuroscience trainees.

project_terms:
Acute Disease;Aging;Alzheimer's Disease;Area;Arts;Biology of Aging;Biosensor;Brain;Clinical;Consensus;Development;Diagnosis;Disease;Drug abuse;Faculty;Institutional National Research Service Award;Internet;Journals;Kentucky;Link;Literature;Metabolic;Methods;Mitochondrial Diseases;Multimedia;Neurobiology;Neurodegenerative Disorders;Neurologic;Neurosciences;Neurosciences Research;Oxidative Stress;Pathology;Postdoctoral Fellow;Program Evaluation;Questionnaires;Research;Signal Transduction;Societies;Students;Translational Research;Trinucleotide Repeats;United States National Institutes of Health;Universities;addiction;cell motility;day;expectation;lectures;neuropathology;programs;protein aggregation;sensory system;symposium


application_id: 7290998
project_number: 5R43MH078437-02
project_title: Genetic Test for Schizophrenia Susceptibility: A Targeted Approach
administering_ic: NIMH
award_notice_date: 2007-08-10
opportunity_number: PA-06-016
application_type: 5
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)B]
contact_pi_person_id: 8483374
contact_pi: BRENNAN, MARK DAVID
other_pis: Not Applicable
congressional_district: 04
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: 2007-09-01
budget_end_date: 2008-08-31
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:
22q;Affect;African American;Alleles;American;Behavioral;Biological Markers;Bipolar Disorder;Candidate Disease Gene;Chromosomes;Clinical Research;Complex;DNA Resequencing;Diagnosis;Diagnostic;Disease;End Point;European;Family;Family health status;Frequencies (time pattern);Genes;Genetic;Genetic Heterogeneity;Genetic Markers;Genetic screening method;Genome;Genotype;Goals;Haplotypes;Health Personnel;Human;Individual;Intellectual Property;Licensing;Lod Score;Maps;Methods;Microsatellite Repeats;Molecular;National Institute of Mental Health (U.S.);Nature;Odds Ratio;Patients;Phenotype;Polymerase Chain Reaction;Population;Population Control;Predisposition;Quantitative Trait Loci;Research;Research Personnel;Rights;Risk;Risks Relative;SNP genotyping;Sampling;Schizophrenia;Services;Single Nucleotide Polymorphism;Susceptibility Gene;Testing;Variant;base;genetic linkage analysis;improved;microdeletion;novel;transmission process


