# projects

application_id: 7417255
project_number: 2P42ES007380-12
project_title: Project 1: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
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: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Antiatherogenic;Antioxidants;Atherosclerosis;Blood Vessels;CAV1 gene;Cardiovascular Diseases;Cause of Death;Caveolae;Caveolins;Cells;Chemical Exposure;Chemicals;Chronic;Critical Pathways;Data;Development;Diet;Dietary Component;Dietary Fats;Dietary Fatty Acid;Dietary Intervention;Disease;Endothelial Cells;Event;Exposure to;Fatty Acids;Fatty Acids Omega-3;Fatty Acids Omega-6;Flavonoids;Functional disorder;Genes;Health;Hypertriglyceridemia;In Vitro;Incidence;Inflammatory;Inflammatory Response;Intervention;Lead;Link;Lipids;Mediating;Membrane;Membrane Lipids;Mus;Numbers;Nutrient;Nutritional;Obesity;Outcome;Pathology;Plants;Play;Polychlorinated Biphenyls;Population;Process;Property;Rate;Recommendation;Regulation;Reporting;Risk;Risk Factors;Role;Science of nutrition;Signal Pathway;Signal Transduction;Testing;Therapeutic Intervention;Toxic effect;United States;base;bioactive food component;cardiovascular disorder risk;caveolin 1;in vivo;mouse model;novel;pollutant;prevent;response;superfund chemical;trafficking;uptake


application_id: 7417155
project_number: 3R01NS045087-02S2
project_title: Early Treatment of ALS with Nutrition and NIPPV
administering_ic: NINDS
award_notice_date: 2007-05-03
opportunity_number: PAR-01-119
application_type: 3
activity_code: R01
ic: NS
serial_number: 045087
suffix: S2
program_official: CONWIT, ROBIN
project_start_date: 2004-08-01
project_end_date: 2009-11-30
study_section: Neurological Sciences and Disorders K Study Section[NSD-K]
contact_pi_person_id: 1975664
contact_pi: KASARSKIS, EDWARD JOSEPH
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
project_abstract:
Studies to date indicate that Percutaneous Endoscopic Gastrostomy (PEG) and Non-Invasive PositivePressure Ventilation (NIPPV) improve survival in Amyotrophic Lateral Sclerosis (ALS) even thoughintroduced late in the disease. We hypothesize that early intervention may improve outcome even further.However many issues regarding the early use of these treatments preclude the design of a Phase III clinicaltrial to test this hypothesis. Common to both NIPPV and nutrition is a lack of a reliable indicator of earlyrespiratory or nutritional insufficiency. With respect to nutrition we need reliable and cost effective methodsto determine a patient's energy (i.e. caloric) requirements during different stages of the illness and base therecommendation for PEG on the adequacy of energy intake. For NIPPV we need to identify factors thatinfluence acceptance and tolerability of this therapy and measurements of early respiratory dysfunction. Therefore we propose this multicenter Pilot Study to develop methods for a defmitive Phase III trial. TheSpecific Aims of this Pilot Study are: 1) To develop and validate strategies to improve tolerability ofNIPPV to identify factors that influence acceptance of this treatment modality and to evaluate measures ofearly respiratory dysfunction; and 2) To develop and validate methods to determine energy balance in ALS.In this Pilot Study all 11 sites will enroll patients using a stratified design based on FVC (80-95% vs 50-79%) and offer NIPPV as they decline to the lower limit of this FVC level. Six sites will collect additionaldetailed information to critically evaluate acceptability of NIPPV devise strategies to improve tolerance andvalidate this approach as well as collect respiratory measurements that may allow earlier identification offailure. The other 5 sites will use the "gold standard" Doubly Labeled Water method in a longitudinal designto derive empiric equations to reliably predict individual energy needs based on easily performed clinicalmeasures. The results of this Pilot Study will allow us to develop and validate methods so that we can designa multicenter Phase III trial to determine the efficacy of early NIPPV and nutritional intervention. Inaddition our results will be immediately applicable for use by clinicians in practice and will provide the basisto re-formulate the experimental design of future drug trials in ALS.

project_terms:
Activities of Daily Living;Address;Am 80;Amyotrophic Lateral Sclerosis;Area;Arts;Caring;Classification;Clinical;Clinical Research;Clinical Trials Phase III;Complex;Daily;Dietary Intervention;Disease;Early Intervention (Education);Early identification;Early treatment;Energy Intake;Energy Metabolism;Enrollment;Environmental air flow;Equation;Experimental Designs;Failure (biologic function);Figs - dietary;Functional disorder;Future;Gastrostomy;Goals;Gold;Health;Individual;Institutes;Intervention;Invasive;Investigation;Label;Measurement;Measures;Medical;Methods;Modality;Muscle;Nutritional;Nutritional Support;Outcome;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Preparation;Pressure- physical agent;Quality of life;Randomized;Recommendation;Sample Size;Science of nutrition;Site;Sleep;Staging;Standards of Weights and Measures;Structure;Techniques;Testing;Time;Vital capacity;Water;base;concept;cost effective;design;energy balance;improved;prevent;programs;prospective;respiratory


application_id: 7416641
project_number: 5R01NS047341-05
project_title: Survival signaling in CNS neurons exposed to DNA damage
administering_ic: NINDS
award_notice_date: 2008-04-18
application_type: 5
activity_code: R01
ic: NS
serial_number: 047341
program_official: JACOBS, TOM P
project_start_date: 2004-08-15
project_end_date: 2010-05-31
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
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: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): Neurons are targets for damaging stimuli which may trigger cell death and in consequence serious neurological diseases. Interestingly most neurons survive minor damages which they are challenged with during the life span. Therefore one can propose existence of a mechanism that helps neurons to survive the initial injury and resume proper functions after an insult. Identification of this mechanism may result in development of treatments that would harness the intrinsic neuronal defense machinery to combat against neurological diseases. An important damaging stimulus in the CNS is oxidative stress. It exerts its toxic effects at least in part through injury of DNA whose integrity is critical for proper neuronal survival. Indeed neurons are very sensitive to DNA damage. Interestingly DNA damaging agents that are used in cancer therapy frequently produce neurological side effects. Our recently published results indicate that Extracellular Signal Regulated Kinase 1/2 (ERK1/2) is activated in rat cortical neurons by a neurotoxic DNA-damaging drug cisplatin (CPDD) (J Biol Chem 278:43663-43671). Furthermore we have found that inhibition of ERK1/2 pathway enhances toxic response to CPDD. Consequently the general aim of our proposal is testing a hypothesis that neuronal DNA damage activates ERK1/2 to suppress neuronal death and to enhance repair of the cellular damage. We will approach this goal by (i) identification of the mechanism behind ERK1/2 mediated protection against DNA damage (ii) dissection of the pathway linking DNA damage and survival signaling by ERK1/2 (iii) identification of factors which could enhance defensive signaling by ERK1/2 in neurons and finally by (iv) evaluation of ERK1/2 activation as a general compensatory response to diverse forms of DNA injury. To realize the proposal we will use cultured rat primary neurons. The proposed research may result in identification of new drug targets for treatment of neurological diseases and/or deleterious neurological side effects of cancer therapy.

project_terms:
Address;Adverse effects;Affect;Alzheimer's Disease;Antineoplastic Agents;Apoptosis;Appendix;CPDD protocol;Camptothecin;Cell Death;Central Nervous System Neoplasms;Cerebellum;Cessation of life;Cisplatin;Country of Poland;Couples;Cyclic AMP;Cyclophosphamide;Cytarabine;DNA Damage;DNA Repair;DNA strand break;Data;Disease;Dissection;Drug Delivery Systems;Evaluation;Ganglia Spinal;Genomics;Goals;Hippocampus (Brain);Injury;Institutes;Intercalating Agents;International;Light;Link;Longevity;Mediating;Minor;Mitogen-Activated Protein Kinase 3;Molecular and Cellular Biology;N-Methyl-D-Aspartate Receptors;Nervous system structure;Neurologic;Neurons;Operative Surgical Procedures;Outcome;Oxidative Stress;Parkinson Disease;Pathology;Pathway interactions;Pharmaceutical Preparations;Publishing;Rattus;Regulation;Research;Research Personnel;Signal Pathway;Signal Transduction;Stimulus;Stress Genotoxic;System;Testing;Toxic effect;Universities;base;cancer therapy;drug development;improved;irradiation;nervous system disorder;neuron apoptosis;neuron loss;neuronal survival;neurotoxic;neurotoxicity;novel;nucleoside analog;post-doctoral training;repaired;response;small molecule;stroke;therapy development


application_id: 7415218
project_number: 5R01DA019433-03
project_title: Evaluation of Novel Treatments for Stimulant Dependence
administering_ic: NIDA
award_notice_date: 2008-05-07
application_type: 5
activity_code: R01
ic: DA
serial_number: 019433
program_official: BOUGH, KRISTOPHER J
project_start_date: 2006-08-15
project_end_date: 2011-05-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant):  Recent surveys in the U.S. reveal that about 2.6 million individuals reported use of cocaine/crack in the past month. Despite a concerted research effort to develop an effective pharmacotherapy no broadly effective therapies have been discovered. Cocaine exerts its reinforcing effects largely through interactions with central dopamine pathways and chronic use of cocaine leads to dysregulation of these neural systems. This application proposes to examine a novel agent aripiprazole (Abilify(r)) for its potential efficacy against cocaine by employing well-controlled experimental methods in a human laboratory setting. Aripiprazole is the newest atypical antipsychotic marketed in the U.S.; its neuropharmacological profile is truly unique and sets it apart from all other atypical neuroleptics. Aripiprazole has a high affinity for D2 and 5-HT1a receptors where it acts as a partial agonist and at 5-HT2 receptors where it acts as an antagonist. We hypothesize that aripiprazole may both block the synaptic effects of cocaine and improve the neural perturbations resulting from chronic cocaine use. Healthy adult cocaine-dependent volunteers (n=36) who also smoke cigarettes will be enrolled as inpatients for 45 days. Following a brief wash-out and single-blind placebo lead-in they will be randomly assigned to 1 of 3 treatment groups (015 or 30 mg aripiprazole p.o/day) under double-blind conditions. Cocaine challenge sessions will be conducted during the placebo lead-in acute dosing phase and at steady-state. During each phase the direct pharmacodynamic and pharmacokinetic interaction between cocaine and aripiprazole will be examined in cocaine dose-effect challenge sessions. The effects of aripiprazole treatment on the reinforcing effects of cocaine will be examined directly with a self-administration procedure that employs alternative reinforcers and has been well-characterized by our laboratory. Cocaine will be examined over a range of doses relevant to those used illicitly and pharmacodynamic assessments will be multi-dimensional including subjective objective physiological and behavioral outcomes. In addition because preliminary data suggest that atypical antipsychotics may reduce cigarette smoking a secondary aim is to examine directly the effects of aripiprazole on smoking behavior in comparison to placebo. This study provides a unique opportunity to examine smoking under controlled conditions during a period of confinement; both smoking topography procedures and naturalistic smoking measures will be employed. Overall this project will explore the potential therapeutic efficacy of a novel agent aripiprazole for the treatment of cocaine dependence while simultaneously providing the requisite safety data needed to launch an outpatient clinical trial and exploring the potential efficacy of this agent for smoking reduction or cessation.

project_terms:
Abstinence;Abuse Cocaine;Acute;Adult;Adverse effects;Affinity;Agonist;Antipsychotic Agents;Attenuated;Behavioral;Chronic;Cigarette Smoker;Class;Clinical Research;Clinical Trials;Cocaine;Condition;Coupled;Crack Cocaine;Data;Dependence;Dependence Tobacco;Dependences Cocaine;Dopamine;Dopamine Agonists;Dopamine Antagonists;Dopamine D2 Receptor;Dopamine Receptor;Dopaminergic Agents;Dose;Double-Blind Method;Drug Kinetics;Enrollment;Environment;Evaluation;Exhibits;Homeostasis;Human;Individual;Inpatients;Laboratories;Laboratory Procedures;Marketing;Measures;Mediating;Methodology;Methods;Otsuka brand of aripiprazole;Outcome;Outpatients;Pathway interactions;Patients;Personal Satisfaction;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phase;Physiological;Placebos;Play;Procedures;Property;Psychostimulant dependence;Randomized;Range;Rate;Relative (related person);Reporting;Research;Risk;Role;Safety;Schizophrenia;Self Administration;Serotonin;Site;Smoke;Smoker;Smoking;Smoking Behavior;Study Interdisciplinary;Supervision;Surveys;Synapses;System;Tobacco;Treatment Efficacy;United States;Withdrawal Symptom;aripiprazole;atypical antipsychotic;cigarette smoking;craving;day;design;dopamine system;improved;mood regulation;novel;public health medicine (field);receptor;reinforcer;relating to nervous system;response;restoration;theories;volunteer


application_id: 7415194
project_number: 5R21AT003488-02
project_title: Inhibition of Cholesterol Synthesis by Policosanol
administering_ic: NCCIH
award_notice_date: 2008-03-28
opportunity_number: PA-05-141
application_type: 5
activity_code: R21
ic: AT
serial_number: 003488
program_official: WEBER, WENDY J
project_start_date: 2007-05-01
project_end_date: 2010-04-30
study_section: ZAT1-DB(23)
contact_pi_person_id: 1859126
contact_pi: PORTER, TODD D
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): Over-the-counter botanicals and nutritional supplements have gained great popularity among the public as safe and effective means to treat chronic and acute diseases and are widely viewed as safe alternatives to prescription medicines. Hypercholesterolemia is a widespread problem for which there is great interest in alternative medicines and policosanol is a relatively new product derived from sugar cane that has gained considerable attention as a means to reduce blood cholesterol levels. This research will investigate a possible mechanism by which policosanol decreases blood cholesterol levels. Most current evidence indicates that this mixture of long-chain alcohols inhibits or suppresses HMG-CoA reductase activity the regulatory step in cholesterol synthesis. To test this hypothesis the effect of policosanol on HMG-CoA reductase activity will be evaluated in cultured hepatoma cells and in whole animals and the mechanism by which policosanol inhibits this enzyme will be determined. Preliminary studies demonstrate that policosanol does not directly inhibit HMG-CoA reductase indicating that intracellular activation/metabolism of policosanol or the activation of a modulatory pathway is necessary for the suppression of this key cholesterolgenic enzyme. Studies will test the hypothesis that peroxisomal metabolism of policosanol results in the activation of AMP-kinase which then inactivates HMG-CoA reductase by phosphorylation. An alternative hypothesis that policosanol is metabolized to a direct inhibitor of HMG-CoA reductase will also be tested. HMG-CoA reductase expression and activity and AMP-kinase activity will be measured in hepatoma cells and in preparations from the livers of animals treated with policosanol. Finally to determine if peroxisomal oxidation of policosanol is necessary the ability of policosanol to inhibit cholesterol synthesis in mice that lack peroxisomal oxidation pathways will be determined. These studies should establish a solid mechanistic understanding of how policosanol decreases cholesterol synthesis and lowers blood cholesterol levels and may provide a basis for predicting how the use of this compound might interact either favorably or unfavorably with prescription Pharmaceuticals used for the treatment of hypercholesterolemia.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Acute Disease;Adverse effects;Alcohols;Alternative Medicine;Animals;Attention;Blood;Botanicals;Cells;Cholesterol;Cholesterol Synthesis Inhibition;Chronic;Conflict (Psychology);Dietary Supplements;Dose;Enzymes;Fatty Acids;Hepatic;Hydroxymethylglutaryl-CoA Reductase Inhibitors;Hydroxymethylglutaryl-CoA reductase;Liver;Measures;Medicine;Metabolism;Monkeys;Mus;Oryctolagus cuniculus;Pathway interactions;Pharmacologic Substance;Phosphorylation;Preparation;RNA Interference;Rattus;Research;Solid;Sterols;Testing;Water;adenylate kinase;base;cane includes canes of all materials adjustable or fixed with tip;hepatoma cell;hypercholesterolemia;in vivo;inhibitor/antagonist;interest;man;oxidation;policosanol;prescription document;prescription procedure;sugar


application_id: 7414686
project_number: 3R01ES011314-05S1
project_title: Arsenic Induced Miotic Arrest Associated Apoptosis
administering_ic: NIEHS
award_notice_date: 2007-04-27
application_type: 3
activity_code: R01
ic: ES
serial_number: 011314
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2003-08-01
project_end_date: 2009-04-30
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Arsenic is a natural contaminant of drinking water in many parts of the world is a known human carcinogen and is #1 on the EPA list of hazardous chemicals. Cancers most often associated with chronic arsenism are squamous and basal cell carcinomas of the skin. How arsenic causes cancer is unknown. However the National Research Council Report on Arsenic in Drinking Water concluded that the most likely mode of action is induction of numerical and structural chromosomal abnormalities. Arsenite the carcinogenic form of arsenic found in drinking water disrupts mitosis causing an anaphase delay and induces aneuploidy in normal diploid human fibroblasts and peripheral blood lymphocytes and mitotic arrest associated apoptosis (MAAA) in p53 deficient human fibroblasts. The sensitivity of p53 deficient human cells to arsenite induced MAAA suggests that the mechanism of arsenite carcinogenesis is different than sunlight induced skin carcinogenesis in which p53 mutation is an early and common event. The hypothesis to be investigated is that p53 relieves the arsenite-induced anaphase block by activation of the G2 checkpoint response which inactivates cyclin B/cdc2 and derepresses the mitotic exit network and allow the cells to escape arsenite induced MAAA. It is the prevention of apoptosis in arsenic intoxicated cells that allows genetic instability (aneuploidy) after mitotic disruption. Identification of the cellular factors that interact with p53 or the p53 regulated genes to prevent mitotic arrest associated apoptosis and to allow cells to proceed through mitosis with a delay will provide valuable information regarding the mode of action of arsenite. The specific aims proposed are: 1.) Determine activation of the G2 checkpoint pathway in p53(+) and p53(-) cells arrested by arsenite in mitosis; 2.) Test by overexpression and targeted knockdown of G2 checkpoint proteins the role of G2 checkpoint activation in the escape from arsenite induced anaphase block; 3.) Test whether arsenic associated skin tumors are p53 wild type or mutant. The results of these studies will identify players mediating release from arsenite induced mitotic arrest and will provide valuable information on the mechanism of arsenic induced carcinogenesis clues to the usefulness of arsenite as a chemotherapeutic agent and valuable information on the mode of action of mitosis disrupting drugs in killing human cells.

project_terms:
Anaphase;Aneuploidy;Apoptosis;Arsenic;Arsenites;Basal cell carcinoma;Cancer Etiology;Carcinogens;Cells;Chemicals Hazardous;Chronic;Cyclin B;DNA;Data;Diploidy;Disruption;Event;Exons;Fibroblasts;Genes;Genetic;Genomics;Human;Individual;Killings;Malignant Neoplasms;Mediating;Mitosis;Mitotic;Mitotic Checkpoint;Monitor;Mutation;National Research Council (U.S.);PTCH gene;Pathway interactions;Peripheral Blood Lymphocyte;Pharmaceutical Preparations;Play;Prevention;Protein Overexpression;Proteins;RNA Messenger;Reporting;Role;Skin Carcinogenesis;Skin Neoplasms;Structural Chromosomal Abnormality;TP53 gene;Telomerase;Testing;Tetanus Helper Peptide;Tetracycline;Tetracyclines;Time;UV induced;United States Environmental Protection Agency;cancer cell;carcinogenesis;chemotherapeutic agent;cytotoxicity;drinking water;genetic regulatory protein;mutant;neoplastic cell;prevent;protein expression;response;sunlight-induced;tumor;vector


application_id: 7414662
project_number: 2R42AA015475-02
project_title: Potential anti-relapse drugs: a plant genomics approach
administering_ic: NIAAA
award_notice_date: 2008-09-29
opportunity_number: RFA-AA-07-010
application_type: 2
activity_code: R42
ic: AA
serial_number: 015475
program_official: EGLI, MARK
project_start_date: 2004-09-28
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZAA1 JJ (17)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Agonist;Alcohol withdrawal syndrome;Alcoholism;Animal Model;Biological Factors;Biotechnology;Categories;Central Nervous System Diseases;Chemicals;Class;Condition;Coreopsis;Cultured Cells;Drug Delivery Systems;Drug Industry;Ensure;Genomics;Glutamates;Helianthus;Hyperactive behavior;Ilex vomitoria;Insecta;Intellectual Property;Investigation;Kentucky;Lead;Ligands;Lobelia;Marketing;Mediating;Medicine Traditional;Methods;Modeling;Modification;Molecular;Molecular Target;Mutagenesis;N-Methyl-D-Aspartate Receptors;Nerve Degeneration;Neuroprotective Agents;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plant Extracts;Plants;Population;Prevalence;Production;Property;Receptor Inhibition;Relapse;Sales;Screening for Neuroblastoma;Screening procedure;Sectors Commercial;Small Business Technology Transfer Research;Solidago;Technology;Testing;Therapeutic;Toxic effect;Universities;Withdrawal;acamprosate;alpha-bungarotoxin receptor;base;commercialization;conditioning;desensitization;design;drug discovery;drug relapse;high throughput screening;model design;mutant;neurotoxicity;novel;programs;receptor;size;smoking cessation


application_id: 7414637
project_number: 7R21NS052302-03
project_title: Cannabinoid modulation of epileptiform activity in mice
administering_ic: NINDS
award_notice_date: 2007-05-08
opportunity_number: PA-03-107
application_type: 7
activity_code: R21
ic: NS
serial_number: 052302
program_official: FUREMAN, BRANDY E
project_start_date: 2005-07-01
project_end_date: 2009-06-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  A principal goal of epilepsy research is to identify and develop novel treatment strategies for seizure control that may be relatively selective for modulation of the synaptically reorganized circuitry in the epileptic brain. The objective of this Exploratory/Developmental (R21) research proposal is to identify the effects of exogenous and endogenous cannabinoids on neurons of the dentate gyrus in mice with pilocarpine-induced temporal lobe epilepsy (TLE) characterized by chronic spontaneous seizures mossy fiber sprouting and increased neuronal excitability and synchrony. The use of cannabinoids for treating seizure disorders has been proposed but results of case study analyses have been mixed. The goal of this proposal is to determine how cannabinoids modulate activity in the dentate gyrus in a murine model of TLE in order to understand effects of the substance on a system that has undergone synaptic reorganization (versus effects on normal neural circuits). Most known central effects of cannabinoids are mediated by cannabinoid type 1 receptors (CB1R) usually located on presynaptic terminals. In the hippocampus cannabinoids suppress synaptic input-especially feedback inhibition--to principal neurons including dentate gyrus granule cells. Although cannabinoids appear to suppress some types of seizures the cellular "disinhibitory" properties appear to be proconvulsive in normal brains. Recent analyses suggest that cannabinoids may suppress seizure activity in the epileptic brain. However no studies at the cellular level have been performed in the dentate gyrus in an animal model of TLE (i.e. having cell loss axon sprouting and synaptic reorganization). Preliminary data presented here suggest that in the absence of GABAA receptor-mediated inhibition cannabinoids can inhibit epileptiform discharges that are attributable to activation of newly-formed recurrent excitatory circuitry in the dentate gyrus in mice with pilocarpine-induced TLE. Using electrophysiological anatomical and molecular biological techniques the hypotheses that: 1) cannabinoids inhibit new recurrent excitatory circuitry; 2) cannabinoids inhibit granule cells directly and 3) CB1R expression is upregulated in animals with TLE and synaptic reorganization will be tested in a murine model of TLE developed in this lab. Understanding these effects may promote more effective treatment strategies designed specifically for TLE patients whose brains have undergone a degree of synaptic reorganization.

project_terms:
action potentials;cannabinoid receptor;cannabinoids;dentate gyrus;disease /disorder model;electrophysiology;epilepsy;granule cell;immunocytochemistry;laboratory mouse;neuropharmacology;neurophysiology;neuroregulation;photolysis;pilocarpine;receptor expression;temporal lobe /cortex;voltage /patch clamp


application_id: 7414565
project_number: 5R01CA100323-05
project_title: Autoantibodies in NSCLC as Markers for Disease
administering_ic: NCI
award_notice_date: 2008-02-28
application_type: 5
activity_code: R01
ic: CA
serial_number: 100323
program_official: KIM, KELLY Y
project_start_date: 2003-09-05
project_end_date: 2011-02-28
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): The use of only age and smoking history as selection criteria in population-based CT screening trials has afforded a low yield of cancer detection at significant cost. Moreover the routine identification of indeterminate pulmonary nodules during CT screening often requires additional workup magnifying the cost and adding potential morbidity from related interventional diagnostic procedures. We have developed a blood test for NSCLC that may address these limitations when integrated into the early detection paradigm. Specifically we exploited the expansive autoantibody repertoire of lung cancer patients to develop a multi-marker assay that compensates for NSCLC heterogeneity. Capture proteins were selected from cDNA tumor libraries using antibodies in patient plasma and in turn used to measure tumor-associated antibodies as markers of disease. Fluorescent microarray was adapted as a platform to accommodate a multiple marker approach. Individual markers were ranked by statistical differences between case and control samples and Receiver Operating Characteristic (ROC) was used to statistically define an optimal combination of those markers with high discriminatory value. Classifiers for a combined marker set were then built on known case and control samples and used to predict disease in available samples. Performance results indicate excellent potential for clinical utility. Having successfully completed the biomarker discovery phase of this project the current proposal has three primary objectives: 1) To evaluate assay performance for established lung cancer diagnosed in an expanded clinical population 2) to define a role for this assay in management of radiographically identified indeterminate pulmonary nodules independent of a screening study and 3) to confirm results that indicate this marker set may detect cancer and predict the onset of NSCLC prior to radiographic detection in a screened population. Relevance to Public Health. A blood test for lung cancer could improve the capability and cost- effectiveness of early detection as a viable strategy for reducing mortality from this disease.