application_id: 7289861
project_number: 5R44DE017301-03
project_title: Novel Rinse to Treat Oral Candidiasis in Cancer Patients
administering_ic: NIDCR
award_notice_date: 2007-08-08
opportunity_number: PA-06-120
application_type: 5
activity_code: R44
ic: DE
serial_number: 017301
program_official: LUNSFORD, DWAYNE
project_start_date: 2005-09-02
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-K(11)B]
contact_pi_person_id: 6681790
contact_pi: BHATT, BAKUL M
other_pis: Not Applicable
congressional_district: 21
department: Unavailable
primary_duns: 145377966
primary_uei: CATLLUJNR7W4
duns_number: 145377966
uei: CATLLUJNR7W4
fips: US
organization_id: 1829501
organization_name: BIOMEDICAL DEVELOPMENT CORPORATION
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 78212
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Oral candidiasis (oropharyngeal candidosis or thrush) is a common infection in immunosuppressed individuals and if not blunted can transit to esophageal candidosis or life-threatening candidemia. These potentially life-threatening fungal infections originate from the endogenous flora of the individual. For cancer patients radiation therapy or chemotherapy further suppresses the immune system and causes the patient to become more susceptible to oral candidiasis and/or systemic fungal infections (fungemia a fungal infection disseminated by the blood). Oral candidiasis is generally treated with systemic antifungals or oral rinses. Fluconazole tablets and clotrimazole troches are the most popular therapies. Fluconazole is indicated for use for the treatment of oral candidiasis with a single daily dose for two weeks. However certain Candida organisms in biofilms have a dramatically reduced susceptibility to antifungal drugs including Fluconazole. Furthermore side effects of Fluconazole include nausea vomiting abdominal pain headaches dizziness drowsiness fever diarrhea rash and changes in the sense of taste. The most serious effect is liver toxicity but this usually reverses after treatment when the drug is stopped. Nonetheless the scope and severity of the side effects can cause some patients not to be compliant with their prescribed drug regimen. Clotrimazole is used 4 to 5 times daily for 1 to 2 weeks. Its side effects include an altered sense of taste nausea and an upset stomach. Once again patient compliance with the prescribed drug regimen can be an issue not only because of the side effects but also because the patient must take 4 to 5 doses daily. The goal of this project is to develop a safe effective mouthwash without side effects to treat oral candidiasis in head and neck cancer patients. The Specific Aims include implementing current Good Manufacturing Practices (cGMP) including long-term stability studies filing an Investigational New Drug application with the FDA and conducting clinical efficacy trials in cancer patients to demonstrate efficacy. Candida spp. exist in 40-80% of normal individuals in the mouth intestines and vagina. However Candida spp. are extremely opportunistic and if immune systems are compromised and the environment changes Candida spp. can begin to rapidly multiply resulting in candidiasis and engender a potentially deadly disease. Given the large numbers of cancer patients worldwide coupled with other high risk immuno- compromised individuals such as patients infected with HIV along with the growing number of patients with xerostomia (dry mouth) a safe effective mouth rinse without side effects could have profound public health benefits.

project_terms:
Abdominal Pain;Acute;Adverse effects;Aftercare;Animals;Antifungal Agents;Antifungal Therapy;Bacteria;Biocide;Biological Assay;Blood;Cancer Patient;Candida;Candida albicans;Candidiasis;Cells;Cheek structure;Clinical;Clinical Trials;Clinical Trials Phase I;Clinical Trials Phase II;Communities;Compliance behavior;Coupled;Daily;Dental Calculus;Dental Enamel;Dentists;Development;Diarrhea;Disease;Dizziness;Doctor of Medicine;Doctor of Pharmacy;Doctor of Philosophy;Dose;Drowsiness;Drug Resistance Fungal;Drugs Investigational;End Point;Endocrinologist;Environment;Esophageal;Exanthema;Fever;Fluconazole;Food;Formulations Drug;Fungemia;Goals;Guanosine Monophosphate;HIV;Hamsters;Head and Neck Cancer;Headache;Health Benefit;Hepatotoxicity;Human;Hypersensitivity;Immune system;In Vitro;Individual;Infection;Intestines;Investigational New Drug Application;Iodine;Killings;Life;Malignant Neoplasms;Metabolic;Miconazole;Microbial Biofilms;Molecular;Mouthwash;Mycoses;Nausea;Nausea and Vomiting;Numbers;Oral;Oral candidiasis;Oral cavity;Oral mucous membrane structure;Organism;Oropharyngeal;Participant;Patients;Periodontitis;Pharmaceutical Preparations;Phase;Predisposition;Prescriptions Drug;Principal Investigator;Protocols Treatment;Radiation Oncologist;Radiation therapy;Rattus;Research;Research Personnel;Resistance;Risk;Safety;Severities;Site;Stomach;System;Tablets;Taste Perception;Time;Tooth Erosion;Toxic effect;Treatment Effectiveness;United States Food and Drug Administration;Vagina;Virus;Week;Xerostomia;Yeasts;antimicrobial;candidemia;chemotherapy;clinical efficacy;cytotoxic;day;design;dosage;efficacy trial;experience;fungus;head and neck cancer patient;immunosuppressed;in vitro Assay;in vitro Model;microbicide;novel;public health medicine (field);thrush (bird)