project_terms:
Address;Age;Antibodies;Antibodies Tumor;Appearance;Autoantibodies;Bacteriophages;Benign;Biological Assay;Biological Markers;Blinded;Blood Tests;Cancer Detection;Cancer Patient;Carcinoma Non-Small-Cell Lung;Chest;Clinical;Clinical Research;Coin Lesion Pulmonary;Complement;Criteria Selection;DNA Complementary;Detection;Diagnosis;Diagnostic Procedure;Disease;Disease Marker;Disease Outcome;Dose;Early Detection Research Network;Early Diagnosis;Environment;Equipment and supply inventories;Glass;Heterogeneity;High-Risk Cancer;Imaging Techniques;Incidence;Individual;Kentucky;Lesion;Libraries;Lung;Lung diseases;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Morbidity - disease rate;Mortality Vital Statistics;Non-Malignant;Patients;Performance;Phase;Plasma;Population;Positron-Emission Tomography;Protein Array;Proteins;Rate;Receiver Operating Characteristics;Reporting;Research Personnel;Risk;Role;Sampling;Scanning;Screening procedure;Sensitivity and Specificity;Serological;Slide;Smoking History;Staging;Testing;Tumor Markers;Validation;X-Ray Computed Tomography;base;cancer diagnosis;case control;clinical application;cost;cost effectiveness;design;follow-up;improved;performance tests;programs;public health medicine (field);tool;tumor


application_id: 7414518
project_number: 5R01DE017680-02
project_title: P. gingivalis: Role of GSK3 in Host Inflammation
administering_ic: NIDCR
award_notice_date: 2008-03-11
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: LUMELSKY, NADYA L
project_start_date: 2007-04-25
project_end_date: 2012-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7618997
contact_pi: MARTIN, MICHAEL
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: 2008-04-01
project_terms:
Abscess;Affect;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Cell Nucleus;Cell surface;Cells;Chronic;Dendritic Cells;Disease;Event;Figs - dietary;Foundations;Gene Expression;Glycogen Synthase Kinase 3;Host Defense;Immune;Immune response;Immune system;Immunity;Inflammation;Inflammatory;Inflammatory Response;Interleukin-10;Interleukin-12;Interleukin-6;Invaded;Laboratories;Mediating;Microbe;Modeling;Mus;Nature;Numbers;Organism;Pathogenesis;Pathway interactions;Periodontal Diseases;Phosphotransferases;Play;Porphyromonas gingivalis;Principal Investigator;Process;Production;Property;Protein Isoforms;Receptor Activation;Receptor Signaling;Regulation;Reporting;Role;Severity of illness;Signal Pathway;Signal Transduction;Signaling Molecule;Solid;TLR2 gene;TLR4 gene;Toll-like receptors;base;cytokine;design;desire;in vivo;inhibitor/antagonist;macrophage;microorganism interaction;mouse model;pathogen;programs;response;therapeutic target


application_id: 7414485
project_number: 5R01CA111987-04
project_title: Sphingosine Kinase Compartmentalization in Tumorogenesis
administering_ic: NCI
award_notice_date: 2008-04-04
application_type: 5
activity_code: R01
ic: CA
serial_number: 111987
program_official: YASSIN, RIHAB R
project_start_date: 2005-07-15
project_end_date: 2010-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1923480
contact_pi: WATTENBERG, BRIAN W.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to identify molecular targets in sphingolipid signaling pathways for the development of therapeutics to treat cancer. The focus of the present proposal is the signaling enzyme sphingosine kinase-1 which produces the potent second messenger sphingosine-1-phosphate. Sphingosine kinase represents a candidate target for cancer therapy. This concept is based on the observations that sphingosine kinase is overexpressed in many tumors and that experimental overproduction of sphingosine kinase transforms cells from a growth-controlled state to a tumorigenic state. The localization of sphingosine kinase to distinct intracellular sites is key to its ability to transform cells. The proposed experimental plan will determine why localization is important for transformation. This will form the basis for a discovery of novel molecular targets involved in the transforming ability of sphingosine kinase. To accomplish this goal three specific aims are proposed. Specific Aim 1. Determine the activation-dependent subcellular localization of sphingosine kinase and sphingolipid metabolites affected by SK activity. Specific Aim 2. Determine the role of SK localization in cellular transformation and protumorigenic pathways. Specific Aim 3. The plasma membrane sphingosine-1-phosphate transport mechanism. Determine the mechanism and functional effects of enhanced sphingosine-1-phosphate secretion by activation of hSK-1.

project_terms:
Address;Affect;Agonist;Apoptotic;Binding (Molecular Function);Biochemical;Cell Proliferation;Cell membrane;Cell physiology;Cell secretion;Cellular Membrane;Ceramides;Cytosol;Data;Development;Elements;Endoplasmic Reticulum;Enzymes;Future;Goals;Growth;Housekeeping;Human;Intracellular Membranes;Knowledge;Laboratories;Lead;Lipids;Localized;Malignant Neoplasms;Mediating;Membrane;Models Experimental;Molecular;Molecular Target;Movement;Neoplasms Experimental;Oncogenic;Pathway interactions;Phosphorylation;Process;Production;Protein Overexpression;Proteins;Range;Receptor Activation;Regulation;Research;Research Personnel;Role;SPHK1 enzyme;Second Messenger Systems;Signal Pathway;Signal Transduction;Signaling Molecule;Site;Specificity;Sphingolipids;Sphingosine;Sphingosine-1-Phosphate Receptor;Testing;Therapeutic;Time;Work;base;cancer therapy;carcinogenesis;cell transformation;clinical application;concept;design;extracellular;inhibitor/antagonist;inorganic phosphate;lipid transport;member;metaplastic cell transformation;novel;programs;second messenger;sphingosine 1-phosphate;sphingosine kinase;tool;trafficking;tumor growth;tumorigenesis;tumorigenic


application_id: 7414460
project_number: 5R01NS051568-02
project_title: Mechanisms of Cerebral Vascular Remodeling
administering_ic: NINDS
award_notice_date: 2008-05-16
opportunity_number: PAS-04-072
application_type: 5
activity_code: R01
ic: NS
serial_number: 051568
program_official: JACOBS, TOM P
project_start_date: 2007-06-01
project_end_date: 2012-05-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
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_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;A Mouse;Abbreviations;Adenosine Diphosphate;Agonist;Albumins;Alteplase;Alzheimer's Disease;Antioxidants;Arginine;Attenuated;Basement membrane;Blood - brain barrier anatomy;Blood Vessels;Blotting Western;Brain;Butyric Acid;Butyric Acids;Caliber;Cerebrum;Collagen;Constriction procedure;Cystathionine;Dementia;Dementia Vascular;Diabetic Angiopathies;Disintegrins;Disruption;Endothelial Cells;Extracellular Matrix;Extravasation;Fluorescence;Functional disorder;GABA-A Receptor;Gelatinase A;Gelatinase B;Goals;Heterozygote;Homocysteine;Homocystine;Hydrolase;Hyperhomocysteinemia;Knock-out;Label;Ligase;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Metalloproteases;Methionine;Methylenetetrahydrofolate reductase (NADPH);Mice Knockout;Microvascular Permeability;Muscimol;N-Methylaspartate;NADH oxidase;NADP;NOS3 protein human;Neurotransmitters;Niacinamide;Nitric Oxide Synthase;Norepinephrine;Oxidation-Reduction;Patients;Permeability;Plasma;Polymerase Chain Reaction;Process;Proteome;RNA Messenger;Reactive Nitrogen Species;Reactive Oxygen Species;Research Personnel;Secondary to;Seizures;Stress;Structure of thyroid parafollicular cell;Testing;Therapeutic;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Topical application;Transgenic Organisms;Vascular Diseases;Vascular remodeling;Wild Type Mouse;cerebrovascular;gamma-Aminobutyric Acid;in vivo;innovation;micrography;mouse model;novel;peroxiredoxin;programs;receptor;relating to nervous system;stroke;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;vasoactive agent


application_id: 7414083
project_number: 5R01CA107575-05
project_title: Anoikis Effect by Quinazolines on Prostate Growth
administering_ic: NCI
award_notice_date: 2008-04-11
application_type: 5
activity_code: R01
ic: CA
serial_number: 107575
program_official: ARYA, SURESH
project_start_date: 2004-05-01
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZRG1-UROL(01)]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Loss of apoptotic control in prostate growth disorders involves the altered expression/activation of downstream intracellular effectors of apoptosis signaling pathways.  Re-instating functional apoptotic mechanisms by targeting specific components in this pathway are of high significance in the regulation of prostate growth.  Recent studies documented the ability for quinazoline-based a1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in human prostate smooth muscle benign and malignant epithelial cells via an a1-adrenoceptor independent mechanism and suppress tissue vascularity.  Our hypothesis is that quinazoline-based a1-adrenoceptor antagonists suppress prostate growth by inducing apoptosis (via induction of intracellular signaling effectors) and inhibit angiogenesis by promoting anoikis (via interference with extracellular matrix attachments).  To test this hypothesis the following aims are proposed: In Specific Aim 1 we will use DNA microarray analysis and proteomic analysis to identify intracellular signaling effectors of apoptosis induced by quinazoline-based a1-adrenoceptor antagonists in prostate benign and malignant cells.  Specific Aim 2 will identify the extracellular matrix components involved in quinazoline-induced anoikis in prostate epithelial and endothelial cells with focus on Fas-Fasligand-caspase-8 activation mechanism and integrin effectors.  Specific Aim 3 will establish that the quinazolines doxazosin and terazosin suppress prostate vasculature and inhibit tissue angiogenesis in patients after a1 blockade treatment. Immunohistochemical analysis will be performed on tissue specimens from BPH patients treated with a1 blockade (for obstructive symptoms) using antibodies against Factor VIII (microcrossed density) vascular endothelial growth factor (VEGF) and focal ashesion kinase (FAK).  The goal of the proposed studies is to determine the early response genes at the intracellular (TGF-beta) and extracellular matrix (integrins) environment underlying the quinazoline-mediated apoptosis targeted by this pharmacologic intervention in benign and malignant prostate growth.  Potential results will establish the apoptotic/anoikis effect by the quinazolines as a significant phenomenon with clinical relevance in development and progression of benign prostatic hyperplasia (BPH) prostate cancer.

project_terms:
Adrenergic Receptor;Anoikis;Antibodies;Apoptosis;Apoptotic;Benign;Characteristics;DNA Microarray Chip;DNA Microarray format;Development;Doxazosin;ERG gene;Endothelial Cells;Environment;Epithelial;Extracellular Matrix;Factor VIII;Focal Adhesion Kinase 1;Goals;Growth;Growth Disorders;Induction of Apoptosis;Integrins;Intervention;Malignant - descriptor;Malignant Epithelial Cell;Malignant neoplasm of prostate;Mediating;Microarray Analysis;Myocytes Smooth Muscle;Pathway interactions;Patients;Phosphotransferases;Prostate;Prostate carcinoma;Prostatic Diseases;Prostatic Hypertrophy Benign;Prostatic Neoplasms;Prostatic hypertrophy;Proteomics;Quinazolines;Regulation;Signal Pathway;Signal Transduction;Smooth muscle (tissue);Specimen;Symptoms;Testing;Therapeutic;Tissues;Transforming Growth Factor beta;Tumor Angiogenesis;Vascular Endothelial Growth Factors;angiogenesis;base;cancer cell;caspase-8;clinically relevant;density;terazosine


application_id: 7414066
project_number: 5K08NS050110-05
project_title: Alpha-synuclein mRNA is a putative microRNA target
administering_ic: NINDS
award_notice_date: 2008-04-16
application_type: 5
activity_code: K08
ic: NS
serial_number: 050110
program_official: SUTHERLAND, MARGARET L
project_start_date: 2005-05-01
project_end_date: 2010-04-30
study_section: Neurological Sciences Training Initial Review Group[NST]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
Small regulatory RNAs participate in many eukaryotic cell functions microRNAs (miRNAs) the major subclass of small regulatory RNAs in animal species regulate gene expression post-transcriptionally by destabilizing and/or reducing the translation of specific 'target' mRNAs. Post-transcriptional gene regulation has revolutionary implications yet very little is known of the roles played by miRNAs in neurons or neurodegenerative disease. AIM 1: CHARACTERIZE THE POLYRIBOSOMAL miRNP IN NEURON-LIKE CELLS. miRNA-related biochemistry is poorly understood. We hypothesize that miRNA-containing polyribosomal ribonucleoprotein complexes (miRNPs) represent the biochemical substrate for miRNA:mRNA regulation. We will partially purify the polyribosomal miRNP from Weri retinoblastoma cells to characterize the biochemical properties and the protein components of this important particle. AiM 2: IDENTIFY AND CHARACTERIZE miRNA:mRNA PAIRS. Although hundreds of human miRNAs are known most mRNA targets are unknown. We discerned "rules" that govern miRNA:target mRNA interaction. Using these guidelines our bioinformatician collaborators predict mRNA targets regulated by human miRNAs. We will use cell biological tools to verify hypothesized miRNA-mRNA partners relevant to human neurological diseases. AIM 3: CHARACTERIZE A miRNA INTERACTION THAT MAY REGULATE THE EXPRESSION OF ALPHA-SYNUCLEIN (A-SN). On the basis of preliminary evidence we hypothesize that an evolutionarily conserved sequence element in the 3'-untranslated region of A-SN mRNA is recognized by a specific miRNA (miR-93). A-SN protein plays a central role in some neurodegenerative diseases and itsregulation by a miRNA would have important implications in neurobiology neurodegenerative disease and RNA biology. We will study this interaction using neuronal cell lines as a prototype of miRNA:mRNA validation. We will also extend the analyses to human brain tissue in health and disease.

project_terms:
3' Untranslated Regions;Amyotrophic Lateral Sclerosis;Animals;Appendix;Biochemical;Biochemistry;Bioinformatics;Biological;Biological Assay;Biology;Blotting Northern;Cell Line;Cell Line Tumor;Cell physiology;Cells;Co-Immunoprecipitations;Complex;Computational algorithm;Condition;Conserved Sequence;Disease;Eukaryotic Cell;Fragile X Syndrome;Gene Expression;Gene Expression Regulation;Guidelines;Health;Human;Immunohistochemistry;In Situ;In Situ Hybridization;Indium;Journals;Medical;Mental Retardation;MicroRNAs;Nerve Degeneration;Neurobiology;Neurodegenerative Disorders;Neurons;Neurosciences;Paper;Parkinson Disease;Physiological;Play;Polyribosomes;Process;Property;Proteins;RNA;RNA Messenger;Regulation;Research;Retinoblastoma;Ribonucleoproteins;Role;Role playing therapy;Science;Specificity;System;TSC1 protein human;Techniques;Testing;Translations;Tuberous Sclerosis;Validation;alpha synuclein;base;brain tissue;nervous system disorder;novel;particle;protein expression;prototype;synuclein;tool


application_id: 7413799
project_number: 3R21NS053593-01S2
project_title: Novel High Content Vascular Patterning Assay(RMI)
administering_ic: NINDS
award_notice_date: 2007-04-26
opportunity_number: RFA-RM-05-011
application_type: 3
activity_code: R21
ic: NS
serial_number: 053593
suffix: S2
program_official: SCHEIDELER, MARK A
project_start_date: 2005-09-30
project_end_date: 2008-08-31
study_section: ZNS1-SRB-G(01)
contact_pi_person_id: 1881039
contact_pi: MOHAN, ROYCE
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Angiogenesis the growth of new blood vessels occurs in a diverse array of human diseases. Even thoughanti-angiogenesis remains a large market for Pharmaceuticals high content high throughput cell basedassays for angiogenesis inhibitor discovery remain to be developed for this application. It is our belief thatdeveloping new assays as screening tools for discovery of inhibitors that target endothelial cell differentiationcan prove to be an efficient means of identifying new classes of anti-angiogenic drugs. Here we propose todevelop a high content vascular patterning assay that can likely be adopted for high throughput screening(HTS). We plan to build a prototype of a powerful high content screening platform by interfacing highthroughput screening capability with multiparameter optical imaging of endothelial cell patterning in three-dimensional (3-D)matrices. Our innovative approach to achieve these goals will be accomplished throughthe following aims. In Specific aim 1 we will develop and validate a 3-D endothelial cell patterning assay (3-D ECPA). We will accomplish this by developing methods to generate highly robust multicellular endothelialcell spheroids on microcarrier beads and array the spheroids in 3-D collagen matrix in 384 well opticalscreening plates. In addition these assays will be performed under hypoxic environment. In Specific Aim 2we plan to develop and validate a high content (HC)image analysis platform for use with 3-D ECPA . Thiswill be accomplished by developing software that identifies novel features of endothelial cell patterning in 3-Dmatrix and apply automated analysis to obtain morphogenic findgerprints. Finally we will validate the 3-DECPA and image analysis software for HTS application by screening a diversity set of natural products. Webeleve that this HC-HTS platform will offer unique opportunities to screen vast numbers of small moleculeinhibitors of angiogenesis and assist in drug discovery.

project_terms:
3-Dimensional;Adopted;Angiogenesis Inhibitors;Belief;Biological Assay;Biological Factors;Blood Vessels;Cell Differentiation process;Cells;Class;Collagen;Computer software;Condition;Endothelial Cells;Environment;Goals;Hypoxia;Image Analysis;Marketing;Methods;Numbers;Optics;Pattern;Pharmacologic Substance;Screening procedure;angiogenesis;antiangiogenesis therapy;base;drug discovery;drug testing;high throughput screening;human disease;inhibitor/antagonist;innovation;new growth;novel;optic imaging;prototype;small molecule;software development;tool


application_id: 7413673
project_number: 5R01HL083122-02
project_title: Prostanoid-dependent abdominal aortic aneurysm formation
administering_ic: NHLBI
award_notice_date: 2008-05-14
application_type: 5
activity_code: R01
ic: HL
serial_number: 083122
program_official: TOLUNAY, ESER
project_start_date: 2007-05-01
project_end_date: 2011-04-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8351945
contact_pi: LOFTIN, CHARLES DAVID
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Our recent report together with our preliminary studies show that genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) reduces the incidence and severity of AAAs in mice chronically infused with angiotensin II (Angll). Furthermore significant COX-2 expression is increased in AAAs as compared to the uninvolved aorta. Our preliminary studies also show that the expression of the PGE2 receptor EP4 is significantly increased in aneurysmal tissue. However the role of the prostanoid receptors in AAA formation is not clearly defined. The long-term objectives of this proposal are to elucidate mechanisms by which prostanoids contribute to AAAs. We propose the hypothesis that COX-2 participates in all stages of Angll- induced AAA development through preferential synthesis of PGE2 and TXA2 which specifically activate EP4 and TP receptors respectively. This hypothesis is based on previous observations that a) Explant cultures from human AAAs express significant levels of COX-2. b) PGE2 contributes to vascular pathology by increasing expression and/or activation of matrix metalloproteinases and inducing smooth muscle cell apoptosis. c) TXA2 increases adhesion molecule expression and contributes to influx of macrophages in the vessel wall. Therefore we propose the following specific aims: 1) Determine the role of COX-2 at multiple stages of AAA formation. These studies will use mice genetically deficient in COX-2 as well as the COX-2- specific inhibitor celecoxib. 2) Determine the effect of genetic deficiency of the prostanoid receptors EP4 and TP on AAA formation. These studies will provide a mechanistic view of the role of COX-2-dependent prostanoids and will provide insight into the development of novel therapeutics for AAAs. The objectives of the proposed studies are to identify new treatments for abdominal aortic aneurysms (AAAs). AAAs are a life-threatening disease which afflict approximately 5% of the male population over the age of 65 and once the disease has formed there is an increased chance for rupture of the aorta an event which most people do not survive. The cause of aortic aneurysms in humans is not known but is thought to involve inflammation within the wall of the aorta. Therefore we will use an animal model of this disease to determine the mechanisms by which this disease occurs in humans. These studies are important as they will help identify non-surgical treatments for this disease in humans.

project_terms:
Abdomen;Abdominal aorta structure;Angiotensin II;Animal Disease Models;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Aorta;Aortic Aneurysm;Aortic Aneurysm Abdominal;Apoptosis;Arachidonic Acids;Attenuated;Binding (Molecular Function);Biological;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell Adhesion Molecules;Chronic;Data;Development;Dinoprostone;Disease;Disease regression;EP4 receptor;Effectiveness;Elderly;Event;Genetic;Health;Human;Incidence;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Infusion procedures;Life;Matrix Metalloproteinases;Mediating;Metabolic;Modeling;Mus;Myocytes Smooth Muscle;Operative Surgical Procedures;Pathology;Pharmaceutical Preparations;Pharmacological Treatment;Play;Population;Prostaglandin E Receptor;Prostaglandin H2;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Isoforms;RNA Messenger;Reporting;Research Personnel;Role;Rupture;Severities;Staging;Stimulus;Testing;Thinking function;Thromboxane A2;Thromboxane Receptor;Tissues;WFDC2 protein human;Wild Type Mouse;Work;aging population;base;celecoxib;chemokine;cyclooxygenase 1;cyclooxygenase 2;inhibitor/antagonist;insight;interest;macrophage;male;monocyte;novel therapeutics;programs;receptor;response


application_id: 7410039
project_number: 5R01AG027219-03
project_title: SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT
administering_ic: NIA
award_notice_date: 2008-04-24
application_type: 5
activity_code: R01
ic: AG
serial_number: 027219
program_official: SUNEJA, SANOJ
project_start_date: 2006-08-01
project_end_date: 2011-04-30
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Mounting evidence suggests that individuals with mild cognitive impairment (MCI) have an increased likelihood to develop Alzheimer's disease (AD). It is unclear what early pathophysiological changes may underlie this transition. The brains of individuals with definite AD manifest several pathological changes including a substantial loss of synapses in association areas of the neocortex. Recent work has now demonstrated that synaptic loss provides an excellent correlation with cognitive ability and provides a strong correlate of dementia. The relationship between synapse loss early cognitive decline such as that observed in MCI is poorly understood. There is increasing evidence that amyloid beta peptide (Abeta) and oxidative damage may be fundamentally involved in the pathogenesis of AD and contribute to MCI. The interaction between Abeta oxidative damage and synapse loss may provide important keys to the mechanisms that lead to MCI. This proposal will examine the hypothesis that synapse loss is associated with cognitive deficits observed in the early phase of the disease process and is responsible for amnestic memory problems associated with MCI. Studies will be carried out on short postmortem interval brains from individuals characterized as no cognitive impairment (NCI) MCI and early AD and evaluation of total synapses will be obtained by coupling unbiased stereology with transmission electron microscopy. Since Abeta is considered by many researchers to play an important role in progression of AD we will study the relationship of soluble Abeta1-42 with synaptic loss and pre/post synaptic proteins. The specific aims will also test the hypothesis that oxidative damage is an early indicator of MCI and is associated with changes in total synaptic numbers in neocortical association areas known to be affected early in AD. Finally we will study possible changes in mitochondrial bioenergetics that occur in MCI and early AD since mitochondria can be affected by both Ap and oxidative stress and are important for synapse function. Successful completion of the proposed studies will lead to new insights into the mechanisms underlying MCI and early AD and contribute to the development of effective pharmacologic therapies for AD.

project_terms:
4 hydroxynonenal;Accounting;Acrolein;Affect;Alzheimer's Disease;Amyloid beta-Protein;Area;Autopsy;Bioenergetics;Brain;Chromosome Pairing;Cognitive;Cognitive deficits;Coupling;DLG4 gene;Dementia;Development;Diagnostic;Disease;Evaluation;Event;F2-Isoprostanes;Failure (biologic function);Growth Associated Protein 43;Hippocampus (Brain);Impaired cognition;Individual;Inferior;Lead;Lesion;Link;Lobule;Memory;Mitochondria;Neocortex;Neurofibrillary Tangles;Numbers;Oxidative Stress;Parietal;Pathogenesis;Pathologic;Performance;Phase;Play;Process;Proteins;Research Personnel;Role;Science of neurochemistry;Senile Plaques;Sensory;Severities;Structure of postcentral gyrus;Synapses;Testing;Thinking function;Transmission Electron Microscopy;Work;cognitive function;insight;mild cognitive impairment;neocortical;presynaptic density protein 95;sensory cortex;synaptic function


application_id: 7409966
project_number: 5R01NS048191-05
project_title: Mitochondrial Uncoupling as a Therapeutic Target in TBI
administering_ic: NINDS
award_notice_date: 2008-02-22
application_type: 5
activity_code: R01
ic: NS
serial_number: 048191
program_official: HICKS, RAMONA R
project_start_date: 2004-02-01
project_end_date: 2011-01-31
study_section: Special Emphasis Panel[ZRG1-CDIN(01)Q]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
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_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a devastating healthcare problem in the United States however there are currently no pharmacological treatments approved for the clinical treatment of this condition. Compelling experimental data demonstrates that mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of brain injury. This proposal focuses on mild mitochondrial uncoupling as a novel therapeutic intervention following traumatic brain injury. The premise being that TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to mitochondrial dysfunction. Mitochondrial uncouplers are compounds that facilitate the movement of protons from the mitochondrial inner-membrane space into the mitochondrial matrix. Uncoupling can also be mediated via the activation of endogenous mitochondrial uncoupling proteins (UCP) that can be modulated by fasting. While long-term complete uncoupling of mitochondria would be detrimental a transient or "mild uncoupling" could confer neuroprotection. Mild uncoupling during the acute phases of TBI would be expected to reduce mitochondrial Ca2+ uptake (cycling) and ROS production. The proposed experiments are designed to test the novel hypothesis that mild mitochondrial uncoupling is neuroprotective following traumatic brain injury. Specifically we will determine 1) if mitochondrial uncouplers increase tissue sparing and improve behavioral outcome following TBI 2) if mitochondrial uncouplers maintain mitochondrial integrity and bioenergetics following TBI and 3) examine the mechanism(s) underlying the neuroprotection afforded by fasting following traumatic brain injury. The experiments will determine the optimal dose and time post-injury to administer uncouplers to afford optimal neuroprotection and reduce cognitive defects following a mild or severe TBI in rats. Next we will examine mitochondrial function following mild or severe TBI in rats to determine if mitochondrial uncouplers maintain mitochondrial integrity. Finally using a reductionist approach we will employ several strategies including the use of UCP-2 transgenic mice insulin-induced hypoglycemia and ketone administration to determine specific mechanisms involved in fasting-mediated neuroprotection following TBI. The proposed experiments may pinpoint important mitochondrial events that could be potential novel targets for the treatment of TBI and perhaps other acute neuronal injuries.