application_id: 7289820
project_number: 5U10EY010403-14
project_title: OCULAR HYPERTENSION TREATMENT STUDY (OHTS)
administering_ic: NEI
award_notice_date: 2007-02-05
opportunity_number: EY93-01
application_type: 5
activity_code: U10
ic: EY
serial_number: 010403
program_official: EVERETT, DONALD F
project_start_date: 1994-01-01
project_end_date: 2008-12-31
study_section: Vision Research and Training Committee[VSN]
contact_pi_person_id: 6517188
contact_pi: SOLTAU, JOERN B
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This is an application to become a participating Clinical Center int he         Ocular Hypertension Treatment Study (OHTS).  The complete details of the        OHTS rationale design and methods are contained in the OHTS Manual of         Procedures.                                                                                                                                                     This proposal provides complete documentation of the ability of the             Department of Ophthalmology and Visual Sciences of the University of            Louisville College of Medicine to screen large numbers of ocular                hypertensive patients and to enroll at lease 50 eligible patients over a        24-month period.                                                                                                                                                Documentation is provided of the capabilities of the proposed investigators     and their staff for performance of the study in accordance with the details     of the OHTS Manual of Procedures.                                                                                                                               The chairman of the Department of Ophthalmology and Visual Sciences is an       investigator and has committed the resources of the department to this          study.  In addition all fellowship-trained glaucoma specialists in the         Louisville community are co-investigators and are committed to the success      of this study.  This unanimous support represents the strength of the           commitment of the Department of Ophthalmology and the glaucoma community in     Louisville to the Ocular Hypertension Treatment Study.  Patients will be        drawn from two general eye clinics three glaucoma sub-specialty practices      and d large health maintenance organization.                                                                                                                    By conducting this study in the kentucky Lions Eye Research Institute           (KLERI) we ensure that we will have ample facilities and personnel for the     protocol.  We have space dedicated for clinical research.  We have              experienced personnel to cross cover the study personnel.  The clinical         coordinator/technician is experienced in ophthalmic photography and will be     trained to back up our ophthalmic photographer.  We have a study                coordinator working on other projects who will be crossed-trained to back       up the clinical coordinator/technician.

project_terms:
Back;Chairperson;Clinic;Clinical;Clinical Research;Commit;Communities;Documentation;Enrollment;Ensure;Eye;Fellowship;Glaucoma;Health Maintenance Organizations;Human Resources;Kentucky;Manuals;Medical Specialities;Medicine;Methods;Numbers;Ocular Hypertension;Ophthalmology;Panthera leo;Patients;Performance;Photography;Procedures;Protocols documentation;Research Institute;Research Personnel;Resources;Specialist;Training;Universities;Work;college;design;experience;hypertension treatment;success;vision science


application_id: 7288554
project_number: 3U01CA114622-02S1
project_title: Appalachia Community Cancer Network
administering_ic: NCI
award_notice_date: 2006-09-21
opportunity_number: RFA-CA-05-012
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2005-05-06
project_end_date: 2010-04-30
study_section: ZCA1
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
project_terms:
cancer prevention;cancer risk;cervix neoplasms;clinical research;colorectal neoplasms;community health services;cooperative study;education evaluation /planning;health care policy;health care service availability;health disparity;health science research;health services research tag;human subject;interview;lung neoplasms;medically underserved population;neoplasm /cancer diagnosis;neoplasm /cancer education;social support network;socioeconomics;training