project_terms:
24-Dinitrophenol;4 hydroxynonenal;Abbreviations;Acetoacetates;Acids;Acute;Address;Adenosine Triphosphate;Adult;Animals;Attenuated;Behavioral;Bioenergetics;Blood Glucose;Brain Injuries;Brain Injuries Acute;Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone;Cell Death;Cell Survival;Clinical Treatment;Cognitive;Condition;Data;Defect;Dinitrophenols;Disruption;Dose;Electron Transport;End Point;Event;Excitatory Amino Acids;Fasting;Fatty Acids Nonesterified;Functional disorder;G Cells;Glutamates;Healthcare;Hippocampus (Brain);Homeostasis;Hydroxybutyrates;Hydroxyl Radical;Hypoglycemia;Injury;Inner mitochondrial membrane;Insulin;Intervention;Isoxazoles;Ketone Bodies;Ketones;Ketoses;Ketosis;Knock-out;Lead;Light;Link;Measures;Mediating;Membrane Potentials;Mice Transgenic;Mitochondria;Mitochondrial Matrix;Modeling;Morphology;Movement;Neuronal Injury;Outcome;Pathway interactions;Pharmacological Treatment;Phase;Process;Production;Proteins;Proton Pump;Protons;Publishing;Rain;Rattus;Reactive Oxygen Species;Recovery of Function;Role;Synapses;System;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Traumatic Brain Injury;UCP2 protein;United States;Up-Regulation (Physiology);Work;alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;amino 3 hydroxy 5 methylisoxazole 4 propionate;base;behavior measurement;beta-Hydroxybutyrate;concept;controlled cortical impact;design;excitotoxicity;glucose metabolism;improved;injured;innovation;male;mesoxalonitrile;mitochondrial dysfunction;mitochondrial membrane;mitochondrial uncoupling protein;morris water maze;neuron loss;neuropathology;neuroprotection;novel;novel therapeutics;phenylhydrazone;protein expression;research study;therapeutic target;uptake


application_id: 7409316
project_number: 1F31AA017346-01
project_title: The role of PKC epsilon in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2007-09-28
application_type: 1
activity_code: F31
ic: AA
serial_number: 017346
program_official: RADAEVA, SVETLANA
project_start_date: 2007-12-01
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZAA1 JJ (14)]
contact_pi_person_id: 9020505
contact_pi: KAISER, JONATHAN PHILLIP
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: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant): Hepatic Steatosis is a critical stage in the pathology of alcoholic liver disease. It has been suggested that not only does the severity of steatosis predict the severity of later stages of ALD but that preventing steatosis caused by ethanol could also prevent the later stages of ALD (i.e. fibrosis and cirrhosis). In a previous study done by our laboratory it was shown that metformin an insulin sensitizing drug blocks steatosis caused by ethanol suggesting that insulin resistance could play a causal role in ethanol-induced steatosis. Protein kinase c-epsilon (PKCe) has been shown to cause hepatic insulin resistance as well non-alcoholic fatty liver disease therefore we hypothesize that PKCe has a causal role in ALD by causing hepatic insulin resistance. This hypothesis will be tested via the following Specific Aims. 1). To test the hypothesis that PKCe has a causal role in ethanol-induced steatosis. In the Preliminary Studies it was shown that acute ethanol exposure leads to an increase in PKCe activity before the onset of ethanol-induced steatosis. Next we determined that PKCe-/- mice are partially protected against steatosis due to ethanol. The goal of this aim is to build on these Preliminary Studies. 2). To determine the mechanism by which ethanol is increasing diacylglycerol (DAG) synthesis. One of the prominent activators of PKCe is DAG. De novo DAG formation can be increased by alcohol via an increase in flux of long chain fatty-acyl CoAs and/or glyceraldehyde-3-phosphate into the triacylglycerol pathway. However the relative contributions of these potential pathways are unclear. Therefore the goal of this aim is to determine the relative contribution of these 2 potential pathways of DAG formation under these conditions. 3). To test the hypothesis that PKCe and Gdc1 inhibition will prevent liver damage owing to chronic exposure. We expect the results of Specific Aims 1 and 2 to determine that PKCe plays a causal role in ethanol-induced steatosis. However the role of this enzyme in chronic ethanol exposure is not yet known. Therefore the goal of this aim is to determine the effect of genetic inhibition of PKCe and Gdc1 on liver damage caused by chronic ethanol exposure. ALD is one of the leading causes of death in the world affecting millions of people per year. From the years 1985 to 1992 it is estimated that over $148 billion was spent to treat people with this disease. However due to poor understanding of the biochemical mechanisms responsible for ALD there is no FDA approved therapy to treat the disease. Therefore the goal of this work is to provide better understanding of the mechanisms responsible for ALD in hopes of identifying a therapeutic target to not only prevent but also reverse the progression of the disease.

project_terms:
12-diacylglycerol;Acute;Affect;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animal Model;Biochemical;Cause of Death;Chronic;Cirrhosis;Clinic;Condition;Data;Development;Diglycerides;Disease;Disease Progression;Enteral;Enzymes;Epidemiologic Studies;Ethanol;Fatty Acids Nonesterified;Fatty Liver;Fibrosis;Genetic;Glyceraldehyde 3-Phosphate;Glycerol;Goals;Health;Hepatic;Inflammation;Insulin;Insulin Resistance;Laboratories;Liver;Liver diseases;Measures;Mediating;Metformin;Modeling;Mus;Necrosis;Oxidative Stress;Oxidoreductase;Pathology;Pathway interactions;Personal Satisfaction;Phosphotransferases;Play;Population;Protein Kinase;Relative (related person);Risk;Role;Serum;Severities;Staging;Testing;Therapeutic;Triglycerides;United States Food and Drug Administration;Work;alcohol exposure;indexing;inorganic phosphate;insulin sensitizing drugs;insulin signaling;non-alcoholic fatty liver;prevent;protein kinase C epsilon;therapeutic target


application_id: 7408299
project_number: 1R34NS056635-01A2
project_title: CASTBI Trial Planning Grant: Cyclosporine in Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2007-12-14
opportunity_number: PAR-06-460
application_type: 1
activity_code: R34
ic: NS
serial_number: 056635
suffix: A2
program_official: JANIS, SCOTT
project_start_date: 2008-01-01
project_end_date: 2008-12-31
study_section: Neurological Sciences and Disorders K Study Section[NSD-K]
contact_pi_person_id: 7875441
contact_pi: YOUNG, ALFRED BYRON
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
project_abstract:
DESCRIPTION (provided by applicant): Head injury is a complex disease involving two distinct patterns of injury primary injury and secondary injury. There is significant morbidity and mortality associated with brain injury with about 50000 deaths and 235000 hospitalizations each year. In spite of major advancements in the understanding of the molecular mechanisms associated with secondary injury induced by traumatic brain injury (TBI) failure to discover a therapeutic agent to mitigate these affects in humans has been a persistent disappointment to researchers. Several agents have shown promise in the laboratory but have not translated into success beyond the animal model. When trials were comprehensively reviewed inadequate statistical sensitivity inadequate pre-clinical data and lack of drug disposition data documenting access to the brain were identified as important contributing factors. Cyclosporine A (CsA) has been shown in multiple animal models to be neuroprotective by attenuating mitochondrial dysfunction and preventing axonal destruction thus improving outcomes. Animal studies have shown that a continuous infusion preceded by a bolus dose given within 12 hours of injury maximizes CsA protective effects. In addition our early clinical trial investigations of CsA in severe TBI have shown that the drug is safe that higher continuous infusion doses are more effective that CsA is detected in the central nervous system and that CsA treated patients have a trend toward better outcomes. This planning grant proposal is necessary to complete the steps required for the initiation of a Phase III multi-center clinical trial in severe TBI patients evaluating CsA therapy (CASTBI). A double-blind placebo controlled trial of 1218 patients investigating CsA will be designed to test the hypothesis that patients suffering from a severe TBI treated with a continuous infusion of CsA for three days will have an improved functional outcome compared to placebo. The primary endpoint assessment of functional outcome will be the Glasgow Outcome Scale at 6 months. This planning grant period will be used to: (1) identify executive committee and sub-committee members; (2) finalize study documents including protocol manual of operations case report forms and investigational new drug application; (3) recruit study sites; (4) prepare and validate the data management systems; (5) develop training and certification materials for outcome assessments; (6) organize investigator's meeting; and (7) prepare Phase III CASTBI grant for submission.

project_terms:
Affect;Animal Model;Animals;Attenuated;Bolus Infusion;Brain;Brain Injuries;Case Report Form;Certification;Cessation of life;Clinical Data;Clinical Trials;Clinical Trials Phase III;Complex;Continuous Infusion;Craniocerebral Trauma;Cyclosporine;Cyclosporins;Data;Disease;Dose;End Point;Failure (biologic function);Glasgow Outcome Scale;Grant;Grants Applications;Hospitalization;Hour;Human;Injury;Investigation;Investigational New Drug Application;Laboratories;Manuals;Members Committee;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Multi-Institutional Clinical Trial;Neuraxis;Operative Surgical Procedures;Outcome;Outcome Assessment (Health Care);Patients;Pattern;Pharmaceutical Preparations;Phase;Placebos;Protocols documentation;Recruitment Activity;Research Personnel;Site;Statistical sensitivity;System;TBI Patients;Testing;Therapeutic Agents;Training;Translating;Traumatic Brain Injury;data management;day;design;double-blind placebo controlled trial;functional outcomes;improved;mitochondrial dysfunction;pre-clinical;prevent;protective effect;success;trend


application_id: 7408069
project_number: 5T32AG000242-15
project_title: The Molecular and Cellular Basis of Brain Aging
project_terms: Aging;Base of the Brain;Molecular
administering_ic: NIA
award_notice_date: 2008-04-07
opportunity_number: PA-02-109
application_type: 5
activity_code: T32
ic: AG
serial_number: 000242
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1994-09-30
project_end_date: 2009-04-30
study_section: ZAG1-ZIJ-6(J1)
contact_pi_person_id: 8535427
contact_pi: GASH, DON MARSHALL
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
project_abstract:
DESCRIPTION (provided by applicant): The goal of this Training Program is to prepare promising graduate students and postdoctoral fellows for successful careers in the neurobiology of aging. We will provide broad-based training in modern concepts in the neurobiology of aging with an emphasis on cellular and molecular mechanisms underlying aging processes and possible therapeutic interventions. The unifying focus of the training faculty is our interest in understanding both normal and pathological mechanisms by which the nervous system responds to changes that occur with age and emerging concepts in therapeutic intervention. This Training Program provides the formal framework for faculty in different departments who share a common interest in the molecular - cellular basis of brain aging and translational research to provide in-depth training in aging. The emphasis of the Training Faculty complement each other: some focus on processes that occur in the brain during normal aging others emphasize the neuropathological processes of diseases and injuries that predominate in the aging brain and there is a combined interest in applying this knowledge to treating neural disorders of aging. Thus trainees will learn from faculty who utilize a broad spectrum of state-of-the-art methodological approaches to probe critical questions in aging research. Our successes attest to our ability to identify attract train and place promising young investigators in the area of the neurobiology of aging. Now more than ever before we are particularly qualified to train graduate students and postdoctoral fellows. The national need for training new investigators in the area of aging is clear due to our changing demography and the increasing average lifespan. Normal aging or pathology of the nervous system underlies much age-associated morbidity. Only if we better understand the basic mechanisms that regulate the aging of the brain and apply this to the treatment of the elderly can we hope to improve the quality of life during the latter half of the lifespan. Our ability to attract and train graduate students and postdoctoral fellows to meet the challenges in the area of the neurobiology of aging will be greatly enhanced by this Training Program.


application_id: 7408062
project_number: 5R01HL088012-02
project_title: Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
administering_ic: NHLBI
award_notice_date: 2008-03-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 088012
program_official: WANG, LAN-HSIANG
project_start_date: 2007-04-18
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1-CVS-D(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with cardiac arrhythmia and sudden cardiac death (SCO). Hey increases the iNOS activates matrix metalloproteinase (MMP) disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interrupts cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. The novelty of this proposal is that Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA an excitatory neurotransmitter) receptor-1 and blockade of NMDA-R1 reduces SCO. The central hypothesis of this proposal is that Hcy increases iNOS mtNOS activities superoxide levels metalloproteinase activity disrupts connexin-43 exacerbates endothelial-myocyte uncoupling and induces cardiac failure by activating NMDA-R1. Specific Aim #1: To determine whether Hey exacerbates heart failure and endothelial-myocyte uncoupling by increasing iNOS and rendering ineffective eNOS and nNOS by behaving as an agonist to NMDA-R1. CBS heterozygote (-/+) knockout (CBSKO) mice will be crossbred with iNOS homozygote (-/-) knockout (iNOSKO) mice producing wild type (WT) CBSKO iNOSKO and CBS/iNOS (-/+; -/-) double knockout (doubleKO). In these mice chronic volume overload heart failure will be created by aorta-venacava (AV) fistula. NMDA-R1 will be blocked by dizocilpine (MK-801). The endothelial-myocyte coupling will be determined in cardiac rings. LV levels of NMDA-R1 iNOS nNOS and eNOS will be measured. Specific Aim #2: To determine whether Hey increases MMP-2 -9 -13 ADAM-12 decreases TIMP-4 and degrades connexin-43 in heart failure by inducing NMDA-R1. MMP and TIMP activities will be measured by innovative 2-zymography (MMP functional proteomics) and reverse zymography respectively. The degradation of connexin-43 collagen and elastin will be measured by Western analysis. Specific Aim #3: To determine whether Hey decreases LV mitochondrial thioredoxin peroxiredoxin and SOD and increases NADH oxidase and mtNOS activity in heart failure by activating NMDA-R1. In hearts in situ labeling will be performed for thioredoxin peroxiredoxin SOD and NADH oxidase. These studies will delineate the mechanism of Hcy-dependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure and will have therapeutic ramifications for sudden cardiac death.

project_terms:
3-deazaadenosine;Abbreviations;Acetylcholine;Address;Adenosine Diphosphate;Agonist;Alteplase;Aorta;Arginine;Arrhythmia;Attenuated;Basement membrane;Blotting Western;Bradykinin;Breeding;Cardiac;Chronic;Collagen;Connexin 43;Coupling;Crossbreeding;Cystathionine;Death Sudden Cardiac;Disintegrins;Disruption;Dose;EKG QRS Complex;Echocardiography;Eicosatrienoic Acid;Elastin;Electrocardiogram;Endothelial Cells;Endothelin-1;Endothelium;Environment;Extracellular Matrix;Failure (biologic function);Fibrosis;Fistula;Fluorescent Dyes;Gelatinase A;Goals;Heart;Heart Rate;Heart failure;Heterozygote;Homocysteine;Homocystine;Homozygote;Hydrolase;Hydroxyeicosatetraenoic Acids;Hyperhomocysteinemia;Image;In Situ;Knock-out;Label;Left ventricular structure;Lipopolysaccharides;Localized;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Metalloproteases;Methionine;Methylenetetrahydrofolate reductase (NADPH);Mitochondria;Mus;Muscle Cells;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NADH oxidase;NADP;NOS1 protein human;NOS3 protein human;Neurons;Neurotransmitter Receptor;Niacinamide;Nitric Oxide;Nitric Oxide Synthase;Nitroprusside;Norepinephrine;Oxidation-Reduction;Oxides;Pattern;Polymerase Chain Reaction;Preparation;Production;Proteomics;Radio;Reactive Nitrogen Species;Reactive Oxygen Species;Relaxation;Research Personnel;Shunt Device;Superoxide Dismutase;Superoxides;Tachycardia Ventricular;Tail;Telemetry;Therapeutic;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinases;Veins;Ventricular Fibrillation;analog;dizocilpine;in vivo;innovation;membrane-type matrix metalloproteinase;peroxiredoxin;programs;relating to nervous system;relaxing factor;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;tumor necrosis factor receptor superfamily member 10b protein mouse


application_id: 7408035
project_number: 5R01AA003624-29
project_title: Control of drug and ethanol metabolism
administering_ic: NIAAA
award_notice_date: 2008-04-11
opportunity_number: PA-05-074
application_type: 5
activity_code: R01
ic: AA
serial_number: 003624
program_official: GENTRY, THOMAS
project_start_date: 1978-03-01
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: N
project_terms:
A Mouse;Acute;Alcohol consumption;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Bile duct structure;Chronic;Cirrhosis;Clinic;Clinical Treatment;Deposition;Disease;Drug Controls;Enteral;Ethanol;Ethanol Metabolism;Fatty Liver;Fibrin;Fibrosis;Genetic;Health;Hepatic;Human;Individual;Inflammation;Injury;Knowledge;Ligation;Liver;Liver Fibrosis;Mediating;Metalloproteases;Metformin;Modeling;Mus;Necrosis;Numbers;Pathway interactions;Personal Satisfaction;Plasminogen Activator Inhibitor 1;Play;Population;Prevention;Process;Purpose;Recovery;Relative (related person);Research Personnel;Resolution;Rodent Model;Role;Staging;Steatohepatitis;Testing;Transplantation of liver;Up-Regulation (Physiology);Very low density lipoprotein;Work;alcohol exposure;fibrogenesis;hepatic necrosis;insulin signaling;mouse model;novel;prevent;problem drinker;programs


application_id: 7408026
project_number: 5R01CA102102-04
project_title: BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
administering_ic: NCI
award_notice_date: 2008-03-06
application_type: 5
activity_code: R01
ic: CA
serial_number: 102102
program_official: FU, YALI
project_start_date: 2005-05-01
project_end_date: 2010-03-31
study_section: Bio-Organic and Natural Products Chemistry Study Section[BNP]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): Gilvocarcins and jadomycins are angucyclin-derived anticancer drugs/antibiotics possessing unique molecular frames whose common biosynthetic key step is an oxidative rearrangement catalyzed by a closely related set of enzymes.   
  
The gilvocarcins produced by various Streptomyces strains including Streptomyces griseoflavus Go 3592 represent a distinct family of interesting aryl C-glycoside antitumor drugs with a coumarin-based aromatic core that promote specific DNA interactions when photoactivated by near UV light. This class of anticancer drugs shows excellent antitumor activity and remarkably low toxicity. Its unprecedented molecular architecture in conjunction with its unique biological activity makes the gilvocarcins an excellent target for biosynthetic studies and the development of novel photoactivatable anticancer drugs through combinatorial biosynthesis. The drugs may be useful for the treatment of special cancers such as brain tumors colon skin lung and prostate cancers or leukemia. The jadomycins are antibiotics/antifungals whose structure is characterized by an unusual insertion of an amino acid building block after an oxidative bond breakage.  
  
Previous biosynthetic studies suggest for both gilvocarcins and jadomycins a pathway dominated by a type-2 polyketide synthase (PKS) leading initially to an angucycline type drug intermediate which then oxidatively rearranges into the final molecular frame. Selected intriguing post-PKS tailoring steps namely the oxidative rearrangement (gilvocarcin and jadomycin biosynthesis) the unusual C-glycosylation step (gilvocarcin biosynthesis) and the formation of the vinyl group side chain of gilvocarcin V are key biosynthetic features responsible for the generation of structural elements which are essential for the unique biological activity of the gilvocarcin drugs. The investigation of these cascades of post-PKS tailoring biosynthetic key reactions found in both the jadomycin and gilvocarcin biosyntheses is a main goal of the research since it as an interesting model for post-PKS enzyme complexes their mechanisms interactions substrate binding/passing modes etc. This topic has never been studied in detail despite the importance of such tailoring steps for the biological activity of polyketide drugs. The understanding of these biosynthetic steps and the enzymes responsible for their execution will ultimately pave the way for the generation of more potential and more selective drugs through combinatorial biosynthetic methods. The following specific aims will be addressed: (1) Characterization of the late steps of the gilvocarcin and jadomycin biosynthesis; (2) Generation of new gilvocarcin analogues by inactivation and recombination of selected post-PKS tailoring genes; (3) Characterization of key enzymes of the gilvocarcin and the related jadomycin biosynthetic pathway to understand their mechanism-of-action and substrate specificity range their interaction; and (4) assessment of the antitumor activity of gilvocarcin and newly generated analogues from specific aim 2. The long-term goal of this research is to develop improved anticancer drugs for the treatment of special cancers.

project_terms:
Address;Amino Acids;Anabolism;Antibiotics Antifungal;Antineoplastic Agents;Architecture;Binding (Molecular Function);Biological;Brain;Brain Neoplasms;C-glycoside;Class;Colon;Coumarins;DNA;DNA Sequence Rearrangement;Development;Elements;Enzymatic Biochemistry;Enzymes;Family;Figs - dietary;Foundations;Gene Cluster;Generations;Genes;Genus Cola;Goals;Histones;Investigation;Knowledge;Lead;Light;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Modeling;Modification;Molecular;Multienzyme Complexes;Object Attachment;Oxygenases;Pathway interactions;Pharmaceutical Preparations;Production;Property;Prostate;Range;Reaction;Recombination Genetic;Research;Route;Side;Skin;Streptomyces;Streptomyces lividans;Structure;Substrate Interaction;Substrate Specificity;Toxic effect;alpha benzopyrone;analog;anticancer activity;antineoplastic antibiotics;antitumor drug;base;combinatorial;drug biological activity;gilvocarcin V;glycosylation;glycosyltransferase;improved;interest;jadomycin B;leukemia;mutant;novel;polyketide synthase


application_id: 7407954
project_number: 1P01AA017103-01
project_title: Administrative Core
administering_ic: NIAAA
application_type: 1
activity_code: P01
ic: AA
serial_number: 017103
project_start_date: 2008-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZAA1 BB (90)]
subproject_number: 9001
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
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: 2007-12-01
budget_end_date: 2009-08-31
project_abstract:
ADMINISTRATIVE COREThe University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary program focusing onalcohol-nutrient interactions and alcohol-induced organ injury and their prevention and/or treatment. Basicscience and clinical investigators from several departments within the School of Medicine the DentalSchool the Kent School of Social Work and the School of Public Health and Information Sciences havecoalesced into a cohesive research unit to examine selected research questions regarding the specificnutrient interactions in organ and systemic sequelae of alcohol abuse. The Center will be administrativelylocated within the Department of Medicine at the U of L Health Sciences Center. The Principal Investigatorand Center Director Dr. Craig McClain reports to the Executive Vice President for Health Sciences of theUniversity of Louisville Dr. Larry Cook. Administrative support for the Center will be provided by the CenterBiostatistician Dr. Datta and a half-time administrator. The Executive Committee will be the guiding groupfor the ULARC. In addition the External Advisory Committee and the Internal Advisory Committee willprovide oversight and consultation. The theme of alcohoknutrient interactions and alcohol-induced organinjury is unique and innovative amongst alcohol centers. The administrative core has a major educationfocus including the development of a K-12 type program for translational investigators. The administrativecore focuses on collaborative interactions and mentoring (examples of both are highlighted). Innovation andtranslational research with a goal of transforming clinical practice are important directions for theAdministrative Core. The Administrative Core will be established to: 1) provide direction and prioritization ofULARC activities and assure proper accounting of grant monies; 2) coordinate the activities of the SupportCore and pilot projects; 3) ensure the quality of all ULARC functions; 4) develop a curriculum to train clinicaland translational alcohol researchers; and 5) disseminate pertinent information to ULARC investigators andthe scientific and lay community.