application_id: 7288122
project_number: 1P01NS058484-01
project_title: Administration and statistics
administering_ic: NINDS
application_type: 1
activity_code: P01
ic: NS
serial_number: 058484
project_start_date: 2007-01-01
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZNS1 SRB-R (24)]
subproject_number: 7714
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
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: 2007-05-01
budget_end_date: 2008-04-30
project_abstract:
The goal of the Administrative and Biostatistical Core is to facilitate the research aims of all projects andcores of the program project and thereby support the overall objective of evaluating the hypothesis thatcalpain inhibition is a rational and viable therapeutic target for traumatic brain injury. The Administrative andBiostatistical Core will: Provide strong leadership for the program project and an administrative structure toimplement the goals of all projects and cores; Provide biostatistical support for all projects and cores;Coordinate supervise and promote integration of the cores and projects; Provide administrative supervisionand coordination of all fiscal matters of the program project; Facilitate communication between projects andcores through organized monthly scientific meetings of all investigators; Provide scientific review ofaccomplishments and future directions by convening meetings of the internal and external advisorycommittees; Ensure the ethical treatment of animals used in the program project studies by compliance withnational and institutional animal welfare guidelines; Fulfill all NIH requirements and regulations includingprovision of progress and financial reports and an acceptable mechanism for data sharing; and finally toprovide a stimulating research environment for the successful conduct and completion of the goals of thisprogram project.

project_terms:
Advisory Committees;Animal Welfare;Animals;Archives;Attenuated;Biological Markers;Biometry;Calpain;Cognitive;Communication;Consultations;Data;Data Interpretation Statistical;Ensure;Environment;Figs - dietary;Future;Goals;Guidelines;Leadership;Nerve Degeneration;Reagent;Regulation;Reporting;Research;Research Design;Research Personnel;Sample Size;Science of Statistics;Structure;Supervision;Traumatic Brain Injury;United States National Institutes of Health;motor deficit;programs;therapeutic target


application_id: 7287691
project_number: 5R03CA125781-02
project_title: Chemopreventive properties of aryl hydrocarbon receptor antagonists
administering_ic: NCI
award_notice_date: 2007-08-28
opportunity_number: PAR-04-147
application_type: 5
activity_code: R03
ic: CA
serial_number: 125781
program_official: PERLOFF, MARJORIE
project_start_date: 2006-09-18
project_end_date: 2009-08-31
study_section: ZCA1-SRRB-F(O1)
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 aryl hydrocarbon receptor (AHR) may play in important role in the etiology of tobacco smoke induced lung cancer and may also be an important target for effective chemopreventive approaches. Our initial data performed in human lung epithelial cells indicates that constituents present in cigarette smoke condensate can act as AHR agonists and that several dietary flavonoids in particular apigenin emodin and kaempferol appear to act as effective AHR antagonists. The hypothesis to be tested in this proposal is that the AHR is an important pharmacological target of dietary flavonoids that will be effective for chemoprevention of tobacco smoke induced lung cancer. Specific Aims: (1) Determine the extent to which cigarette smoke condensate activates and flavonoids inhibit the AHR and cell transformation. (2) Determine whether apigenin inhibits cigarette smoke condensate-induced malignant transformation of human lung epithelial cells in vivo.

project_terms:
A/J Mouse;ARNT gene;ARNT protein human;Abbreviations;Agonist;Apigenin;Aryl Hydrocarbon Receptor;Biological Markers;CYP1A1 gene;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Classification;Data;Dietary Flavonoid;Dioxins;Emodin;Enzymes;Epithelial Cells;Etiology;Event;Flavonoids;Gene Expression;Gene Targeting;Goals;Human;In Vitro;Incidence;Kaempferols;Literature;Longevity;Lung;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediator of activation protein;Metabolic Activation;Modeling;Mortality Vital Statistics;Passive Smoking;Pathway interactions;Personal Satisfaction;Play;Process;Property;Proteins;Receptor Cell;Receptor Signaling;Relative (related person);Research;Response Elements;Role;Role playing therapy;Signal Pathway;Smoke;Staging;System;Testing;Tobacco;Tobacco smoke;Tobacco use;Tumor Promotion;Validation;Woman;Xenograft procedure;base;cell transformation;cigarette smoke;dietary constituent;genotoxicity;in vivo;kaempferol;keratinocyte;lung carcinogenesis;lung tumorigenesis;men;mouse model;receptor;research clinical testing;response;tumor;tumor growth