project_terms:
Accounting;Administrator;Advisory Committees;Alcohol abuse;Alcoholic Liver Diseases;Alcohols;American;Animals;Area;Basic Science;Biology;Cardiomyopathies;Clinical;Clinical Investigator;Communities;Consultations;Country;Data;Development;Disease;Drug or chemical Tissue Distribution;Educational Curriculum;Educational aspects;Ensure;Etiology;Excretory function;Fetal Alcohol Syndrome;Funding;Future;Goals;Grant;Health;Health Sciences;Hepatitis C;Histologic;Human;Individual;Information Sciences;Injury;Intake;Interactions Food;Investigation;Literature;Maps;Medicine;Mentors;Metabolic;Mission;Names;National Institute on Alcohol Abuse and Alcoholism;Nutrient;Nutrition Alcohol;Nutritional;Nutritional status;Obesity;Organ;Overweight;Patient Care;Physicians;Pilot Projects;Predisposition;Prevention;Prevention intervention;Principal Investigator;Process;Process of absorption;Range;Reporting;Research;Research Infrastructure;Research Personnel;Resistance;Role;Schools;Schools Dental;Schools Medical;Schools Public Health;Science of nutrition;Score;Social work (field);Steatohepatitis;Strategic Planning;TNFRSF5 gene;Time;Training;Training Programs;Translational Research;United States;United States National Institutes of Health;Universities;alcohol effect;alcohol research;base;cooking;drug development;drug metabolism;gene interaction;human study;immune function;innovation;interdisciplinary approach;interest;multidisciplinary;nonalcoholic steatohepatitis;problem drinker;programs;success;translational study


application_id: 7407494
project_number: 5R01DA011551-10
project_title: Structure and Function of CB2 Cannabinoid Receptor
administering_ic: NIDA
award_notice_date: 2008-03-25
application_type: 5
activity_code: R01
ic: DA
serial_number: 011551
program_official: HILLERY, PAUL
project_start_date: 1998-09-30
project_end_date: 2011-04-30
study_section: Molecular, Cellular and Developmental Neurosciences 5[MDCN-5]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this research proposal is to identify the molecular basis underlying the functions of the CB2 cannabinoid receptor. To achieve this purpose the following steps will be taken. In Aim 1 and 2 the interactive mutagenesis molecular modeling and new compound testing studies will be carried out. This combined approach has advanced our understanding and should continue to reveal new insights on how cannabinoid ligands are recognized by their receptors the origin of receptor subtype-selectivity and how these receptors are activated/inactivated. Cannabinoid receptors share many of the conserved sequence motifs seen in other well-studied G protein-coupled receptors (GPCRs) such as rhodopsin and biogenic amine receptors. However several helix-bending residues and motifs and a key disulfide bridge present in many other GPCRs are missing in cannabinoid receptors. In Aim 3 Ligand binding crevice exposure of two transmembrane domains of CB2 cannabinoid receptor will be mapped using substituted-cysteine accessibility method. This approach should elucidate structural and functional consequences of the sequence divergence in these trasmembrane domains of cannabinoid receptors.   In Aim 4 Disulfide bond formation of CB2 receptor will be determined directly by the state-of-art methodologies of mass spectrometry. Investigating the unique disulfide bond or absence of a disulfide bond should provide important helix folding information of CB2 receptor and this will have important implications regarding ligand binding crevice and activation mechanisms of this receptor. Finally in Aim 5 effort will be devoted to over-express and purify large amounts of functional CB2 receptor. This challenging task if successfully completed should have a significant impact by providing the badly needed pure receptor proteins for future high-resolution biophysical studies. Overall This study should help us to understand in more molecular detail the structure and function of CB2 receptor. CB2 is primarily distributed in the immune system. It is very important for the immune-modulatory effects of marijuana. In the long run this study should also help us to develop better cannabinoid mimetics for the treatment of immune system illnesses such as inflammation and autoimmune diseases. The drugs that specifically targeted at CB2 should be devoid of psvchoactive side effects of marijuana.

project_terms:
Absence of pain sensation;Adverse effects;Affinity;Agonist;Agreement;Amino Acids;Analgesics;Arts;Autoimmune Diseases;Binding (Molecular Function);Biochemical;Biogenic Amine Receptors;Cannabinoids;Cellular biology;Characteristics;Chemicals;Chromatography Affinity;Class;Cloning;Collaborations;Condition;Conserved Sequence;Crystallography X-Ray;Cysteine;Decompression Sickness;Development;Disulfide Linkage;Disulfides;Dopamine D2 Receptor;Ensure;Ether Ethyl;Ethers;Exhibits;Family;Fingerprint;Future;G-Protein-Coupled Receptors;Glaucoma;Goals;Growth;Helix (Snails);Helix of ear;Hydrogen Bonding;Hydroxyl Radical;Immune;Immune system;Inflammation;Ions;Ligand Binding;Ligands;Liquid Chromatography;Maps;Marihuana;Medical;Metals;Methodology;Methods;Modeling;Modification;Molecular;Molecular Biology;Molecular Conformation;Mutagenesis;Mutation;Nature;Neuraxis;Nuclear Magnetic Resonance;Numbers;Peptide Fragments;Peptides;Peripheral;Pharmaceutical Preparations;Pharmacology;Pichia;Positioning Attribute;Procedures;Process;Production;Proline;Property;Protein Chemistry;Protein Overexpression;Protein Processing Post-Translational;Proteins;Proteomics;Purpose;Receptor Activation;Receptor Cannabinoid CB2;Receptors Immunologic;Research Design;Research Personnel;Research Proposals;Resolution;Rhodopsin;Running;Site;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spectroscopy Fluorescence;Spectrum Analysis Mass;Structure;Surface;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Transmembrane Domain;Work;Yeasts;aminoacid sequence of protein;base;cannabinoid receptor;design;disulfide bond;improved;insight;mimetics;molecular modeling;novel;programs;protein structure;receptor;receptor structure function;scale up;tool


application_id: 7407362
project_number: 5R01CA115942-03
project_title: Mechanism of PCNA-dependent 5'-> 3' Mismatch Excision
administering_ic: NCI
award_notice_date: 2008-05-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 115942
program_official: OKANO, PAUL
project_start_date: 2006-07-01
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1-GGG-E(90)S]
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: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): 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 that defects in MMR genes lead to severe genomic instability and eventually to cancer predisposition including hereditary non-polyposis colorectal cancer (HNPCC) and certain types of sporadic cancers. MMR in human cells is nick-directed and involves at least nine proteins which are MutS alpha MutS beta MutL alpha EXO1 polymerase delta PCNA RFC RPA and HMGB1. Despite extensive investigations on the initiation of mismatch-provoked excision which appears to require MutS alpha PCNA RPA and EXO1. However how mismatch recognition by MutS proteins leads to a strand-specific excision at a single-stranded break several hundred base pairs away from the mismatch is not understood. Three current models on mismatch- provoked excision are quite controversial in terms of how many MutS molecules are required and how the strand discrimination signal is recognized. Recently mismatch-provoked excision has been reconstituted. Interestingly EXO1 a 5'?>3' exonuclease was reported to be capable of bi-directional removal of mismatch; and EXO1-catalyzed 5' excision is independent of PCNA. Given the importance of PCNA in mismatch- provoked excision and the involvement of four exonucleases in the E. coli methyl-direct MMR we hypothesize that multiple nucleases are involved in the human reaction. Indeed we have recently identified a novel 5'?>3' mismatch excision pathway which depends on at least MutS alpha PCNA a novel 5' nuclease and a stimulating factor. This application proposes to purify and characterize both the novel 5' nuclease and the excision stimulating factor and eventually reconstitute the PCNA-dependent 5' excision reaction in vitro using purified proteins. The purified system will then be used to evaluate three controversial models to elucidate the molecular mechanism of mismatch-provoked excision. Since defects in mismatch excision genes e.g. the EXO1 gene are associated with cancer development identifying the components required for the novel 5' excision pathway will provide new diagnostic markers for HNPCC and other MMR deficient cancer syndromes.

project_terms:
Agreement;Base Pairing;Cells;DNA;Defect;Dependency (Psychology);Development;Discrimination (Psychology);Disease;EXO1 gene;Escherichia coli;Excision;Exonuclease;Genes;Genome;Genomic Instability;Goals;HMGB1 gene;Health;Hereditary Nonpolyposis Colorectal Neoplasms;Human;In Vitro;Investigation;Laboratories;Lead;Maintenance;Malignant Neoplasms;Mismatch Repair;Modeling;Molecular;Mus;PCNA gene;Pathway interactions;Polymerase;Positioning Attribute;Predisposition;Proteins;Reaction;Reporting;Role;Signal Transduction;Syndrome;System;Work;base;expectation;novel;novel diagnostics;nuclease;reconstitution;spleen exonuclease


application_id: 7406729
project_number: 5R01DA017711-04
project_title: Stimulant Abuse Pharmacotherapy: Novel Antipsychotics
administering_ic: NIDA
award_notice_date: 2008-03-24
application_type: 5
activity_code: R01
ic: DA
serial_number: 017711
program_official: OVERSBY, STEVEN
project_start_date: 2005-08-01
project_end_date: 2010-04-30
study_section: ZDA1-RXL-E(07)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Methamphetamine abuse is a significant public-health concern and is the primary form of amphetamine abused in the United States. Between 1996 and 2002 the number of Americans that reported using methamphetamine increased by 250%. Amphetamine admissions to treatment program increased by nearly 500% between 1992 and 2002. Methamphetamine use made up 90% of all amphetamine treatment admissions. Because of the public-health concerns identifying an effective pharmacotherapy for the management of methamphetamine dependence is imperative. Methamphetamine is thought to exert its. behavioral effects by promoting the release of several monoamines including dopamine (DA) serotonin (5- HT) and norepinephrine (NE) which has prompted some theoreticians to suggest targeting multiple systems for the development of a pharmacotherapy. Partial agonists at these neurotransmitter systems may represent a novel and effective means to treat stimulant dependence. In support of this notion partial agonists at D2 and 5-HT1A receptors attenuate many of the behavioral effects of amphetamines in laboratory animals In the present application we propose a series of experiments to determine the efficacy of iripiprazole an atypical antipsychotic that is a D2 and 5-HT1A partial agonist and a 5-HT2A antagonist as a putative pharmacotherapy for methamphetamine dependence. The results of a recent experiment conducted in our laboratory suggest that aripiprazole significantly attenuates the discriminative-stimulus and some of the positive subjective effects of d-amphetamine in humans. The present project has three specific aims. The first specific aim is to characterize the behavioral pharmacology of methamphetamine in humans. The second specific aim is to assess the safety and tolerability of methamphetamine in combination with aripiprazole. The third specific aim is to determine the efficacy of aripiprazole as a putative pharmacotherapy by examining the discriminative-stimulus reinforcing and subjective effects of methamphetamine in humans following chronic pretreatment with aripiprazole. The proposed research will provide initial scientific and clinical information regarding the use of aripiprazole as a pharmacotherapy for the treatment of methamphetamine dependence and guide the design of future clinical trials.

project_terms:
Abuse Amphetamine;Addiction Opiate;Admission activity;Adverse effects;Affinity;Age;Agonist;American;Amphetamines;Animals;Animals Laboratory;Antipsychotic Agents;Attenuated;Basic Science;Behavioral;Binding (Molecular Function);Buprenorphine;Chronic;Clinical;Clinical Trials;Cocaine;Data;Dependence;Development;Development Computer Systems;Dextroamphetamine;Discrimination (Psychology);Disruption;Dopamine;Dose;Elevation;Future;Gender;HTR2A gene;Human;Individual;Individual Differences;Laboratories;Maintenance;Measures;Mediating;Methamphetamine;Methylphenidate;Movement Disorders;Neurotransmitters;Norepinephrine;Numbers;Opioid;Patients;Pharmaceutical Preparations;Pharmacotherapy;Procedures;Prolactin;Psychostimulant dependence;Questionnaires;Rate;Receptor Serotonin 5-HT1A;Recording of previous events;Reporting;Research;Research Personnel;Safety;Series;Serotonin;Serum;Specificity;Status Socioeconomic;Stimulus;System;Tail;Thinking function;United States;aripiprazole;atypical antipsychotic;behavior measurement;behavioral pharmacology;design;drug discrimination;human study;improved;monoamine;motor control;novel;programs;public health medicine (field);receptor;research study;serotonin receptor;stimulant abuse;treatment program


application_id: 7406034
project_number: 5T35DK072923-03
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2008-03-27
opportunity_number: PAR-04-090
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: PODSKALNY, JUDITH M,
project_start_date: 2006-05-01
project_end_date: 2011-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
This proposal describes a short-term summer training program for medical students focused on exposing students to career opportunities in basic and clinical research related to diabetes obesity endocrine disorders metabolic diseases and kidney diseases. This application addresses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The training program will include didactic instruction as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. These faculty have long-standing success in mentoring medical and graduate students and post-doctoral fellows. Students who have completed at least one year of medical school will be eligible to apply for this 10-week training program. Trainees will be selected based upon their academic performance letters of recommendation and matching their research interests and career goals with suitable mentors. We have been successful in recruiting students from minority rural and economically disadvantaged backgrounds. The students will participate in an established 10-week didactic summer program: "From Bench to Bedside: Introduction to Clinical Research" which included bioethics as well as Endocrine-specific seminars and journal clubs in basic and clinical research. Students will present posters of their research at the end of the program. The training program will begin with six trainees and increase to ten trainees as the program matures. Over the past 6 years the University of Louisville has increased its commitment to health science research and infrastructure graduate education and minority recruitment making this short-term training program for medical students particularly timely

project_terms:
Accounting;Address;Animal Experimentation;Animal Model;Animals;Animals Laboratory;Antineoplastic Agents;Appendix;Area;Authorship;Award;Awards and Prizes;Awareness;Basic Science;Belief;Biochemistry;Bioethics;Biohazardous Substance;Biomedical Research;Blood Vessels;Calendar;Cardiovascular Diseases;Career Choice;Caring;Categories;Chemicals;Clinic;Clinical;Clinical Endocrinology;Clinical Medicine;Clinical Research;Clinical Trials;Clinics and Hospitals;Communities;Confidentiality;Conflict (Psychology);Conflict of Interest;Consultations;Data;Detection;Device or Instrument Development;Diabetes Mellitus;Disadvantaged;Discipline;Distress;Doctor of Philosophy;Doctor of Veterinary Medicine;Education Medical;Education Medical Graduate;Educational Curriculum;Educational aspects;Emergency Situation;End Point;Endocrine;Endocrine System Diseases;Endocrinology;Engineering;Ensure;Environment;Environmental Health;Equipment;Estrogen Receptors;Ethics Committees Research;Ethics Research;Euthanasia;Evaluation;Event;Faculty;Foundations;Freedom;Friends;Functional disorder;Funding;Future;Goals;Graduate Education;Grant;Hand;Hazard Controls;Hazardous Substances;Hazardous Waste;Hazards Health;Health;Health Insurance Portability and Accountability Act;Health Sciences;Healthcare;Healthy People 2010;Horns;Hospitals;Hour;Human;Human Resources;IACUC;Individual;Instruction;Intellectual Property;Intramural Research;Issues Ethical;Jewish follower of religion;Joints;Journals;Kidney Diseases;Laboratories;Laws;Lead;Learning;Legal;Letters;Libraries;Literature;Malignant neoplasm of breast;Malignant neoplasm of thyroid;Master of Public Health;Measures;Medical;Medical center;Medicine;Mentors;Metabolic Diseases;Metabolism;Minority;Modeling;Molecular;Molecular Biology;Molecular Genetics;Monitor;National Research Service Awards;Nebraska;Notification;Numbers;Obesity;Operative Surgical Procedures;Oral;Ownership;Pain;Paper;Participant;Patient Care;Peer Review;Performance;Pharmacology;Policies;Postdoctoral Fellow;Principal Investigator;Private Practice;Prize;Procedures;Process;Productivity;Program Evaluation;Publications;Published Comment;Publishing;Purpose;Qualifying;Radiation;Radiation Interaction;Radioactive;Radiobiology;Rate;Readiness;Reading;Recombinant DNA;Recommendation;Recruitment Activity;Regulation;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Residencies;Resources;Review Committee;Rewards;Running;Rural;Safety;Sampling;Schools Medical;Science;Scientist;Score;Selective Estrogen Receptor Modulators;Series;Services;Societies;Solutions;Stress;Structure;Students;Students Medical;Techniques;Terminology;Texas;Thyroid Diseases;Thyroid carcinoma;Time;Training;Training Programs;Training and Education;Translating;Translational Research;Translations;United States National Institutes of Health;United States Office of Research Integrity;Universities;Week;Work;abstracting;animal care;anticancer research;base;bench to bedside;career;chemical release;concept;data acquisition;day;experience;frontier;hazard;health science research;human study;human subject;interest;lecturer;lectures;member;multidisciplinary;occupational health/safety;peer;posters;professor;programs;radiochemical;rehearsal;response;role model;skills;success;symposium;teacher;theories;volunteer;wasting


application_id: 7405577
project_number: 2R44AR049941-02
project_title: Durable Muscle-Prosthetic Bond for Artificial Tendons
administering_ic: NIAMS
award_notice_date: 2008-04-30
opportunity_number: PA-07-280
application_type: 2
activity_code: R44
ic: AR
serial_number: 049941
program_official: PANAGIS, JAMES S
project_start_date: 2005-09-15
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZRG1 MOSS-L (10)]
contact_pi_person_id: 9182453
contact_pi: JUNCOSA-MELVIN, NATALIA
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 969951859
duns_number: 969951859
fips: US
organization_id: 4007401
organization_name: CARDIOENERGETICS, 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: 2008-05-01
budget_end_date: 2009-04-30
project_abstract:
DESCRIPTION (provided by applicant):  A coupling mechanism with the strength to fix a forcefully contracting muscle to a totally inert prosthesis or to bone would meet a serious and common need in clinical orthopaedics.  We have explored a new approach to such a coupling. The hypothesis was that a coupling prosthesis with a low-mass high-surface configuration designed to transfer force by shear would transfer greater loads without pressure-damage to tissue than can be transferred by the interlocking mechanism of sutures or staples. The resulting device is the OrthoCouplerTM. The Phase I feasibility study results exceeded expectations. This was a 60 day assessment reattaching 8 goat semitendinosus (hamstring) muscles; 7 completed all testing - 6 with paired experimental/control data one with experimental alone. Each proposed Aim was met:--devices were built validated for cyclic fatigue life implanted and succeeded clinically. Excised specimens were 2.5 times the strength of an expertly applied state-of-the art-control (Krackow stitches under close direction of a senior orthopaedic oncologic surgeon). The proposed work applies the OrthoCoupler in goats to the most demanding setting imaginable - restablishing the knee extensor mechanism after complete excision of quadriceps tendon patella and patellar tendon securing the cut quadriceps muscle stump to a tibial bone plate. This succeeded in four pilot animals - (servohydraulic testing to over 1000 N with femur fracturing without pullout). Specific Aim (1) assesses in a random block study the efficacy of two plausible improvements each intended to facilitate ease of operative use compatible with minimally invasive placement (2) standardizes design and fabrication with a contracted 'GMP' manufacturer and (3) rigorously reprises preclinical testing in a 'GLP' facility. Achieving these three specific aims would place the device at a decisive competitive advantage relative to any present alternative and ensure our overriding long-term objective - commercialization of OrthoCoupler in a range of specific configurations for a market of over 20000 muscle-to-prosthetic applications annually including but by no means limited to orthopaedic oncology revision arthroplasty expanded tendon transfer and sports-injury reconstruction.  PUBLIC HEALTH RELEVANCE:  We have developed and patented a new technology for durable strong connections with tissue not having sufficient strength for conventional sutures or staples. A dominant need for this is in several orthopaedic dilemmas - sports injury reconstruction orthopaedic oncology revision joint replacement and tendon transfers. Pilot studies have succeeded in the most demanding application possible reattachment of the body's most powerful muscle the quadriceps femoris and the proposal will expand that work in an extended term goat model.

project_terms:
Acute;Animals;Arthroplasty;Arthroplasty Replacement;Arts;Athletic Injuries;Autopsy;Biological Assay;Biomechanics;Bone and Bones;Bone plates;Bone structure of tibia;Clinical;Collaborations;Collagen;Compatible;Confounding Factors (Epidemiology);Contracts;Counseling;Coupling;Data;Development;Device Designs;Devices;Documentation;Ensure;Excision;Failure (biologic function);Fatigue;Feasibility Studies;Femoral Fractures;Fiber;Filament;Filler;Fright;Funding;Genus Capra;Goals;Goat;Grant;Guanosine Monophosphate;Hand;Histologic;Implant;In Vitro;International;Invasive;Joint Revision;Joints;Knee;Knee bone;Laboratories;Legal patent;Life;Malignant Neoplasms;Manufacturer Name;Marketing;Medical Device;Microencapsulations;Modeling;Modification;Muscle;Needles;Object Attachment;Operative Surgical Procedures;Orthopedics;Performance;Phase;Pilot Projects;Placement;Plant Roots;Plants;Polymers;Postoperative Period;Preclinical Testing;Pressure- physical agent;Procedures;Process;Prosthesis;Protocols documentation;Qualifying;Randomized;Range;Rate;Rehabilitation therapy;Relative (related person);Reporting;Sampling;Schedule;Score;Secure;Simulate;Site;Soil;Solid;Specimen;Sports Medicine;Standards of Weights and Measures;Suggestion;Surface;Surgeon;Surgical Oncologist;Surgical sutures;Tendon Transfer;Tendon structure;Testing;Time;Tissues;United States Food and Drug Administration;Validation;Variant;Weight-Bearing state;Work;Wound Healing;base;clinical application;commercialization;day;design;expectation;experience;implantation;improved;manufacturing process;new technology;novel strategies;oncology;pilot trial;prospective;public health medicine (field);reconstruction;research study;response;sample fixation;success


application_id: 7405539
project_number: 1R41NS061459-01
project_title: Novel Neuroprotectants for TBI
administering_ic: NINDS
award_notice_date: 2008-02-08
opportunity_number: PA-07-281
application_type: 1
activity_code: R41
ic: NS
serial_number: 061459
program_official: HICKS, RAMONA R
project_start_date: 2008-02-15
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (11)]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 791384774
duns_number: 791384774
fips: US
organization_id: 10013797
organization_name: STALLION THERAPEUTICS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405360001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-02-15
budget_end_date: 2010-07-31
project_abstract:
DESCRIPTION (provided by applicant): There are no FDA approved pharmacological therapies for the acute treatment of traumatic brain injury (TBI) that mitigate damaging neurological effects. However the potential for effective pharmacological intervention exists in that a majority of post-traumatic degeneration results from pathochemical and pathophysiological cascades of secondary events that occur in the minutes hours and even days after the primary mechanical damage to tissue. Early factors in these secondary cascades include excessive release of the excitatory neurotransmitter glutamate NMDAR over stimulation a massive increase in intracellular calcium mitochondrial metabolic failure and activation of the proteolytic enzyme calpain. Despite ample demonstration that targeting glutamate receptor-mediated excitotoxicity is neuroprotective in various animal models of neurological injury; no NMDAR antagonist has shown adequate efficacy and safety to be approved in man for TBI. Reasons frequently cited for the clinical failure of NMDAR antagonists include unacceptable side effects that required dosing regimes lower than needed for maximum efficacy and the administration of drug too long after the insult. Early generations of NMDAR antagonists (channel blockers and competitive blockers of glutamate or glycine binding) were associated with significant psychotic and cardiovascular side effects. NMDAR antagonists that selectively interact with NMDA receptors containing the NR2B subunit as noncompetitive allosteric antagonists are better tolerated than prior generation NMDAR blockers. One in this class CP101606 yielded promising results in a phase IIa study in TBI patients. Recently NeurOp Inc showed that a new generation of NR2B specific NMDAR blockers under development having a unique disease activated mechanism offer potent neuroprotection in animal models of ischemia. Exemplary of the class NeurOp's 93-31 exerts minimal NMDAR antagonism at normal pH but offers potent NMDAR block at the reduced pH known to accompany ischemia. By blocking NMDAR only when and where needed pH sensitive NMDAR antagonists are expected to offer a much improved therapeutic index over prior generation drugs. In this project we shall explore whether the pH drop that accompanies TBI is adequate to activate NeurOp's 93-31 and whether this compound provides neuroprotection in an animal model of TBI. Narrative: About 1.5 million people suffer traumatic brain injury in the US each year. Thousands experience long lasting brain injury that interferes with their ability to lead productive and full lives. We plan to test a promising new class of therapeutics for traumatic brain injury.

project_terms:
Acute;Adverse effects;Animal Model;Animals;Binding (Molecular Function);Binding Sites;Brain;Brain Injuries;Brain region;Calcium;Calpain;Cardiovascular system;Cerebral Ischemia;Cerebrum;Class;Clinical;Cytoskeletal Proteins;Development;Disease;Dose;Dose-Limiting;Drops;Endopeptidases;Event;Failure (biologic function);Functional disorder;Generations;Glutamate Receptor;Glutamates;Glycine;Hour;Injury;Intervention;Ischemia;Laboratories;Lead;Length;Life;Mechanics;Mediating;Metabolic;Mitochondria;Modeling;Models Neurological;Motor;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NMDA receptor antagonist;Nerve Degeneration;Nervous System Physiology;Neurologic;Neuroprotective Agents;Neurotransmitters;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Phase;Preservation Biological;Principal Investigator;Property;Proteolysis;Purpose;Recovery;Safety;Secondary to;Spectrin;Testing;Therapeutic;Therapeutic Index;Time;Tissues;Trauma Nervous System;Traumatic Brain Injury;United States Food and Drug Administration;Work;attenuation;base;channel blockers;controlled cortical impact;day;excitotoxicity;experience;fluoromethyl 22-difluoro-1-(trifluoromethyl)vinyl ether;improved;injured;man;mitochondrial dysfunction;mouse model;neuroprotection;novel;prevent;programs;research study


application_id: 7404610
project_number: 5R01HD023333-16
project_title: Listening Skills in children with and without cochlear implants
administering_ic: NICHD
award_notice_date: 2008-04-03
application_type: 5
activity_code: R01
ic: HD
serial_number: 023333
program_official: KAU, ALICE S
project_start_date: 1989-04-01
project_end_date: 2012-03-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1963999
contact_pi: WIGHTMAN, FREDERIC L
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_terms:
Acoustics;Address;Adolescence;Adopted;Adult;Affect;Age;Algorithms;Attention;Auditory;Bilateral;Child;Child Development;Cochlear Implants;Communication;Complex;Computer information processing;Condition;Cues;Data;Deafness;Dependence;Detection;Development;Discrimination (Psychology);Ear structure;Environment;External auditory canal structure;Failure (biologic function);Frequencies (time pattern);Funding;Goals;Hearing;Hearing Impaired Persons;Implant;Individual;Individual Differences;Knowledge;Laboratories;Language;Life;Lipreading;Masks;Measurable;Measurement;Measures;Modeling;Noise;Numbers;Participant;Performance;Peripheral;Placement;Population;Positioning Attribute;Principal Investigator;Process;Publishing;Reading;Rehabilitation therapy;Relative (related person);Research;Research Personnel;Resolution;School-Age Population;Score;Signal Transduction;Simulate;Sound - physical agent;Source;Speech;Stimulus;Techniques;Teenagers;Testing;Training;Uncertainty;Visual;Weight;Work;age effect;age related;base;concept;desire;expectation;hearing impairment;implantation;programs;research study;segregation;selective attention;simulation;skills;speech recognition;stimulus processing;virtual


application_id: 7400171
project_number: 1R43HD057663-01
project_title: Adaptive Control of Flexion Withdrawal Reflex Stimulator for Locomotor Rehabilita
administering_ic: NICHD
award_notice_date: 2008-09-15
opportunity_number: PA-07-280
application_type: 1
activity_code: R43
ic: HD
serial_number: 057663
program_official: SHINOWARA, NANCY
project_start_date: 2008-09-19
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (02)]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-19
budget_end_date: 2011-03-31
project_abstract:
DESCRIPTION (provided by applicant): Recovery of independent locomotion is among the most significant therapeutic aims following incomplete spinal cord injury (iSCI) and may lead to dramatic improvements in quality of life for the affected individual as well as dramatic cost savings to both the affected individual and to the health care system.  Several studies from various research groups have shown that functional electrical stimulation (FES) used in conjunction with bodyweight supported gait training is a safe and effective method for retraining the neural circuits to improve locomotion.  FES may be used to either directly stimulate the tibialias anterior to assist with foot-drop OR to elicit the flexion withdrawal reflex (FWR) resulting in hip/knee flexion and ankle dorsiflexion.  FES for foot drop is commonly used and several commercial products have resulted.  Efficacy of the FWR technique has been demonstrated for individuals undergoing rehabilitation following iSCI.  While FWR offers several clinically significant advantages in locomotor retraining widespread clinical acceptance of the technique has not been achieved.  We assert that FWR would be more widely practiced in gait rehabilitation: 1) if a low cost practical comprehensive system were available to implement the technique and 2) if the system involved an FES unit that automatically controlled stimulation intensity and timing such that the therapist did not have to custom fit the stimulation to the client or adjust the stimulation pattern to maintain performance.  We propose GaitSTIM" a novel rehabilitation system indicated for FES-augmented walking therapy.  Offering foot-drop and FWR operating modes FES will be delivered by a device with autonomous adaptive stimulation control and completely integrated sensing technologies.  The system will additionally offer audible/visual cues to engage the client in the therapy and performance-based reports for clinicians which may assist in prescription and provide the documentation necessary to justify additional therapeutic sessions.  The goals of this Phase I SBIR project are to demonstrate feasibility of our concept sensor-based adaptive stimulation approach for control of the FWR response.  We will: 1) develop and fabricate a proof-of-concept sensing system to test the FWR operating mode; 2) develop adaptive stimulation control algorithms to modulate the FWR stimulus based on measurements from our sensors; and 3) validate the sensor-based adaptive stimulation control concept in a feasibility study in which individuals with iSCI perform overground walking during which FWR is elicited by either the investigational device or a manually controlled laboratory stimulator.   The Phase I feasibility study will be conducted in collaboration with the Miami Project to Cure Paralysis (Miami FL) under the direction of Edelle Field-Fote PT PhD.  The target markets for this device would be clinics who serve patients undergoing rehabilitation following iSCI injury or stroke.  The target price for the system will be $4000.  PUBLIC HEALTH RELEVANCE: The proposed work may benefit public health through development of a clinically viable electrical stimulation based rehabilitation device for use in locomotor training following spinal cord injury or stroke.  Compared to existing devices and techniques the adaptively controlled electrical stimulation component and tight integration of instrumentation control stimulation visualization and reporting features may improve efficacy and availability of the therapeutic intervention for many affected individuals.

project_terms:
Acceleration;Affect;Algorithms;Ankle;Ankle joint structure;Anterior;Ants;Area;Back;Bilateral;Biomechanics;Client;Clinic;Clinical;Collaborations;Communication;Cost Savings;Cues;Custom;Data;Development;Devices;Doctor of Philosophy;Documentation;Drops;Electric Stimulation;Event;Exercise;Feasibility Studies;Floor;Foot-drop;Gait;Goals;Government;Healthcare Systems;Hip region structure;Imagery;Individual;Injury;Intervention;Joints;Knee;Laboratories;Lead;Learning;Left;Leg;Locomotion;Locomotor retraining;Manuals;Marketing;Measurement;Measures;Mechanics;Memory;Methods;Movement;Muscle;Nerve;Numbers;Orthotic Devices;Outcome;Output;Paralysed;Participant;Patients;Pattern;Performance;Pes;Phase;Pilot Projects;Price;Quality of life;Randomized;Range;Range of Motion Articular;Range of motion exercise;Recovery;Reflex action;Rehabilitation Research;Rehabilitation device;Rehabilitation therapy;Reporting;Research;Research Design;Research Laboratory;Right-On;Sampling;Science of Statistics;Self-Help Devices;Side;Signal Transduction;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Solutions;Speed (motion);Spinal cord injury;Step training;Stimulus;Structure;Structure of common peroneal nerve;Subgroup;Support System;System;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Time;Training;Visual;Walkers;Walking;Weight;Wireless Technology;Withdrawal;Work;auditory feedback;base;clinically relevant;clinically significant;concept;cost;design;electronic stimulator;improved;instrumentation;neural circuit;novel;prescription document;prescription procedure;prototype;public health medicine (field);research and development;response;restoration;robot assistance;sensor;stroke;success;volunteer


application_id: 7395153
project_number: 2R44DK070374-03
project_title: A Test for Salt Sensitivity in People with Essential Hypertension
administering_ic: NIDDK
award_notice_date: 2008-03-04
opportunity_number: PA-07-280
application_type: 2
activity_code: R44
ic: DK
serial_number: 070374
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Cellular and Molecular Biology of the Kidney Study Section[CMBK]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Project Summary:  In Phase I we developed a model system and a prototype Salt Sensitivity Assay to establish  proof-of-principle . In Phase II we propose the evaluation of the prototype that will quantitatively measure our biomarker in the target population. An ideal biomarker for salt sensitivity would be one that is linked to the underlying cause of salt sensitivity and not disease symptoms. It is our hypothesis that this biomarker can be accurately measured using a monoclonal antibody-based direct quantitative ELISA. The assay will allow physicians to identify salt sensitivity in newly diagnosed hypertensive patients so that appropriate therapy can begin as early as possible. The information gained from this accurate screening test will lead to basic research investigations of the biological mechanisms underlying salt sensitivity and its pathophysiological consequences such as hypertension CHF renal disease and edema. We request Phase II support so that we can evaluate our prototype Salt Sensitivity Assay in a pivotal study with the ultimate goal of obtaining FDA approval. In addition our proposal also addresses several research questions and explores an exciting new secondary application of our assay in the assessment of renal function.  
  
Project Narrative   
Hypertension affects almost 50 million people in the United States which places them at higher risk for chronic renal failure and cardiovascular disease. Of those affected about half are salt-sensitive. We will develop an ELISA for hypertensive people that can be used to distinguish between salt sensitive and salt resistant individuals.

project_terms:
Acute;Address;Adult;Affect;Affinity;Animal Model;Animals;Archives;Award;Basic Science;Biochemical;Biological;Biological Assay;Biological Markers;Biological Models;Blood;Blood Pressure;Bolus Infusion;Cardiovascular Diseases;Clinical Research;Clinical Trials;Collaborations;Condition;Development;Diabetes Mellitus;Diagnostic;Diet Sodium-Restricted;Disease;Edema;End stage renal failure;Endocrine;Endocrinology;Enteral;Enzyme-Linked Immunosorbent Assay;Essential Hypertension;Ethics Committees Research;Evaluation;Excretory function;Funding;Goals;Heart;Hematological Disease;Homeostasis;Hour;Human;Hypertension;Individual;Infusion procedures;Institutes;Intake;Intestines;Investigation;Kidney;Kidney Diseases;Kidney Failure Chronic;Knock-out;Laboratories;Lead;Letters;Link;Lung;Maine;Marketing;Measures;Monoclonal Antibodies;Mus;NIH Program Announcements;National Institute of Digestive Diseases and Kidney Disorders;Natriuretic Peptides;Newly Diagnosed;Oral;Participant;Patients;Peptides;Personal Satisfaction;Phase;Physicians;Physiological;Plasma;Play;Preparation;Principal Investigator;Protocols documentation;RNA Messenger;Radioimmunoassay;Rattus;Reagent;Regulation;Renal function;Reporting;Request for Applications;Research;Research Personnel;Resistance;Risk;Rodent Model;Role;Sampling;Schools Medical;Screening procedure;Series;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Sodium;Sodium Chloride;Staging;Stomach;Symptoms;Target Populations;Testing;United States;United States Food and Drug Administration;United States National Institutes of Health;Urine;Work;base;guanylin;human study;mouse model;normotensive;polyclonal antibody;programs;prohormone;prototype;research study;response;salt intake;salt sensitive;scale up;uroguanylin;urologic;validation studies


application_id: 7395057
project_number: 1R43CA117283-01A2
project_title: A Novel Biotherapeutic Treatment for Pancreatic Cancer
administering_ic: NCI
award_notice_date: 2008-09-15
opportunity_number: PA-07-280
application_type: 1
activity_code: R43
ic: CA
serial_number: 117283
suffix: A2
program_official: HAIM, TODD E
project_start_date: 2008-09-15
project_end_date: 2010-09-14
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
project_abstract:
DESCRIPTION (provided by applicant): Carcinoma of the pancreas is the 4th leading cause of cancer deaths. The American Cancer Society has estimated 37170 new cases and 33370 deaths in 2007. The cancer generally develops without early symptoms and most patients present to treating physicians with advanced-stage of the disease. Surgery radiation therapy chemotherapy immunotherapy and vaccine therapy are treatment options that only marginally prolong survival or relieve symptoms in the cancer patients. As a result the 5-year survival rate is less than 4%. The development of more effective therapeutic interventions represents a significant unmet medical need. Bexion Pharmaceuticals LLC is developing a novel first-in-class biotherapeutic compound consisting of two active components for treating pancreatic cancer. Six lines of preliminary studies suggest the feasibility of the in vitro and in vivo studies proposed in this application. These are: 1) the ability to manufacture sufficient quantities of the anti-neoplastic compound 2) the compound inhibited growth of over 50 tumor cells but not normal cell lines 3) the lack of toxicity in small rodents in initial toxicity studies 4) the effectiveness of the compound to inhibit tumor growth in a human pancreatic tumors generated in immunodeficient mice 5) the compound traffics to and deposits at tumor sites and 6) the mechanisms of action in non-pancreatic tumors are exerted through induction of programmed cells death. We hypothesize that the anti-neoplastic compound induces programmed cell death of pancreatic tumor cells in vitro as well as tumors in vivo. The goals of this SBIR Phase 1 feasibility study are: 1) to ascertain that the complex formation of the two active ingredients but not the non-complexed mixture of the two components is necessary for growth inhibition of the PANC-1 and MIA PaCa-2 cells in vitro and to inhibit the growth of the tumors generated by these 2 cell lines in nude mice and 2) to correlate elevated ceramide levels increased caspase activities and induction of DNA fragmentation with the efficacy of the nanovesicles. The successful completion of these goals will be followed by toxicology absorption/disposition/metabolism/excretion (ADME) pharmacology and chemistry/ manufacturing/control (CMC) studies filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. These activities will be proposed in a SBIR Phase 2 application. Pancreatic cancer is the 4 leading cause of cancer death. Current treatments are surgery chemotherapy radiation therapy and immunotherapy but they are considerably ineffective. Bexion Pharmaceuticals Inc. is diligently developing a novel anti-pancreatic biotherapeutic agent that holds great promise in improving the prognosis of the disease.

project_terms:
American Cancer Society;Animal Model;Animals;Apoptosis;Apoptotic;Aspartate;Autopsy;Biological Assay;Biological Products;Biological Response Modifier Therapy;Blood Circulation;Body Weight;Bromides;Cancer Etiology;Cancer Patient;Cancer cell line;Cancerous;Cell Line;Cell Line Tumor;Cell Survival;Cells;Ceramides;Cessation of life;Characteristics;Class;Clinical Trials Phase II;Complex;Complex Mixtures;Control Groups;Controlled Study;Cyclic GMP;DNA Fragmentation;Deposition;Development;Diagnostic Neoplasm Staging;Disease;Drugs Investigational;Effectiveness;Elevation;End Point;Endopeptidases;Evaluation;Event;Excretory function;Feasibility Studies;Forecast of outcome;Formulations Drug;Freezing;Goals;Growth;Harvest;Human;Hydrolysis;Immunodeficient Mouse;Immunotherapy;In Vitro;Induction of Apoptosis;Injection of therapeutic agent;Investigational New Drug Application;Killings;Kinetics;Malignant Neoplasms;Malignant neoplasm of pancreas;Measurable;Measurement;Measures;Medical;Membrane;Metabolism;Mice Nude;Mus;Normal Cell;Operative Surgical Procedures;Pancreas;Pancreatic Adenocarcinoma;Pancreatic carcinoma;Patients;Peptide Hydrolases;Pharmacologic Substance;Pharmacology;Phase;Physicians;Process of absorption;Production;Radiation therapy;Range;Recombinants;Relative (related person);Rodent;Safety;Science of Chemistry;Screening procedure;Second Messenger Systems;Serine;Signal Transduction;Site;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Sphingomyelins;Staging;Statistically Significant;Survival Rate;Symptoms;Tail;TdT-Mediated dUTP Nick End Labeling Assay;Testing;Therapeutic;Therapeutic Intervention;Therapy Vaccine;Time;Toxic effect;Toxicology;Treatment Efficacy;United States Food and Drug Administration;VP6 protein Rotavirus;Veins;Volume Tumor;Weights Tumor;acid sphingomyelinase;base;beta-Glucosidase Stimulating Protein;cancer therapy;caspase;caspase-3;cell growth;chemotherapy;day;improved;in vivo;liquid chromatography mass spectrometry;mouse model;neoplastic;neoplastic cell;novel;pancreatic neoplasm;pre-clinical;second messenger;size;trafficking;tumor;tumor growth


application_id: 7394975
project_number: 5R01EY017094-03
project_title: Lipids and the Human Tear Film
administering_ic: NEI
award_notice_date: 2008-03-31
application_type: 5
activity_code: R01
ic: EY
serial_number: 017094
program_official: SHEN, GRACE L
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1898534
contact_pi: FOULKS, GARY N
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: 2008-04-01
project_abstract:
DESCRIPTION: Dry eye affects six to seven million people in the United States alone. Meibomian gland disease is even more frequent particularly in older patients. Clinically patients may express a combination of two forms of dry eye aqueous deficient and evaporative. Both mechanisms of development of dry eye share the common feature of instability of the tear film with rapid tear break-up time suggesting there may be a shared structural abnormality of the tear film that is responsible for the instability. Disruption of the normal lipid-protein-aqueous structure of the tear film is probably this mechanical event. Understanding the normal lipid-protein-aqueous structure of the tear film is therefore critical to determine the etiology of the tear film instability due to dry eye disease and meibomian gland disease.  Recent advances in spectroscopic technology make it feasible to measure simultaneously and in individuals without pooling or serial collection the pool of meibomian lipid on the lid margins lipids in the meibomian glands and the lacrimal lipids many of which are bound to lipocalin or complexed with other proteins found in tears. We propose to use the latest spectroscopic innovations to determine the relationships among tear lipid structure interactions rate of tear evaporation dry eye symptoms and tear film instability. Advances in clinical diagnosis make it possible to group patients into a number of categories related to production-deficient and evaporative forms of dry eye and monitor their tear film stability. Because of our expertise in spectroscopic techniques knowledge of lipid structure and access to human tear lipid samples in normal subjects and those with dry eye disease coupled with our clinical expertise we are in a uniquely favorable position to identify the nature of the disturbance of the lipid-protein-aqueous interaction of the tear film that could lead to improved therapy.

project_terms:
Accounting;Affect;Age;Binding (Molecular Function);Blinking;Categories;Characteristics;Classification;Clinical;Collection;Complex;Condition;Coupled;Data;Development;Diagnosis clinical;Disease;Disruption;Doxycycline;Dryness of eye;Educational workshop;Etiology;Event;Eye diseases;Fatty Acids Essential;Film;Functional disorder;Gender;Gland;Goblet Cells;Human;In Situ;In Vitro;Individual;Industry;Knowledge;Lacrimal gland structure;Lactoferrin;Lead;Lipids;MUC5AC gene;Measures;Mechanics;Monitor;Mucins;Muramidase;Nature;Numbers;Pathogenesis;Patients;Positioning Attribute;Production;Proteins;Rate;Research Personnel;Sampling;Scheme;Science of Anatomy;Sjogren's Syndrome;Spectrum Analysis;Sphingolipids;Structure;Structure of meibomian gland;Symptoms;System;Systemic Therapy;Techniques;Technology;Testing;Time;United States;aqueous;conjunctiva;evaporation;human subject;improved;innovation;lacrimal;lipid structure;meibomian gland dysfunction;older patient;programs;sex;tear proteins;volunteer


application_id: 7394954
project_number: 5R01CA102285-05
project_title: Role of MIF in Rb inactivation and Tumorigenesis
administering_ic: NCI
award_notice_date: 2008-05-01
application_type: 5
activity_code: R01
ic: CA
serial_number: 102285
program_official: AULT, GRACE S
project_start_date: 2004-07-01
project_end_date: 2010-04-30
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
budget_start_date: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant): Many human cancers require the production of soluble growth factors for tumor initiation promotion and survival. These extracellular factors contribute to and promote most stages of tumor development. For example 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 breast cancer 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 Rb inactivation is critically important for oncogene-induced malignancies the nature of the signals induced by oncogenes to facilitate this are incompletely understood. We recently discovered that the pro-inflammatory cytokine migration inhibitory factor (MIF) is both necessary and sufficient for mitogen and oncogene-induced cyclin D1 transcription Cdk4 activity and Rb inactivation. Moreover our results reveal that MIF is strongly induced by tumor promoting oncogenes and cells from MIF-deficient mice are resistant to oncogene-induced  malignant transformation. Despite these findings more work is needed to investigate in detail the influence mechanism and effectors of MIFs contribution to Rb inactivation malignant growth properties and de novo tumorigenesis. We hypothesize that MIF promotes both normal and neoplastic cell growth by stimulating RhoA GTPase activity that leads to the activation of the canonical MAP kinase pathway and resulting in cyclin D1 transcription and Rb inactivation. To test the fundamentals of our hypothesis and fulfill the stated objectives of this application the following specific aims are proposed: 1) Examine the regulatory and effector requirements for MIF in cyclin D1 transcription focusing on Rho GTPase activated pathways; 2) Test the requirements for MIF in human breast carcinoma Rho activation cyclin D1 expression and Rb inactivation and; 3) Investigate the contribution and functional requirements for MIF in de novo mammary tumorigenesis. This work should contribute to a greater understanding of the physiologic and pathologic importance of soluble growth factors to cell cycle regulation and neoplastic processes and may reveal a novel 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: 7394953
project_number: 5R24EY015636-05
project_title: Vision Research Infrastructure Development
administering_ic: NEI
award_notice_date: 2008-05-09
opportunity_number: PAR-02-050
application_type: 5
activity_code: R24
ic: EY
serial_number: 015636
program_official: CHIN, HEMIN R
project_start_date: 2004-05-01
project_end_date: 2010-04-30
study_section: ZEY1-VSN(03)
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Although the Department of Ophthalmology and Visual Sciences at the University of Louisville has a large cadre of NEI funded vision scientists it has not previously had funding for core module services.  The purpose of this application is to provide our scientists with additional shared support to enhance their individual research capabilities and enhance further collaboration. Additionally it is oriented to enhance the research capability of the University of Louisville for conducting vision research by encouraging collaborative studies and attracting other scientists to vision research. These goals will be met by operating two research modules which will provide the following services:    l. The Image Acquisition and Analysis Module will provide technical support and expertise in  histological procedures such as conventional histological processing processing frozen tissue  samples/blocks and immunohistochemical staining confocal microscopy etc.  Additionally it will  provide assistance and expertise in the acquisition manipulation and analysis of digital images  captured using various imaging devices such as confocal bright field and fluorescence microscopy.    II. The Flow Cytometry Module will help investigators identify specific cell types in mixed cell populations. Such studies include but are not limited to estimation of subsets of T-cells determination of mitotic state and studies of cell surface receptors and markers.    These services and resources will enhance vision research at the University of Louisville by extending the capability of NEI funded scientists promoting collaboration and attracting new scientist to vision research.

project_terms:
Award;Cancer Center Support Grant;Cells;Collaborations;Core Facility;Depth;Development;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Environment;Eye;Facility Construction Funding Category;Faculty;Flow Cytometry;Fostering;Foundations;Freezing;Fund Raising;Funding;Goals;Human;Image;Imaging Device;Individual;Investigation;Kentucky;Laboratories;Lead;Leadership;Medal;Microscopy Confocal;Microscopy Fluorescence;Mitotic;Ophthalmology;Panthera leo;Pes;Population;Procedures;Process;Productivity;Purpose;Receptors Cell Surface;Recording of previous events;Recruitment Activity;Research;Research Infrastructure;Research Institute;Research Personnel;Research Project Grants;Research Training;Resources;Scientist;Services;Specialist;Staining method;Stains;T-Lymphocyte Subsets;Tissue Sample;Universities;Vision;Vision Disorders;Vision research;Work;cell type;digital imaging;eye center;professor;research facility;vision science


application_id: 7394664
project_number: 1F31NS059274-01A1
project_title: Specific targeting of a neuronal subset using a novel chimeric vector pseudotype
administering_ic: NINDS
award_notice_date: 2007-09-30
application_type: 1
activity_code: F31
ic: NS
serial_number: 059274
suffix: A1
program_official: KLEITMAN, NAOMI
project_start_date: 2008-01-01
project_end_date: 2009-12-31
study_section: Special Emphasis Panel[ZRG1 F01-P (20)]
contact_pi_person_id: 8715331
contact_pi: TRIMBY, CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal will investigate the hypothesis that the rabies virus envelope glycoprotein (RvG) can be used as a base for making a novel chimeric envelope glycoprotein to be called RvGN2 by inserting Loop 2 from Nerve Growth Factor (NGF) in place of the "toxin-like" loop of RvG. Loop 2 confers the ability of NGF to bind the TrkA receptor which is a receptor that is primarily expressed on sensory neurons including those projecting from the dorsal root into lamina I & II of the spinal cord. The RvGN2 chimera will still maintain the ability to be retrogradely transported making the vector more attractive for clinical applications by allowing the potential for a less invasive delivery strategy. The more specific aims of this project will be to test the hypothesis that the RvG can act as a functionally viable basis for engineered retargeting. This will be assessed by immunocytochemistry to detect RvGN2 expression on the surface of transfected cells. The next step will be to test the hypothesis that RvGN2 reporter viruses will preferentially infect cells in vitro that express TrkA over cells that are permissive to wild- type Rabies virus infection. Transient transfection of the TrkA receptor will also be used to "rescue" resistant cell lines. The last aim will test the hypothesis that the in vitro targeting profile will be maintained when RvGN2 reporter virus is administered to rats in vivo by injection into the spinal cord. The second part of this aim is to show that peripheral delivery by intramuscular or intradermal injection will preserve this targeting profile. Immunohistochemistry will then be used on tissue sections with antibodies to detect different markers indicative of separate subsets of neurons. This staining pattern will be compared to the transduction pattern of the reporter viruses to assess which neuronal subpopulations were transduced. At this time viral gene therapy vectors cannot differentiate among subsets of neurons making them impractical to treat many disorders. The capability to selectively target subsets of neurons will allow the basis for treatment of a multitude of disorders from chronic pain to aiding in spinal cord regeneration. And the ability to be retrogradely transported will allow for less invasive delivery of these vectors as opposed to direct injections into the spinal cord.

project_terms:
Amino Acid Sequence;Amino Acids;Animals;Antibodies;Binding (Molecular Function);Brain;Cell Fraction;Cell Line;Cell surface;Cells;Characteristics;Chimera organism;Clinical;Cutaneous;Disease;Endoplasmic Reticulum;Engineering;Figs - dietary;Future;Ganglia Spinal;Gel;Gene Transduction Agent;Genes;Glutamate Decarboxylase;Glycoproteins;Green Fluorescent Proteins;Hela Cells;Herpesvirus 1 Cercopithecine;Heterogeneity Population;Immunohistochemistry;In Vitro;Injection of therapeutic agent;Injections Spinal;Interphase Cell;Intramuscular;Invasive;Lentivirus Vector;Limb structure;Membrane;Mus;Nerve Growth Factors;Nervous system structure;Neurons;Neurons Afferent;Neurotrophic Tyrosine Kinase Receptor Type 1;Neurotrophin 3;Nociception;Numbers;Pain;Pain management;Pattern;Peripheral;Population;Posterior root of spinal nerve;Proteins;Publishing;Rabies virus;Rats Sprague-Dawley;Rattus;Receptor Signaling;Reporter;Reporting;Research;Resistance;Route;Running;Site;Specificity;Spinal Cord;Staining method;Stains;Surface;Testing;Therapeutic;Time;Tissues;Toxin;Transfection;Tropism;Viral;Virion;Virus;Virus Diseases;base;chronic pain;clinical application;fluorophore;gene therapy;glycoprotein G rabies virus;immunocytochemistry;in vivo;intradermal injection;nervous system disorder;neurotropic;novel;proenkephalin;receptor;receptor binding;spinal cord regeneration;success;tool;trafficking;vector;virus envelope


application_id: 7394452
project_number: 5R01DA002243-31
project_title: Degradation of Opioid Peptides
administering_ic: NIDA
award_notice_date: 2008-04-15
application_type: 5
activity_code: R01
ic: DA
serial_number: 002243
program_official: PUROHIT, VISHNUDUTT
project_start_date: 1978-09-30
project_end_date: 2012-04-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
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: 2008-05-01
project_terms:
Affect;Allosteric Regulation;Amyloid;Anions;Binding Sites;Biochemical;Brain;Brain region;Cell Line;Cell membrane;Cleaved cell;Dementia;Drug or chemical Tissue Distribution;Dynorphins;Elderly;Endorphins;Enzymes;Goals;HIV;Hydrolysis;Individual;Insulin;Insulinase;Lead;Membrane;Metabolism;Metalloproteases;Methods;Mice Knockout;Neprilysin;Neuropeptides;Numbers;Opioid;Opioid Peptide;Peptide Hydrolases;Peptide Metabolism;Peptides;Physiological;Property;Range;Regulation;Relative (related person);Reporting;Reports Progress;Research Project Grants;Substrate Specificity;Techniques;Testing;cell type;in vivo;insight;macrophage;membrane activity;novel;peptide hormone;preference


application_id: 7394419
project_number: 5R01NS049954-05
project_title: Novel Imging and Physiological Evaluation of Human SCI
administering_ic: NINDS
award_notice_date: 2008-04-11
opportunity_number: RFA-NS-04-004
application_type: 5
activity_code: R01
ic: NS
serial_number: 049954
program_official: KLEITMAN, NAOMI
project_start_date: 2004-09-15
project_end_date: 2010-04-30
study_section: ZNS1-SRB-R(06)
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
project_abstract:
DESCRIPTION (provided by applicant):   
  
The decision to surgically decompress the spinal cord following spinal cord injury (SCI) is controversial as is the timing of decompression. Multicenter randomized controlled studies of early surgical decompression have not been performed in humans. MR images of the spine reflect the anatomical picture of the spinal cord but do not reflect metabolic status of the tissue or the CSF surrounding the spinal cord and thus may not indicate the precise degree of compression on the spinal cord. We hypothesize that:    
1) quantitative cine phase-contrast magnetic resonance imaging (C-MR) which non-invasively measures flow velocity of cerebrospinal fluid (CSF) above and below the injury will provide additional objective data to assist the decision-making process for surgical decompression and whether use of this data results in better long-term functional outcome following SCL. Within 8 hours after admission all patients will undergo T1- and T2-weighted MR scans followed immediately by a C-MR. Patients with cord compression and evidence of CSF block will undergo immediate decompression surgery. Patients with no MR evidence of spinal cord compression or CSF block will be treated with the best medical care (non-surgical). Patients in whom the anatomical picture (MR scan) and CSF flow pattern (C-MR) are not concordant will be randomized into surgical and non-surgical groups. A variety of functional outcome measures will be performed on admission weekly for one month and at 3 6 9 12 18 and 24 months following SCI to determine whether use of C-MR data results in a better functional outcome.  
2) integrated PET/CT can determine the metabolic status at the site of the injury (as early as possible but within 3 days) after the injury. We will use 18F-deoxyglucose to assess uptake and utilization. This information will attempt to assess whether the injury is complete (irreversible) or incomplete (reversible). We will answer the question if PET/CT is performed early can it be used to predict the outcome of spinal decompression surgery?  
3) tcMMEP and SSEP can be used as non-invasive tools to assess spinal compression. We will measure them on the day of admission and after decompression and correlate them post hoc with the MR and C-MR data all of which will be entered into an NIH-sponsored national SCI database. We will also assess whether these tests can be used to more accurately determine if decompressive surgery can improve the long-term functional outcome by performing these tests weekly for one month and at 3 6 9 and 12 months following SCI.  
4) oximetry at the site of SCI can be used over the first week as a non-invasive monitor of cord ischemia that results from compression and thus as a decision-making tool for decompression. This can be done by correlating the data of each patient  
post hoc with other measures of Aims 1-3.

project_terms:
Acute;Address;Admission activity;Animal Model;Asia;Blinded;Blood Volume;Blood flow;Buffers;Caring;Cerebrospinal Fluid;Chronic Phase;Clinical;Clinical Trials;Compression of spinal cord;Data;Databases;Decision Making;Decompression Surgical;Decompression external;Decompressive incision;Deoxyglucose;Diagnostic;Early Intervention (Education);Evaluation;Evoked Potentials Motor;Experimental Designs;Future;Hour;Human;Hypoxia;Image;Injury;Intervention;Invasive;Ischemia;Magnetic Resonance Imaging;Magnetism;Measures;Medical;Metabolic;Methods;Monitor;Myelography;Nature;Neurological outcome;Neurological status;Operative Surgical Procedures;Outcome;Outcome Measure;Oxygen saturation measurement;PET/CT scan;Pathway interactions;Patients;Pattern;Phase;Physicians;Physiologic pulse;Physiological;Postoperative Period;Procedures;Process;Pulse taking;Randomized;Randomized Controlled Trials;Recovery;Recovery of Function;Resource Allocation;Scanning;Score;Signal Transduction;Site;Spectroscopy Near-Infrared;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Staging;Standards of Weights and Measures;Stimulus;Subarachnoid Space;Surgery Unnecessary;System;Techniques;Testing;Time;Tissues;Training;Vertebral column;Week;Weight;X-Ray Computed Tomography;base;cerebrospinal fluid flow;day;functional outcomes;hemodynamics;improved;indexing;non-invasive monitor;novel;prevent;prospective;spinal shock;success;tool;uptake


application_id: 7394327
project_number: 5T35ES014559-03
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2008-03-20
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Environmental Health Sciences Review Committee[EHS(TB)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
This proposal describes a short-term summer training programfor medical students focused on exposing students to career opportunities in basic and clinical research related to environmental health sciences.This application addresses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Environmental Health Sciences-based researchto medical students in a structured mentored environment.Aim 2: To provide an interactive educational experience that introduces medical students the fundamentalskills necessary for basic translational and clinical Environmental Health Sciences-based research. The training program will include didactic instruction as well as a hands-on-research experience under thedirection of a team of experienced basic and clinical researchscientists centered on a core of NIEHS-funded investigators and collaborating faculty. These faculty have long-standing success inmentoring medical and graduate students and post-doctoral fellows. Students who have completed at leastone year of medical school will be eligible to apply for this 10-weektraining program. Trainees will beselected based upon their academic performance letters of recommendation and matching their researchinterests and career goals with suitable mentors. We have been successful in recruiting students fromminority rural and economically disadvantaged backgrounds. The students will participate in anestablished 10-week didactic summer program: "From Bench to Bedside: Introduction to Clinical Research"which included bioethics as well as Environmental Health Sciences-specific seminars and journal clubs inbasic and clinical research. Students will present posters of their research at the end of the program. Thetraining program will begin with six trainees and increase toten trainees as the program.matures. Over thepast 6 years the University of Louisville has increased its commitment to health science research andinfrastructure graduate education and minority recruitment making this short-term training program formedical students particularly timely. . \

project_terms:
Accounting;Address;American;American Heart Association;Animal Experimentation;Animals;Animals Laboratory;Antineoplastic Agents;Appendix;Area;Authorship;Award;Awards and Prizes;Awareness;Basic Science;Belief;Biochemistry;Bioethics;Biohazardous Substance;Biology;Biomedical Research;Blood Circulation;Blood Vessels;Calendar;Cardiology;Cardiovascular Diseases;Career Choice;Caring;Categories;Chemicals;Clinic;Clinical;Clinical Medicine;Clinical Research;Clinical Trials;Clinics and Hospitals;Communities;Confidentiality;Conflict (Psychology);Conflict of Interest;Consultations;Data;Detection;Device or Instrument Development;Disadvantaged;Discipline;Disease;Distress;Doctor of Philosophy;Doctor of Veterinary Medicine;Education Medical;Education Medical Graduate;Educational Curriculum;Educational aspects;Emergency Situation;End Point;Engineering;Ensure;Environment;Environmental Health;Enzymes;Equipment;Ethics Committees Research;Ethics Research;Euthanasia;Evaluation;Event;Faculty;Foundations;Freedom;Friends;Funding;Future;Goals;Graduate Education;Grant;Hand;Hazard Controls;Hazardous Substances;Hazardous Waste;Hazards Health;Health;Health Insurance Portability and Accountability Act;Health Sciences;Healthcare;Healthy People 2010;Horns;Hospitals;Hour;Human;Human Resources;IACUC;Individual;Instruction;Intellectual Property;Intramural Research;Issues Ethical;Jewish follower of religion;Joints;Journals;Laboratories;Laws;Lead;Learning;Legal;Letters;Libraries;Literature;Master of Public Health;Measures;Medical;Medical center;Medicine;Mentors;Minority;Modeling;Molecular;Molecular Biology;Monitor;National Research Service Awards;Nebraska;Notification;Nuclear Receptors;Numbers;Operative Surgical Procedures;Oral;Ownership;Pain;Paper;Participant;Patient Care;Peer Review;Performance;Pharmacology;Physiology;Policies;Postdoctoral Fellow;Principal Investigator;Private Practice;Prize;Procedures;Process;Productivity;Program Evaluation;Publications;Published Comment;Publishing;Purpose;Qualifying;Radiation;Radiation Interaction;Radioactive;Radiobiology;Rate;Readiness;Reading;Recombinant DNA;Recommendation;Recruitment Activity;Regulation;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Residencies;Resources;Review Committee;Rewards;Running;Rural;Safety;Sampling;Schools Medical;Science;Scientist;Score;Series;Services;Societies;Solutions;Stress;Structure;Students;Students Medical;Techniques;Terminology;Texas;Time;Toxicology;Training;Training Programs;Training and Education;Translating;Translational Research;Translations;United States National Institutes of Health;United States Office of Research Integrity;Universities;Vascular Diseases;Week;Work;abstracting;animal care;base;bench to bedside;career;chemical release;data acquisition;day;drug metabolism;environmental agent;experience;frontier;hazard;health science research;human study;human subject;interest;lecturer;lectures;member;occupational health/safety;peer;posters;professor;programs;radiochemical;rehearsal;response;role model;skills;success;symposium;teacher;theories;volunteer;wasting;xenoestrogen


application_id: 7393811
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Address;Area;Arts;Basic Science;Bioinformatics;Collaborations;Consultations;Data Analyses;Disease;Equipment;Expertise Technical;Grant;Individual;Kentucky;Laboratories;Mediating;Polychlorinated Biphenyls;Procedures;Process;Proteomics;Quality Control;Research;Research Activity;Research Personnel;Research Support;Role;Science of nutrition;Services;Support of Research;Testing;Toxic effect;Universities;cost effectiveness;new technology;programs;statistical service


application_id: 7393810
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Academia;Biochemical;Biomedical Research;Biosensor;Cardiovascular Diseases;Chemicals;Communication Tools;Data;Diabetes Mellitus;Diffusion;Disease;Ensure;Environment;Environmental Health;Exposure to;Feedback;Food;General Population;Government;Guidelines;Health;Health Professional;Hypertension;Individual;Industry;Investigation;Kentucky;Letters;Malignant Neoplasms;Nanotechnology;Nutritional;Pharmacologic Substance;Plants;Polychlorinated Biphenyls;Research;Research Institute;Research Project Grants;Research Outcomes;Role;Science of nutrition;Services;Techniques;Technology;Translating;Translations;Universities;Water;farmer;novel;programs;remediation;sensor


application_id: 7393809
project_number: 5P42ES007380-11
project_title: Core--Superfund InterDisciplinary 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: 2007-04-01
budget_end_date: 2008-03-31
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:
Activities Educational;Address;Affect;Calendar;Chemicals;Collaborations;Communication;Communities;Complex;Detection;Discipline;Economics;Effectiveness;Engineering;Ethics;Evaluation;Faculty;Funding;General Population;Generations;Goals;Home environment;Human;Individual;Institution;Interest Group;Internet;Kentucky;Knowledge;Laws;Life;Measures;Mentors;Minority;Monitor;Outreach Research;Outreach Community;Pamphlets;Problem Solving;Process;Recruitment Activity;Research;Research Personnel;Research Project Grants;Science;Science of nutrition;Scientist;Series;Students;Study Interdisciplinary;System;Toxic effect;Traineeship;Training;Training Programs;Translations;Travel;Universities;interdisciplinary approach;knowledge base;next generation;programs;remediation;research and development;skills;social;socioeconomics;superfund chemical;superfund site;symposium


application_id: 7393808
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Affect;Anthropometry;Antioxidants;Attitude to Health;Behavior;Body Composition;Collaborations;Communities;Community Actions;Diet;Dietitian;Educational aspects;Effectiveness;Environmental Health;Environmental Pollution;Exercise;Exposure to;Face;Family;Fatty acid glycerol esters;Fiber;Food;Funding;Health;Health Knowledge Attitudes Practice;Health Professional;Health education;Individual;Intake;Kentucky;Knowledge;Metabolic;Nutrition Assessment;Outcome;Outreach Community;Pharmacists;Physical activity;Physicians;Polychlorinated Biphenyls;Purpose;Quality of life;Questionnaires;Rate;Records;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Science;Science of nutrition;Series;Services;Surveys;Testing;Tests Pre-Post;Title;Toxic effect;design;improved;insight;interest;nutrition education;programs;tool


application_id: 7393807
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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;Adult;Affect;Affinity;Angiotensin II;Angiotensinogen;Blood Circulation;Blood Pressure;Body Weight;Body Weight decreased;Cardiovascular Diseases;Condition;Data;Development;Diet;Disease;Elevation;Epidemic;Exposure to;Fatty acid glycerol esters;Gene Expression;Health;High Prevalence;Human;Hydrocarbons Chlorinated;Hypertension;Hypertrophy;In Vitro;Individual;Kentucky;Link;Lipid Mobilization;Lipids;Modeling;Nuclear Receptors;Obesity;Obesity Related Hypertension;Overweight;PPAR gamma;Plasma;Polychlorinated Biphenyls;Population;Prevalence;Proteins;Protocols Treatment;Rattus;Renin-Angiotensin System;Rodent;Site;Structure;System;Toxic Environmental Substances;Toxic effect;Work;adipocyte biology;adipocyte differentiation;adipokines;blood pressure regulation;in vivo;lipophilicity;mRNA Expression;receptor;response;superfund chemical;superfund site


application_id: 7393806
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Adhesions;Air Pollution;Animals;Basement membrane;Biological;Biological Models;Biology;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Cancer Biology;Cancer Patient;Capillary Unspecified;Cell Adhesion;Cell Adhesion Molecules;Chemicals;Chlorine;Clinical;Data;Development;Dietary Intervention;Disease;Disruption;Eels;Elements;Endothelial Cells;Endothelium;Endothelium Vascular;Event;Extracellular Matrix;Forecast of outcome;Functional disorder;Genes;Goals;Grants Applications;Infiltration;Injury;Intercellular Junctions;Knowledge;Link;Liver;Lung;Matrix Metalloproteinases;Mediating;Metastatic malignant neoplasm to brain;Mitogen-Activated Protein Kinases;Modeling;Molecular;Neoplasm Metastasis;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pathway interactions;Permeability;Polychlorinated Biphenyls;Protein Kinase;Protein Overexpression;Proteins;Recruitment Activity;Research;Research Proposals;Signal Pathway;Surface;System;Tissues;Up-Regulation (Physiology);base;chemokine;environmental toxicology;in vitro Model;migration;neoplastic cell;novel;prevent;protein expression;response;transcription factor;tumor


application_id: 7393805
project_number: 5P42ES007380-11
project_title: Chloro-Organic Degradation by Nanosized Metallic Systems and by Chelate Modified
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Air;Aspartic Acid;Basic Science;Binding (Molecular Function);Biodegradation;Biological;Borohydrides;Carbon;Chelating Agents;Chemicals;Chlorine;Chlorophenols;Citrate;Citrates;Closure;Condition;Development;Environment;Equilibrium;Film;Free Radical Formation;Generations;Glucose;Hazardous Waste;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;In Situ;Iron;Kinetics;Lead;Literature;Melanocytic nevus;Membrane;Metabolic Detoxication Drug;Metals;Methods;Mole the mammal;Morphology;Parents;Pathway interactions;Personal Satisfaction;Pliability;Pollution;Polychlorinated Biphenyls;Polymers;Precipitation;Range;Rate;Reaction;Reagent;Reducing Agents;Research;Science of Chemistry;Site;Soil;Solvents;Standards of Weights and Measures;Structure;Surface;System;Techniques;Technology;Temperature;Testing;Toxic effect;Translating;Trichloroethylene;Vinyl Chloride;Work;acrylic acid;base;chemical reaction;controlled release;cost;dechlorination;dehalogenation;enzyme immobilization;gluconate;glucose oxidase;nanoparticle;nanosized;novel;particle;prevent;reaction rate;remediation;superfund site;technology development;water quality


application_id: 7393804
project_number: 5P42ES007380-11
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Area;Bacteria;Binding (Molecular Function);Biological;Biological Process;Biosensing Techniques;Cells;Chemicals;Communities;Compact discs;Coupled;Detection;Development;Dioxygenases;Engineering;Environment;Enzymes;Fluorescence;Genes;Genes Reporter;Goals;Health;Human;Label;Liquid substance;Microfluidics;Molecular;Monitor;Mutagenesis;Nature;Operon;Optics;Pathway interactions;Personal Satisfaction;Poisons;Polychlorinated Biphenyls;Property;Proteins;Recombinants;Reporter;Sampling;Series;Signal Transduction;Site;Sites Active;Soil;Solutions;Specificity;System;Testing;Time;Water;analytical method;base;cellular engineering;chemical binding;design;diphenyl;field study;improved;miniaturize;portability;sensor;superfund chemical;tool;wasting


application_id: 7393803
project_number: 5P42ES007380-11
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction
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: 2007-04-01
budget_end_date: 2008-03-31
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:
Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Antiatherogenic;Antioxidants;Atherosclerosis;Cardiovascular Diseases;Cause of Death;Caveolae;Caveolins;Cells;Chronic;Development;Diet;Disease;Endothelial Cells;Environmental Pollution;Event;Fatty Acids;Fatty acid glycerol esters;Functional disorder;Genes;Genes vpr;Hypertriglyceridemia;In Vitro;Incidence;Inflammation;Inflammatory;Intervention;Lead;Ligands;Mediating;Membrane Lipids;Membrane Microdomains;Mus;Nuclear Receptors;Numbers;Nutrient;Nutritional;Obesity;Outcome;Pathogenesis;Pathology;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Play;Polychlorinated Biphenyls;Population;Property;Receptor Signaling;Recommendation;Regulation;Risk;Risk Factors;Role;Science of nutrition;Signal Pathway;Signal Transduction;Testing;Therapeutic Intervention;Toxic effect;United States;caveolin 1;cell growth regulation;in vivo;mouse model;novel;novel therapeutics;superfund chemical;trafficking;uptake


application_id: 7393644
project_number: 5R01HD052694-03
project_title: Endothelin-2 in Ovarian Follicle Rupture
administering_ic: NICHD
award_notice_date: 2008-02-18
application_type: 5
activity_code: R01
ic: HD
serial_number: 052694
program_official: TAYMANS, SUSAN
project_start_date: 2006-05-15
project_end_date: 2011-02-28
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in folliclerupture. The program of ovulation is activated by a surge of luteinizing hormone which initiates dramaticchanges in molecular biochemical and physical aspects of the ovary eventually leading to rupture offollicles. However the factors involved in and the mechanism governing the process of follicle rupture are yetto be unveiled. Using a gene expression profiling approach we have identified EDN-2 a potent smoothmuscle constrictor which is exclusively and transiently expressed in the granulosa cells of periovulatoryfollicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in theovarian tissue while tezosentan an endothelin receptor antagonist released the contraction. These novelfindings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture ofthe follicle. Supporting the hypothesis immunohistochemical analysis identified a well-organized smoothmuscle layer in the theca externa of each follicle which forms a sponge-like smooth muscle network at thewhole ovarian level. Furthermore we found that intraovarian injection of tezosentan prior to ovulationcompletely blocked follicle rupture. In this study we will elucidate the mechanism of EDN-2 action in folliclerupture. We will determine the target tissues of EDN-2 action the endothelin receptor subtype(s) thatmediates EDN-2 action and the ovarian concentration of EDN-2. We will also determine the mechanism ofendothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrice molecules(VIPs PACAPs and prostaglandins). In addition the functional link of progesterone estrogen andprostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposalis in the identification of EDN-2 and the ovarian smooth muscle network as the key components of folliclerupture. The novelty of the proposed experiments is the interdisplinary approachs (genome-wide geneexpression profiling intraovarian injection and isometric tension measurement). The proposed studies areexceptionally important in order to further our understanding of the mechanism of follicle rupture. Theproposed experiments will provide clinical direction in identifying the therapeutic target for the cure ofannovulatory symptoms one of the leading causes of female infertility.

project_terms:
Animal Model;BQ123;Binding Sites;Biochemical;Biochemical Process;Clinical;Constriction procedure;Count;Cyst;Databases;Development;Disease;Endothelin;Endothelin Receptor;Endothelin Receptor Antagonist;Endothelin-2;Estrogen Receptor alpha;Estrogens;Externa Theca;Failure (biologic function);Female infertility;Gene Expression;Gene Expression Profiling;Genes;Genome;Goals;Growth;Hormonal;Immunohistochemistry;In Situ Hybridization;Individual;Indomethacin;Infertility;Injection of therapeutic agent;Isometric Exercise;Knowledge;Label;Lead;Link;Luteinizing Hormone;Mammalian Oviducts;Measurement;Measures;Mediating;Mice Knockout;Models Experimental;Molecular;Molecular Profiling;Mus;Numbers;Oocytes;Ovarian;Ovarian Diseases;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;PTGS2 gene;Pattern;Pituitary Gonadotropins;Porifera;Process;Progesterone;Prostaglandin Receptor;Prostaglandins;RU-486;Radioimmunoassay;Rattus;Receptors Progesterone;Research Personnel;Residual state;Reverse Transcriptase Polymerase Chain Reaction;Role;Rupture;Smooth muscle (tissue);Structure;Structure of corpus luteum of ovary;Symptoms;Syndrome;System;Techniques;Therapeutic;Tissues;Vasoactive Intestinal Peptide;granulosa cell;in vivo;inhibitor/antagonist;intraovarian;novel;programs;receptor;research study;tezosentan;therapeutic target


application_id: 7393525
project_number: 7R01DK056132-06
project_title: Neural Circuitry in the Caudal Solitary Complex
administering_ic: NIDDK
award_notice_date: 2007-05-21
application_type: 7
activity_code: R01
ic: DK
serial_number: 056132
program_official: SATO, SHERYL M
project_start_date: 2001-06-01
project_end_date: 2008-04-30
study_section: Integrative, Functional and Cognitive Neuroscience 1[IFCN-1]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-16
project_abstract:
DESCRIPTION: Regulation of gastrointestinal function by the brain is an             important but inadequately understood component of energy homeostasis in            humans. The long-term objective of this project is to understand the local          neuronal connectivity in the brainstem solitary complex. As the site of first       central synaptic contact for sensory afferent fibers of the vagus nerve from        the digestive tract neurons in the nucleus tractus solitarius (NTS) process        digestive system information prior to further integration via higher brain          areas and eventual activation of motor output to the stomach. Included in the       neuronal circuits controlling autonomic function are local synaptic circuits in     the NTS inputs from CNS regions outside the solitary complex and                  reflex-circuit interactions with vagal motor neurons in the dorsal motor            nucleus of the vagus nerve (DMV). Although the neuronal circuitry of the caudal     solitary complex is the functional substrate for visceral sensory-motor             integration relating to feeding behavior local synaptic connectivity in the        area has not been adequately described. We will use whole-cell patch-clamp          recordings in brain slices to investigate the functional organization of the        caudal solitary complex. We will identify neurons on the basis of their             functional connections with the proximal stomach using in vivo labeling             methods. We will also correlate synaptic responses with quantitative                morphological features using biocytin labeling techniques. Both electrical          stimulation of primary viscerosensory input and photoactivation of caged            glutamate to stimulate discrete sites within the slice will be used to              investigate the local amino acid-mediated synaptic circuitry of the region. The     specific aims of the proposal are designed to test hypotheses regarding the         synaptic circuitry of the solitary complex. The specific hypotheses for the         proposed research are: 1) Gastric-related principal neurons in the NTS are          inhibited by a convergent system of local GABAergic neurons (i.e. lateral          inhibition); 2) small putative inhibitory NTS neurons are activated by local       excitatory NTS neurons; and 3) stomach-projecting neurons in the DMV are            directly inhibited by NTS input. These experiments will result in an                understanding of neuronal connectivity within the NTS and between regions of        the solitary complex. This information is highly relevant to the mechanistic        understanding of feeding behaviors such as receptive relaxation and                 accommodation in the stomach. It will also enhance understanding of the             mechanisms of action for treatments of digestive system-related disorders.

project_terms:
brain cell;brain stem;dorsal motor nucleus;electrophysiology;electrostimulus;gastrointestinal function;immunocytochemistry;laboratory rat;neural information processing;neural transmission;neuroanatomy;neurons;neuroregulation;organ culture;solitary tract nucleus;synapses;vagus nerve;voltage /patch clamp


application_id: 7393339
project_number: 5R01AR045617-07
project_title: Intracellular signaling during skeletal muscle hypertrophy
administering_ic: NIAMS
award_notice_date: 2008-02-19
application_type: 5
activity_code: R01
ic: AR
serial_number: 045617
program_official: BOYCE, AMANDA T
project_start_date: 1999-02-05
project_end_date: 2012-02-29
study_section: Special Emphasis Panel[ZRG1-MOSS-H(02)S]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_terms:
1-Phosphatidylinositol 3-Kinase;Ablation;Aging;Amino Acids;Area;Attenuated;Bed rest;Biogenesis;Cachexia;Clinical;Complex;Cyclin D1;Cyclins;Development;Disruption;Event;Fiber;Funding;Genes cdc;Genetic;Goals;Growth;Growth Factor;Health;IGF1 gene;In Vitro;Incubated;Insulin;Insulin-Like Growth Factor I;Link;Maintenance;Measures;Mechanics;Metabolic;Mice Transgenic;Modeling;Molecular;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Outcome;Phosphoinositide-3-Kinase Catalytic Gamma Polypeptide;Phosphorylation;Phosphotransferases;Process;Protein Biosynthesis;Proteins;Proto-Oncogene Proteins c-myc;Quality of life;RNA Messenger;Raptors;Regulation;Research;Research Personnel;Resistance;Ribosomal RNA;Role;Signal Pathway;Signal Transduction;Signaling Protein;Sirolimus;Skeletal muscle structure;Skeletal system;Stretching;Testing;Transfection;Translational Regulation;Work;c-myc Genes;glucose uptake;in vivo;in vivo Model;insight;insulin receptor substrate 1 protein;knock-down;lipid metabolism;muscle hypertrophy;novel;programs;research study;response;tool


application_id: 7393133
project_number: 5R25HL084695-03
project_title: Summer Undergraduate Experiences In Biomedical Research
administering_ic: NHLBI
award_notice_date: 2008-03-14
opportunity_number: RFA-HL-05-018
application_type: 5
activity_code: R25
ic: HL
serial_number: 084695
program_official: COMMARATO, MICHAEL
project_start_date: 2006-04-07
project_end_date: 2011-03-31
study_section: ZHL1-CSR-B(F1)
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animal Experimentation;Animals;Area;Basic Science;Biomedical Research;Cardiovascular system;Clinical;Collaborations;Country;Data Analyses;Disadvantaged;Doctor of Philosophy;Environment;Ethics;Experimental Designs;Exposure to;Generations;Goals;Investigation;Literature;Medicine;Methods;Minority;Numbers;Perception;Procedures;Research;Research Personnel;Residencies;Schools Medical;Students;Students Medical;Universities;base;clinically relevant;experience;programs;research study


application_id: 7393043
project_number: 1R41HD055009-01A1
project_title: A device containing immobilized chelator to remove aluminum from TPN solutions
administering_ic: NICHD
award_notice_date: 2008-02-28
opportunity_number: PA-07-281
application_type: 1
activity_code: R41
ic: HD
serial_number: 055009
suffix: A1
program_official: RAITEN, DANIEL J
project_start_date: 2008-03-01
project_end_date: 2010-02-28
study_section: Special Emphasis Panel[ZRG1 EMNR-E (10)]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 623014201
duns_number: 623014201
fips: US
organization_id: 10008312
organization_name: ALKYMOS, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405173808
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): A high percentage of the ~ 470000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. This is accomplished with a total parenteral nutrition (TPN) solution which is prepared from component solutions: small and large volume parenterals (SVPs and LVPs). Aluminum (Al) is a common contaminant in some SVPs particularly calcium gluconate solution. Excessive Al can produce toxicity to the skeletal system and brain. The potential for Al toxicity is significantly greater in humans such as premature infants who have reduced renal function because the kidneys excrete Al. Medical personnel who care for neonates have suggested for years that the Al in these solutions needs to be greatly decreased to avoid Al-induced toxicity. The FDA implemented a labeling requirement for these component solutions that sets a maximum Al concentration in LVPs and requires a statement of the maximum Al concentration in SVPs. This merely documents estimated maximum Al concentration. It is not the actual Al concentration nor does this reduce the Al in SVPs. Based on prior work to develop new chemicals that bind Al (chelators) the long-term objective is to develop a flow-through filter device containing a chelator that is immobilized on small polymer beads to remove Al from solutions. Based on results obtained using computational chemistry which predicted the strength of binding of novel immobilized chelators with Al it is proposed to synthesize 3 new chelators which are predicted to be effective in this application and to synthesize 1 of these new chelators with 3 different tethers that link it to a resin bead (creating immobilized chelators). These novel chelators will then be characterized to determine their stability constants with Al and their rate and efficiency to complex Al when introduced in Ca gluconate solution. It is proposed to load this immobilized chelator into a filter cartridge that can be used to remove Al from the SVP solutions as they are dispensed through the cartridge from the SVP storage bottles into the final TPN solution.  
  
Project Narrative: The proposed work will develop new chemicals (chelators) that can be put into a medical device to remove a toxic contaminant aluminum (Al) from intravenous solutions. This will remove the potential for Al to produce toxicity to premature infants and other patients who are exposed to Al through intravenous fluids solving a decades-old problem that has escaped resolution to date.

project_terms:
AA Spectrophotometry;Admixture;Adult;Affinity;Aluminum;Award;Binding (Molecular Function);Birth;Bone Diseases Metabolic;Brain;Calcium;Calcium Gluconate;Caring;Chelating Agents;Chemicals;Child;Cholestasis;Class;Clinical Research;Complex;Daily;Development Economic;Devices;Egtazic Acid;Encephalopathies;Ethics Committees Research;Felis catus;Funding;Goals;Guidelines;Health Personnel;Human;IV Fluid;Infant Premature;Intensive Care Units Neonatal;Intravenous;Intravenous Feeding;Kentucky;Kidney;Knowledge;Label;Legal patent;Length;Ligands;Link;Liver;Marketing;Measures;Medical Device;Modification;Needles;Oral;Parenteral Nutrition;Parenteral Nutrition Total;Patients;Phase;Polymers;Polystyrenes;Production;Rate;Renal function;Reporting;Research;Residual state;Resins Plant;Resolution;Skeletal system;Small Business Technology Transfer Research;Solutions;Testing;Toxic effect;United States Food and Drug Administration;Universities;Visit;Work;base;chemical binding;computational chemistry;computer studies;feeding;functional group;gluconate;hydroxamate;mental development;neonate;novel;potentiometric titration;programs


application_id: 7392935
project_number: 1U01PS000677-01
project_title: PS07-003 Minority HIV/AIDS Research Initiative (MARI)
administering_ic: NCHHSTP
award_notice_date: 2007-09-12
opportunity_number: RFA-PS-07-003
application_type: 1
activity_code: U01
ic: PS
serial_number: 000677
project_start_date: 2007-09-30
project_end_date: 2011-09-29
study_section: Special Emphasis Panel[ZPS1 FXR (03)]
contact_pi_person_id: 1937858
contact_pi: BROWN, EMMA J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-30
project_abstract:
DESCRIPTION (provided by applicant):  The study proposed in this application addresses the second new strategy for HIV prevention under CDC's Advancing HIV Prevention (AHP) initiative; the implementation of new models for diagnosing HIV infections outside medical settings and one of the six research objectives of the RFA Voluntary HIV testing and counseling of heterosexual Black and Hispanic males. The short-term study objective is to identify barriers and facilitators associated with HIV testing and disclosure of HIV+ test results-- black males18 - 64 who self- identify as heterosexual--determining whether these differ by relationship type (wife regular outside female sexual partner causal female sexual partner male sexual partner) and to determine if providing HIV testing options will result in increase acceptability of HIV testing. The long-term objective is to develop an intervention to promote HIV testing and disclosure of HIV positive status to sexual partners that is cultural gender and region specific for rural/small city African American males who self-identify as heterosexual. The study design consists of four phases; Phase 1-Qualitative Descriptive focus groups (n=36) to inform the development of the survey items Phase 2-Cross-sectional Instrument Developments and Testing (n=300) utilizing a mixed method approach of instruments administration and focus groups Phase 3-Cross- sectional survey administration (n=3000) and randomized controlled trial at the individual level (n=300) comparing experimental condition with rapid HIV testing procedure (OraQuick Rapid HIV-1/2 Antibody or OraQuick Advance Rapid HIV-1/2 Antibody) via community outreach with the controlled condition/standard non-rapid OraSure or serological test and Phase 4-Qualitative Descriptive process evaluation utilizing 12 focus groups (N=72 n=36 survey participants who did not participate in the randomized controlled trial and n=36 participants of the randomized controlled trial) to assess attitude toward HIV testing perception of barriers to and facilitators of HIV testing perception of assistance needed to improve HIV+ disclosure skills and perception of strategies to improve HIV testing. The objective of this research has public health relevance to the Black community related to HIV. Three Healthy People 2010 objectives are addressed by this proposed research; 13-7 Increase the number of HIV- positive persons who know their serostatus 3-13 Increase the proportion of HIV-infected adolescents and adults who receive testing treatment and prophylaxis consistent with current Public Health Service treatment guidelines and 5-8 Reduce HIV infections in adolescent and young adult females aged 13 to 24 years that are associated with heterosexual contact. The objective of this research has public health relevance to the Black community related to HIV. Three Healthy People 2010 objectives are addressed by this proposed research: 13-7 Increase the number of HIV- positive persons who know their serostatus; 3-13 Increase the proportion of HIV-infected adolescents and adults who receive testing treatment and prophylaxis consistent with current Public Health Service treatment guidelines; and 5-8 Reduce HIV infections in adolescent and young adult females aged 13 to 24 years that are associated with heterosexual contact.


application_id: 7392336
project_number: 5R01CA118114-02
project_title: Breast Cancer Chemoprevention Strategies
administering_ic: NCI
award_notice_date: 2008-02-27
application_type: 5
activity_code: R01
ic: CA
serial_number: 118114
program_official: PERLOFF, MARJORIE
project_start_date: 2007-04-01
project_end_date: 2011-02-28
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
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: 2008-03-01
project_terms:
17p;Bexarotene;Binding (Molecular Function);Biochemical;Biological Markers;Blotting Western;Breast Cancer Model;Breast Cancer Prevention;Carcinogens;Catechols;Cell Proliferation;Cell-Free System;Chemoprevention;Chemopreventive Agent;Clinical Research;Cytochromes;DNA Adducts;DNA Damage;DNA Repair;Data;Detox;Development;Devices;Diet;Disease;Dose;Ellagic Acid;Enzymes;Epidemiologic Studies;Estradiol;Estrogen Metabolism;Estrogen Receptors;Estrogen Replacement Therapy;Estrogens;Estrogens Catechol;Etiology;Exposure to;Female;Free Radicals;Future;Gene Mutation;Genes;Goals;Hormonal;Hormones;Human;Immunohistochemistry;Incidence;Individual;Intervention;Lead;Lesion;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Gland Parenchyma;Mammary Tumorigenesis;Mammary gland;Measures;Mediating;Mediation;Metabolic;Methods;Modeling;Molecular Profiling;Numbers;Oxidation-Reduction;PCNA gene;Pathway interactions;Performance;Plasma;Proliferation Marker;Property;Proteins;Proteome;Rats Inbred ACI;Rattus;Relative (related person);Research Personnel;Risk;Risk Factors;Standards of Weights and Measures;Subgroup;System;Testing;Time;Tissues;Toxic effect;Week;Woman;Work;adduct;base;carcinogenicity;concept;experience;foodborne;in vivo;indexing;lycopene;novel;oltipraz;prevent;tumor


application_id: 7391656
project_number: 5R01NS049901-05
project_title: Role of Intraspinal Plasticity in Autonomic Dysreflexia
administering_ic: NINDS
award_notice_date: 2008-03-19
opportunity_number: RFA-NS-04-004
application_type: 5
activity_code: R01
ic: NS
serial_number: 049901
program_official: KLEITMAN, NAOMI
project_start_date: 2004-08-02
project_end_date: 2011-04-30
study_section: ZNS1-SRB-R(06)
contact_pi_person_id: 6146950
contact_pi: RABCHEVSKY, ALEXANDER GEORGE
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): Autonomic dysreflexia is a potentially life-threatening complication of spinal cord injury (SCI) that is characterized by episodic hypertension (high blood pressure) due to sudden massive discharge of the sympathetic neurons in the injured spinal cord. The sympathetic neurons enable the 'fight or flight' response of an individual (e.g. more blood flow to the muscles). The reason the sympathetic neurons are so sensitive is that descending inhibitory pathways from higher brain centers are interrupted as a result of the SCI. In spinal injured patients autonomic dysreflexia is frequently triggered by distension of or activity within pelvic viscera (bladder or bowel). Therefore distension of the bladder or bowel sends a signal via sensory neurons to the sacral spinal cord (the lower back). From here the signal is relayed to thoracic and lumbar sympathetic neurons (chest region of the cord) by relay neurons. Because there is no modulating influence from the higher brain the action of the sympathetic neurons is unopposed. As a result the sudden increase in their activity following visceral stimulation causes a sudden rise in blood pressure (up to 200 mmHg) that can cause potentially fatal brain or spinal hemorrhage seizures as well as severe headache shivering sweating and anxiety. Unfortunately little is known about the anatomical or functional relationships between the visceral sensory neurons the spinal relay neurons and the sympathetic neurons. We propose to use a variety of histological and physiological techniques in a well-defined rat model of autonomic dysreflexia to discover the anatomical connections between these three types of neurons that are critical for the development of autonomic dysreflexia. It is currently not known how visceral sensory information entering the lumbosacral spinal cord is relayed to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the thoracolumbar cord. Since nociceptive afferent sprouting after SCI is NGF-dependent and is correlated with the incidence of autonomic dysreflexia we have injected temperature sensitive adenoviruses (Adts) encoding nerve growth factor (NGFAdts) into thoracic lumbar and sacral spinal cord to trigger sprouting to determine which regions are critical for eliciting autonomic dysreflexia. Overexpression of NGFAdts only in the T13/L1 and L6/S 1 segments produced significant increases in arterial blood pressure evoked by colorectal distension versus injured controls injected with GFPAdts. This suggests that following spinal transection pelvic visceral information is relayed from its input site in the lumbosacral dorsal horn to the IML via unidentified projection pathways. This proposal has 4 goals. Firstly we will use anterograde tracing of biotinylated dextran amine (BDA) from the L6/S 1 cord and retrograde transsynaptic tracing of pseudorabies virus (PRV) from sympathetic pre-vertebral ganglia to identify the neural pathways that transmit visceral information from lumbosacral to thoracic cord after SCI. Secondly since NGFAdts exacerbate dysreflexia we will establish whether this correlates with increased pathway sprouting. Thirdly since it is possible that NGF-independent afferents play a role in autonomic dysreflexia we will inject Adts encoding other growth factors FGF-2 NT-3 BDNF and GDNF into multiple levels of the lumbosacral cord. We will also assess their direct influence on lumbar propriospinal neurons by injecting them in the distal thoracic cord. Finally based on our recent evidence we will inject chemorepulsive semaphorin3aAdts after injury into the lumbosacral spinal cord in an attempt to thwart early sprouting events and minimize dysreflexia as well as establish whether chronic injections are capable of inducing retraction of established sprouts. This information will form the basis for developing potential treatments for this common and debilitating complication of SCI.

project_terms:
Acute;Adenoviruses;Affect;Amines;Animal Model;Animals;Anxiety;Appendix;Architecture;Attention;Autonomic Dysfunction;Autonomic Dysreflexia;Axon;Back;Bladder;Blood Pressure;Blood flow;Bone structure of spine;Brain;Brain-Derived Neurotrophic Factor;C Fiber;Calcitonin Gene-Related Peptide;Cells;Chest;Cholera Toxin;Chronic;Colon;Complication;Data;Development;Distal;Dorsal;Equilibrium;Event;Fiber;Fibroblast Growth Factor 2;Ganglia;Ganglia Spinal;Gene Delivery;Genus Cola;Goals;Green Fluorescent Proteins;Growth;Growth Factor;Growth Factor Overexpression;Growth Inhibitors;Headache;Hemorrhage;Herpesvirus 1 Suid;High Blood Pressure;Horseradish;Hypertension;Hypertensive Crisis;Image Analysis;Immunohistochemistry;Incidence;Individual;Inferior;Injection of therapeutic agent;Injections Spinal;Injury;Intestines;Label;Laboratories;Lead;Life;Localized;Location;Measurement;Mediating;Mesentery;Modeling;Monitoring Physiologic;Muscle;Myxoid cyst;Natural regeneration;Nerve Growth Factors;Neural Pathways;Neurons;Neurons Afferent;Neurotrophin 3;Nociception;Pathway interactions;Patients;Pattern;Pelvis;Peripheral;Phase;Physiological;Play;Population;Posterior root of spinal nerve;Process;Protein Overexpression;Quality of life;Rattus;Reflex action;Research;Role;Sacral spinal cord structure;Seizures;Sensory;Severities;Shivering;Signal Transduction;Site;Specific qualifier value;Specificity;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Stimulus;Substance P;Sweat;Sweating;Synapses;System;Techniques;Temperature;Testing;Thinking function;Thoracic spinal cord structure;Time;Tissue Harvesting;Tracer;Vasoconstrictor Agents;Viscera;Visceral;Visceral Afferents;Wheat Germ Agglutinins;Work;adenoviral-mediated;base;biotinylated dextran amine;clinically relevant;colorectal distension;dorsal column;dorsal horn;fighting;gene therapy;glial cell-line derived neurotrophic factor;improved;in vivo;inhibitor/antagonist;injured;innovation;programs;receptor;research study;response;sensory stimulus;spinal pathway


application_id: 7390776
project_number: 5R01AT002890-02
project_title: Novel Herbal Medicine for the Treatment of Prostate Cancer
administering_ic: NCCIH
award_notice_date: 2008-03-13
application_type: 5
activity_code: R01
ic: AT
serial_number: 002890
program_official: SORKIN, BARBARA C
project_start_date: 2007-04-01
project_end_date: 2010-03-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the U.S. and many western countries. Although early diagnosis of PCa has improved significantly in recent years there is a need for more effective treatment strategies for patients presenting with advanced or metastatic disease. Earlier we reported that the chloroform fraction of Rasagenthi Lehyam (cRL) an herbal preparation is effective for the treatment of PCa (Ranga et al. 2004). In subsequent studies we identified the most potent compound (cRL-CI: psoralidin) from the cRL fraction which exhibited more potent anti-cancer effects in PCa cells compared to other isolated components from the cRL fraction. We found that cRL-CI inhibited cell viability and induced apoptosis in PC-3 and DU-145 cells. Additional studies of cRL-CI revealed (i) induction of G2/M arrest of cell cycle (ii) inhibition of NFkB activation (iii) alteration of Bcl2/Bax proteins and (iv) activation of caspase signaling in cell culture models of PCa. In addition in vivo xenograft assays substantiate these in vitro findings and show that cRL-CI inhibits prostate tumor growth in nude mice. Interestingly our results demonstrate that cRL-CI specifically targets cancer cells without causing significant toxicity to normal prostate epithelial cells. Although these results suggest cRL-CI alters molecular signaling its effect on inhibition of pro-survival mechanisms activation of pro-apoptotic signaling and cell cycle arrest are not well understood. Our proposed aims will not only delineate these potential mechanisms of action but will also address the pre-clinical evaluation of cRL-CI against PCa cells. Based on our preliminary studies we hypothesize that cRL-CI will effectively suppress the growth of PCa due to its ability to inactivate NFkB and IAP signaling induce cell cycle arrest and initiate caspase-mediated apoptosis in PCa. This hypothesis will be tested by the following specific aims using in vitro and in vivo approaches. Aim 1. Study the mechanism(s) of NFkB inhibition in PCa by cRL-CI. Aim 2. Elucidate the role of inhibition of apoptosis (lAPs) family proteins in cRL-CI induced apoptosis in PCa cells. Aim 3.Investigate the molecular mechanism(s) for cRL-CI -induced cell cycle arrest in PCa cells. Aim 4.Explore the anti-tumor activity of cRL-CI in animal models. The proposed studies will define the mechanism by which cRL-CI inhibits growth of PCa cells and may lead to the identification of mechanism-based biomarkers. Additionally the results from the proposed studies can be exploited to develop chemotherapeutic and/or chemoprevention strategies for PCa thus leading to clinical trials to determine the efficacy of the cRL-CI against PCa.

project_terms:
Address;Adenocarcinoma;Administration Oral;Animal Model;Apoptosis;Apoptotic;BCL2 gene;BIRC4 gene;Bax protein;Biological Assay;Biological Markers;CDC2 Protein Kinase;Cancer Etiology;Cell Cycle;Cell Cycle Arrest;Cell Survival;Cells;Cessation of life;Chemoprevention;Chloroform;Clinical Trials;Country;Cultured Cells;Data;Disease;Early Diagnosis;Epithelial Cells;Event;Exhibits;G2/M Arrest;G2/M Transition;Gene Expression;Growth;In Vitro;Inhibition of Apoptosis;Lead;Localized;M cell;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Medicine Herbal;Mice Nude;Modeling;Molecular;Mus;Pathway interactions;Patients;Pattern;Phosphorylation;Phosphotransferases;Plant Preparations;Prostate;Prostatic Neoplasms;Protein Family;Proto-Oncogene Proteins c-akt;Radiation therapy;Reporting;Research Personnel;Resistance;Role;Signal Transduction;Stream;Tail;Testing;Toxic effect;Transgenic Organisms;Tumor Tissue;Veins;Xenograft procedure;base;cancer cell;caspase;chemotherapy;improved;in vivo;insight;men;novel;pre-clinical;psoralidin;research clinical testing;research study;survivin;synaptotagmin I;tumor;tumor growth


application_id: 7390740
project_number: 5R01DK055030-08
project_title: LEUKOCYTE ADHESION IN COPPER DEFICIENT MICROCIRCULATION
administering_ic: NIDDK
award_notice_date: 2008-03-11
application_type: 5
activity_code: R01
ic: DK
serial_number: 055030
program_official: MAY, MICHAEL K
project_start_date: 1999-08-01
project_end_date: 2010-03-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 2291964
contact_pi: SCHUSCHKE, DALE A
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: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): Regulation of the microvascular response to inflammatory stimuli is highly dependent upon the interactions between neutrophils and the endothelium. We have shown a significant role for dietary copper in various endothelial interactions in the inflammatory process including nitric oxide (NO)-mediated vasodilation macromolecular leakage and thrombosis. Recently we have studied the role of dietary copper in microvascular control mechanisms with an emphasis on leukocyte/endothelial adhesion. We have demonstrated that dietary copper restriction causes tissue-specific changes in neutrophil/endothelial adhesion and transmigration. Neutrophil accumulation the expression of the adhesion molecule ICAM-1 and the transcription factor NF-kappaB are all greater in the lungs of copper-deficient rats compared to copper-adequate controls. Based on these results we hypothesize that dietary copper deficiency has a priming effect on leukocytes and pulmonary vascular endothelial ceils such that the lung becomes hypersensitive to inflammatory stimuli and more susceptible to the development of acute lung injury. Therefore the specific aims of this study are to: 1) determine the role of dietary copper in leukocyte/endothelial cell interactions in the lung microcirculation; 2) determine the mechanisms by which copper deficiency primes cells for acute inflammation and 3) determine at what concentration of dietary copper the inflammatory mechanisms become enhanced in the in vivo animal microcirculation. Aim #1 will use both in vivo and in vitro models of the lung microcirculation to study leukocyte/endothelial cell adhesion and chemotaxis. Aim #2 will study the role of copper in the NF-kB signaling pathway and in neutrophil priming. Aim #3 will examine these mechanisms under conditions of copper-marginal diets. These experiments have particular relevance since analysis of typical Western diets suggest that 1/3 to 1/2 of those diets may provide less than the RDA of 900mg Cu/day.

project_terms:
Acute;Adhesions;Animals;Blood;Blood Vessels;Cell Adhesion;Cell Adhesion Molecules;Cell Communication;Cells;Chemotaxis;Condition;Copper;Development;Diet;Dietary Copper;Endothelial Cells;Endothelium;Extravasation;Goals;Hemostatic function;Immunologics;Inflammation;Inflammatory;Inflammatory Response;Intake;Intercellular adhesion molecule 1;Leukocytes;Lung;Lung Injury Acute;Mediating;Microcirculation;NF-kappa B;NFKB Signaling Pathway;Nitric Oxide;Process;Process of adhesion;Rattus;Reaction;Regulation;Research;Role;Stimulus;Thrombosis;Tissues;Vascular Endothelial Cell;Vasodilation;Work;base;day;dietary requirement;hypocupremia;in vitro Model;in vivo;neutrophil;prevent;research study;response;transcription factor


application_id: 7390340
project_number: 5R01DA021155-03
project_title: Agonist Replacement Therapy for Cocaine Dependence: Identifying Novel Medications
administering_ic: NIDA
award_notice_date: 2008-02-29
application_type: 5
activity_code: R01
ic: DA
serial_number: 021155
program_official: OVERSBY, STEVEN
project_start_date: 2006-06-01
project_end_date: 2010-03-31
study_section: HIV and Substance Use Research Study Section [NIDA-E]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
Cocaine abuse and dependence continue to be significant public health concerns. The number ofAmericans that used cocaine in the past month the percentage of 12th- 10th- and 8th-graders that usedcocaine in the past year and the percentage of treatment admissions involving cocaine has remained stablein recent years. In 1996 cocaine use cost society over $45 billion due to medical consequences lostproductivity and crime. Because of the public-health concerns and costs associated with its abuseidentifying a pharmacotherapy for cocaine dependence is a priority with the National Institute on Drug Abuse(N.I.D.A.). A pharmacological adjunct for cocaine dependence has not yet been identified. The results of clinical trials suggest that agonist replacement therapies (e.g. d-amphetamine) may beeffective for cocaine dependence. Because cf-amphetamine reduces cocaine use these clinical findings canbe used as a reference to identify human laboratory procedures for screening putative pharmacotherapies.Identifying procedures for assessing the efficacy ofputative pharmacotherapies is important because humanlaboratory studies can be conducted more rapidly/and/efficiently than clinical trials. The present project has two specific aims. The first specific aim is to demonstrate the sensitivity andpredictive validity of human laboratory procedures commonly used to screen putativepharmacotherapies for cocaine dependence. To accomplish this aim we will conduct two "proof-of-concept" studies. We will first demonstrate the safety and tolerability of d-amphetamine-cocainecombinations (Exp. 1). We will then 'demonstrate that d-amphetamine maintenance attenuates thereinforcing effects of cocaine (Exp. 2). The ability to attenuate the reinforcing effects of cocaine may be animportant characteristic of an effective pharmacotherapy. The results of these studies will help elucidate theoptimal conditions (e.g. dose) under which d-amphetamine might be expected to be effective. The second specific aim is to determine the efficacy of atomoxetine (Strattera) as a putativeagonist replacement pharmacotherapy for cocaine dependence. To accomplish this aim we will conducttwo experiments to determine the effects of cocaine during atomoxetine maintenance. We will firstdemonstrate the safety and tolerability of atomoxetine-cocaine combinations (Exp. 3). Finally we willdetermine the reinforcing effects of intranasal cocaine during atomoxetine maintenance (Exp. 4).Atomoxetine a potent norepinephrine uptake blocker was chosen for study because its pharmacologicaland behavioral effects overlap to some extent with those of d-amphetamine but it appears to have lessabuse potential. Identifying novel agonist replacement therapies is important because clinicians may bereluctant to use d-amphetamine because of its abuse potential.

project_terms:
Abuse Cocaine;Accident and Emergency department;Addiction Opiate;Admission activity;Agonist;American;Amphetamines;Attenuated;Behavior;Behavioral;Characteristics;Chronic;Clinical;Clinical Trials;Cocaine;Condition;Crime;Dependence;Dependences Cocaine;Dextroamphetamine;Dose;Drug abuse;Event;Human;Individual;Institutes;Institution;Kentucky;Knowledge;Laboratories;Laboratory Procedures;Laboratory Study;Location;Maintenance;Measures;Medical;Nicotine;Norepinephrine;Numbers;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Procedures;Productivity;Psychostimulant dependence;Publishing;Questionnaires;Recording of previous events;Replacement Therapy;Reporting;Research;Research Design;Research Personnel;Safety;Schedule;Self Administration;Societies;atomoxetine;concept;cost;drug reinforcement;novel;preclinical study;programs;public health medicine (field);research study;stimulant abuse;uptake;volunteer


application_id: 7390269
project_number: 5R01EY016724-03
project_title: Neuroplasticity Genes in Visual Cortex
administering_ic: NEI
award_notice_date: 2008-03-18
application_type: 5
activity_code: R01
ic: EY
serial_number: 016724
program_official: ARAJ, HOUMAM H
project_start_date: 2006-04-01
project_end_date: 2010-03-31
study_section: Central Visual Processing Study Section[CVP]
contact_pi_person_id: 1868720
contact_pi: MOWER, GEORGE D
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: 2008-04-01
project_abstract:
The goal of this proposal is to identify candidate genes controlling neuroplasticity (CPGs) in visual cortex.Dark rearing slows the entire time course of the visual cortical critical period and therefore provides a meansto dissociate changes associated with the state of plasticity from changes associated with maturation. A'differential display PCR screening by this laboratory of all of the expressed genes in the visual cortex ofnormal and dark reared cats at 5 and 20 weeks identified 23 CPGs. CPGs fall into 2 classes: "plasticity"'genes whose expression is enhanced in age/rearing conditions where neuroplasticity is maximal and "anti-plasticity" genes whose expression is opposite. One novel CPG that was identified is Mund3-3 ("anti-plasticity") which plays an essential role in vesicle release at glutamatergic synapses. A novel "plasticity"CPG is disabled-1 (Dab-1) a gene that plays a central role in the migration of cortical neurons. The projectwill address the following specific aims: 1. To test the hypothesis that CPG gene mutation will alter the timecourse of the physiologically defined critical period in mouse visual cortex. Electrophysiological andimmediate early gene expression methodologies will determine the effect of Mund3-3 and Dab-1 mutationon susceptibility to monocular deprivation. 2. To test the hypothesis that "plasticity" and "anti-plasticity" CPGswill show distinct temporal associations with known laminar specific developmental events during the criticalperiod in visual cortex. In situ hybridization and immunohistochemistry will be used to compare "plasticity"and "anti-plasticity" gene/protein expression in layer IV and extragranular visual cortical layers as a functionof age and dark rearing. 3. To verify the identity of previously unsuspected CPGs indicated by the genescreen. Our screen has implicated novel CPGs with documented neurological functions. In addition toMund3-3 and Dab-1 Plasticity Related Gene 1 (PRG-1) which influences axonal outgrowth and two genesassociated with Ras mediated cytoskeletal reorganization (Chimaerinl and Abl interacting protein 2) aretentatively identified. The identification of effector genes which control the visual cortical critical period wouldbe a major step in unraveling molecular mechanisms of neuronal plasticity. Such information is essential tounderstanding processes such as neuronal development regeneration learning and memory and wouldfurther open the possibility of manipulation of nervous system neuroplasticity for therapeutic benefit.

project_terms:
Actins;Address;Age;Animals;Biological;Blotting Northern;Blotting Western;Candidate Disease Gene;Chromosome Pairing;Class;Condition;Critical Period (Psychology);Cytoskeletal Modeling;Darkness;Development;Displays mRNA Differential;Event;FOS Family Genes;Felis catus;Gene Expression;Gene Mutation;Gene Proteins;Genes;Glutamates;Goals;Gold;Immunohistochemistry;In Situ Hybridization;In-Migration;Laboratories;Learning;Mediating;Memory;Methodology;Methods;Mice Mutant Strains;Mitochondria;Modeling;Molecular;Mus;Mutation;Natural regeneration;Nervous System Physiology;Nervous system structure;Neuronal Plasticity;Neurons;Numbers;Ocular dominance columns;Physiological;Play;Polymerase Chain Reaction;Predisposition;Process;Proteins;RNA Messenger;Relative (related person);Research Personnel;Role;Screening procedure;Standards of Weights and Measures;Synapses;Synaptic Vesicles;Testing;Therapeutic;Time;Vesicle;Visual Cortex;Week;Work;base;dark rearing;falls;migration;monocular deprivation;mutant;normal aging;novel;postnatal;programs;protein expression


application_id: 7389540
project_number: 5R01CA124630-02
project_title: PTTG Role in Ovarian Tumorigenesis and Matastasis
administering_ic: NCI
award_notice_date: 2007-12-06
application_type: 5
activity_code: R01
ic: CA
serial_number: 124630
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2007-03-26
project_end_date: 2011-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
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_terms:
5q35.1;AKT Signaling Pathway;Address;Adenoviruses;Aneuploidy;Animal Model;Antineoplastic Agents;Base Sequence;Boxing;Cancer Model;Cause of Death;Cell Proliferation;Cells;Cessation of life;Chromosomal Instability;Chromosome abnormality;Chromosomes;Cloning Molecular;Crossbreeding;Cytoplasm;DNA Complementary;Data;Detection;Developed Countries;Developing Countries;Development;Down-Regulation;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Epithelium;Fetal Kidney;Fetal Liver;Fibroblast Growth Factor 2;Gene Expression;Genes;Genetic;Genetically Engineered Mouse;Genomic Instability;Growth;Gynecologic;Health;Human;IL8 gene;In Vitro;Laboratories;Lead;Localized;Maintenance;Malignant Neoplasms;Malignant neoplasm of breast;Malignant neoplasm of ovary;Mediating;Methods;Mice Nude;Mice Transgenic;Modeling;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Protein;Nuclear Proteins;Oncogene Proteins;Oncogenes;Oncogenic;Ovarian;Ovarian Surface Epithelial-Stromal Tumor;Ovary;PI3K/AKT;PTTG1 gene;PTTG1 protein human;Phenotype;Polymerase Chain Reaction;Preclinical Testing;Prevention;Process;Production;Proline-Rich Domain;Promotor (Genetics);Protein Overexpression;Proteins;RNA Messenger;RNA Small Interfering;Rate;Reporting;Research Personnel;Role;Sequence Analysis Protein;Sister Chromatid;Sister Chromatid Exchange;Staging;Structure;Surface;System;Testis;Time;Transgenic Animals;Tumor Suppression;United States;Vascular Endothelial Growth Factors;Woman;angiogenesis;base;c-myc Genes;cancer diagnosis;cell type;expression vector;gene function;human tissue;in vivo;indexing;knockout animal;loss of function;metaplastic cell transformation;neoplastic;neoplastic cell;novel;ovarian neoplasm;pituitary tumor-transforming proteins;programs;small molecule;therapy development;tumor;tumor growth;tumor initiation;tumorigenesis;tumorigenic


application_id: 7389331
project_number: 7K25AG022464-05
project_title: Osteoblast stimulation effects on osteoclast activity
administering_ic: NIA
award_notice_date: 2007-07-12
opportunity_number: PA-02-127
application_type: 7
activity_code: K25
ic: AG
serial_number: 022464
program_official: WILLIAMS, JOHN
project_start_date: 2003-09-01
project_end_date: 2009-08-31
study_section: Biological Aging Study Section[NIA-B]
contact_pi_person_id: 8145849
contact_pi: SAUNDERS, MARNIE M.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate the mechanisms involved in implant-induced osteolysis and the effect(s) of mechanical loading on this process. Biological training proposed in this application augmented with the applicant's engineering background would enable the applicant to complete the research proposed herein and develop future research aimed at osteolysis. The goal of the current application is to determine the role of the substrate in enhancing the mechanoresponsiveness of osteoblastic cells and the effects of stimulated soluble factors on osteoclastic cells. Specifically we will determine if substrate contributes to cell flattening cell networking and cell-cell communication by analyzing these factors in communication-competent and -deficient osteoblastic cell lines on artificial and native substrates. We will then determine if these factors contribute to the mechanoresponsiveness of osteoblastic cells by quantifying fluid flow-induced cell secreted levels of osteoprotegerin (OPG) and its ligand (RANKL). Finally we will determine if enhanced osteoblastic responsiveness is coupled to an inhibition of osteoclastogenesis and functional osteoclastic activity by quantifying OPG RANKL and bone resorption by osteoclasts in the presence and absence of stimulated media from the osteoblastic fluid flow studies. We propose that a native substrate relative to an artificial substrate contributes to the mechanoresponsiveness of osteoblastic cells by promoting cell flattening cell networking and cell-cell communication. Furthermore we propose that coupling mechanisms exist between osteoblastic and osteoclastic cells which enable the orchestration of bone formation and resorption and that stimulation of osteoblastic activity results in an upregulation of soluble factors promoting inhibition of osteoclastogenesis and osteoclastic activity. Future work will focus on the development of in situ mechanotransduction models incorporating bone substrates. Research in this area will illuminate the mechanisms by which normal cells sense and respond to mechanical loading and the effects of the milieu in this process. This is the first step in understanding the breakdown of these mechanisms associated with disease and altered loading environments. This work has several clinically relevant applications including implant- and metastatic-induced osteolysis osteoporosis osteopetrosis fracture healing and functional tissue engineering.

project_terms:
atomic force microscopy;biological signal transduction;biomechanics;bone regeneration;cell cell interaction;cell communication molecule;clinical research;collagen;extracellular matrix proteins;fibronectins;fluid flow;gap junctions;glycoproteins;human tissue;osteoblasts;osteoclasts;physiologic bone resorption


application_id: 7388601
project_number: 1S10RR024598-01
project_title: Thermo/Finnigan TSQ AM Triple Stage Quadrupole Mass Spectrometer
administering_ic: NCRR
award_notice_date: 2008-02-05
opportunity_number: PAR-07-105
application_type: 1
activity_code: S10
ic: RR
serial_number: 024598
program_official: TINGLE, MARJORIE
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1 BCMB-M (30)]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW 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
project_abstract:
DESCRIPTION (provided by applicant): Lipids are a diverse class of hydrophobic organic compounds that can self associate to form cellular membranes. In addition to this critical structural function lipids store energy and are important precursors for the synthesis of intra- and extra- cellular signaling molecules. Recent advances in the systems-level analysis of lipids have established mass spectrometry as the state-of the-art approach for lipid analysis. Our broad long-term objective is to provide these technologies to advance the research goals of ten highly productive investigators at the University of Kentucky with a shared interest in defining roles of lipids and their metabolites in physiological and pathophysiological processes including cancer inflammation obesity diabetes and cardiovascular disease. The specific aim is to request funds to acquire a Thermo/Finnigan TSQ MS/MS high performance triple stage-quadrupole mass spectrometer to be housed in the University of Kentucky Mass Spectrometry Facility. This instrument will be used to detect structurally characterize and most importantly quantitate phospholipids sphingolipids fatty acids (including eicosanoids) isoprenoids and sterols in samples derived from cellular clinical and/or preclinical sources and to do so with unprecedented resolution precision and sensitivity. No suitable instrument of this configuration and with the required sensitivity is presently available to these investigators for this purpose at the University of Kentucky; other instruments of different configurations potentially available for some of these analyses are heavily used for other purposes. Consequently these investigators are forced to use indirect or inadequate methodologies to accomplish their research goals or to use appropriate instrumentation on a collaborative basis with investigators at other institutions. Acquisition of this instrument would allow this group of investigators to complete their current and future research projects far more efficiently to generate optimal research outcomes.

project_terms:
Arts;Cardiovascular Diseases;Cellular Membrane;Class;Clinical;Diabetes Mellitus;Eicosanoids;Fatty Acids;Funding;Future;Goals;Housing;Inflammation;Institution;Kentucky;Lipids;Malignant Neoplasms;Methodology;Obesity;Performance;Phospholipids;Physiological;Process;Purpose;Research;Research Personnel;Research Project Grants;Research Outcomes;Resolution;Role;Sampling;Signaling Molecule;Source;Spectrum Analysis Mass;Sphingolipids;Staging;Sterols;System;Technology;Universities;base;instrument;instrumentation;interest;isoprenoid;mass spectrometer;pre-clinical


application_id: 7388504
project_number: 1S10RR023580-01A1
project_title: Roche Real-Time Polymerase Chain Reaction Workflow System
administering_ic: NCRR
award_notice_date: 2008-01-30
opportunity_number: PAR-07-105
application_type: 1
activity_code: S10
ic: RR
serial_number: 023580
suffix: A1
program_official: TINGLE, MARJORIE
project_start_date: 2008-02-01
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1 GGG-A (30)]
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
project_abstract:
DESCRIPTION (provided by applicant): We are requesting a Roche real-time polymerase chain reaction (PCR) Workflow System with automated components for preparation of tissues (MagNA Lyser) isolation of nucleic acids (MagNA Pure Compact) and a real-time PCR (LightCycler 480). The LightCycler 480 is a high throughput real- time PCR instrument that detects and quantifies nucleic acid sequences and has a 96- and 384-well plate capacity. This PCR Workflow System is very easy to use is accompanied by powerful software and enables an investigator to go from tissue to nucleic acid quantitation in 3-4 hours. This instrument will be housed in the MicroArray Core Research Facility of the University in the Bosomworth Health Sciences Research Building and will be used by faculty in the Graduate Center for Toxicology and in the Department of Anatomy and Neurobiology. The group of investigators participating in this application includes seven faculty with NIH-supported grant projects who are major users and three additional faculty who are minor users. The research projects are diverse but revolve around three major themes: 1) oxidant-stress induced tissue injury and cancer 2) DNA damage repair and mutagenesis and 3) hormonal regulation of gene expression. We intend to use this instrument for the high-throughput real-time quantitative analysis of RNA transcripts and DNA targets in biological samples and in detection of single nucleotide polymorphisms (SNP) in genes important in cancer. As indicated in the research projects from each investigator the availability of the proposed instrument will significantly improve the scope and timeliness of their studies. Most importantly it will allow the science to determine the pursuit of exciting discoveries in their funded research projects rather than availability of current instruments. The overall goals of this shared multidisciplinary research facility are to use this advanced technology resource to carry out cutting-edge research that characterizes today's biomedical research and to train our doctoral students and postdoctoral fellows in the use of these modern methods that will enable them to develop into successful independent investigators. The research problems addressed by our investigators are highly relevant to major public health problems related to cancer both in the mechanisms of tumor formation the reasons for (lack of) effectiveness of cancer chemotherapeutic drugs and the regulation of genes by hormones that are important in women's health.

project_terms:
Address;Base Sequence;Biological;Biomedical Research;Computer software;DNA;DNA Repair;Detection;Effectiveness;Faculty;Funding;Gene Expression;Gene Expression Regulation;Genes;Goals;Grant;Hormones;Hour;Housing;Injury;Malignant Neoplasms;Methods;Minor;Mutagenesis;Neurobiology;Nucleic Acids;Nucleic acid sequencing;Oxidants;Polymerase Chain Reaction;Postdoctoral Fellow;RNA analysis;Regulations Drug;Research;Research Personnel;Research Project Grants;Resources;Sampling;Science;Science of Anatomy;Single Nucleotide Polymorphism;Stress;Students;Study Interdisciplinary;System;Technology;Time;Tissues;Today;Toxicology;Training;Transcript;Universities;Women's Health;health science research;hormone regulation;improved;instrument;nucleic acid quantitation;public health medicine (field);research facility;tissue preparation;tumor


application_id: 7388271
project_number: 5T32HL072743-05
project_title: Interdisciplinary Cardiovascular Training Program
project_terms: Cardiovascular system;Training Programs
administering_ic: NHLBI
award_notice_date: 2008-02-27
application_type: 5
activity_code: T32
ic: HL
serial_number: 072743
program_official: SCOTT, JANE
project_start_date: 2004-04-01
project_end_date: 2009-04-30
study_section: ZHL1-CSR-G(F1)
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The purpose of this training program is to prepare physicians and bio-medical scientists for academic careers in cardiovascular research.  The theme that permeates this program is that students must be offered both a breadth of exposure and a depth of expertise to acquire the essential aptitude and tools to thrive in an aggressive academic environment.  Each of the 24 training faculty has on-going federal and other research funding collectively totaling $22 million direct cost dollars annually.  They come from four colleges two centers ten departments and the Gill Heart Institute.  One of the distinctive strengths of our instructional team and therefore of this program is that these individuals have a long and well-documented history of collaboration in graduate-training and in the development and maintenance of supplemental training opportunities. Trainees will be recruited from the Integrated Biomedical Sciences program and from other participating academic units.  A curriculum that emphasizes cross-fertilization between the clinical and basic sciences will be provided.  Members of our faculty have an established history of recruiting and training minority students and particular attention will be given to continuing this commitment.  The didactic experience will include formal course work including an opportunity to enroll in a closely mentored scientific writing class and mentored participation in weekly journal clubs topical seminar series and Gill Heart Institute programs.  Research training is the backbone of this program.  Trainees will choose from four areas of research that seek to elucidate the mechanisms of arrhythmogenesis BP regulation/hypertension endothelial function/atherosclerosis and ischemic heart disease/cardiac myocyte dysfunction.  The proposed program provides a setting that will increase the effectiveness and efficiency of our on-going multi-disciplinary approach to graduate education in the cardiovascular sciences.


application_id: 7388148
project_number: 5R01HL086450-02
project_title: An Intervention for Promoting Smoke-free Policy in Rural Kentucky
administering_ic: NHLBI
award_notice_date: 2008-03-13
opportunity_number: PAR-06-039
application_type: 5
activity_code: R01
ic: HL
serial_number: 086450
program_official: JOBE, JARED B
project_start_date: 2007-04-01
project_end_date: 2012-02-28
study_section: Special Emphasis Panel[ZRG1-HOP-S(50)R]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Air;Cessation of life;Clip;Communities;Controlled Study;County;Daily;Diffusion of Innovation;Disease;Educational aspects;Elements;Environment;Experimental Designs;Exposure to;Goals;Health;Intervention;Kentucky;Knowledge;Laws;Life;Maintenance;Measures;Media Printed;Modeling;NIH Program Announcements;Newspapers;Non-smoker;Outcome;Policies;Population;Public Health Practice;Purpose;Rate;Readiness;Research;Resources;Rural;Rural Community;Science;Smoke;Staging;Telephone Interviews;Testing;Time;Tobacco use;Translating;base;community intervention;contextual factors;implementation research;innovation;outreach;public health medicine (field);public policy on tobacco;tobacco control;trend;urban area


application_id: 7387504
project_number: 1R01NS055228-01A2
project_title: Multiple circadian oscillators: Regulation of a neuroendocrine rhythm
administering_ic: NINDS
award_notice_date: 2007-12-07
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: NS
serial_number: 055228
suffix: A2
program_official: MITLER, MERRILL
project_start_date: 2007-12-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1 IFCN-D (02)]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: LEGAN, SANDRA J.
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
project_terms:
Affective;Aging;Area;Attention;Biological Models;Brain;Brain region;Cardiovascular Diseases;Cell Line;Cells;Circadian Rhythms;Cognitive deficits;Depression Postpartum;Disruption;Endocrine;Estrous Cycle;Exhibits;Female;Frequencies (time pattern);GABA-A Receptor;Gender;Gene Expression;Generations;Genes;Goals;Gonadotropin Hormone Releasing Hormone;Gonadotropins;Hamsters;Hormones;In Vitro;Individual;Jet Lag Syndrome;Luteinizing Hormone;Measures;Mental Depression;Modeling;Molecular;Mood Disorders;Morbidity - disease rate;Mus;Mutate;Mutation;Neuroendocrine Cell;Neurons;Neurosecretory Systems;Output;Pacemakers;Pathway interactions;Pattern;Peripheral;Phase;Phenobarbital;Physiological;Postmenopause;Property;Quality of life;Regulation;Reproduction;Role;Signal Transduction;Site;Structure of suprachiasmatic nucleus;Syndrome;Time;Tissues;Transfection;Vasopressins;Woman;Work;aged;base;circadian pacemaker;improved;in vivo;male;obesity risk;receptor;shift work;transmission process


application_id: 7387407
project_number: 5R01HL084611-03
project_title: Role of the Nuclear Receptor Nor-1 in Atherosclerosis and Vascular Injury
administering_ic: NHLBI
award_notice_date: 2008-04-24
application_type: 5
activity_code: R01
ic: HL
serial_number: 084611
program_official: SRINIVAS, POTHUR R
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): The evolving understanding of mechanisms contributing to the development of atherosclerosis and neointima formation following vascular injury has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation and proliferation. Although much attention has focused on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies the nuclear receptor superfamily comprises a large number of so-called orphan nuclear receptors whose target genes and physiological functions are unknown and remain to be discovered.   
  
The neuron-derived orphan receptor-1 (Nor-1) is a constitutively-active transcription factor belonging to the nuclear hormone receptor superfamily. Our Preliminary Data identified Nor-1 expression in human atherosclerotic lesions and in the developing neointima following vascular injury. In response to growth factor stimulation vascular smooth muscle cells (SMC) rapidly express Nor-1 characterizing this nuclear receptor as an early response gene. Experiments using SMC isolated from Nor-1 deficient mice further reveal that Nor-1 expression is required for SMC proliferation cell cycle progression and telomerase activity.   
  
Based on these findings the central hypothesis of this proposal is that Nor-1 functions as a transcriptional regulator of SMC proliferation and thereby contributes to the development of atherosclerosis and neointima formation following vascular injury.   
  
To test this hypothesis we propose the following aims: Specific Aim 1: To determine the transcriptional regulation of Nor-1 expression in SMC. Specific Aim 2: To determine the molecular mechanisms by which Nor-1 regulates SMC proliferation. Specific Aim 3: To determine the contribution of Nor-1 to the development of atherosclerosis by cross- breeding Nor-1 deficient mice to atherosclerosis-susceptible apoE-deficient mice. Specific Aim 4: To determine the contribution of Nor-1 to neointima formation using a model of guide-wire induced femoral artery injury in Nor-1 deficient mice.   
  
Ultimately these experiments may characterize a novel transcriptional pathway regulating SMC proliferation in vascular disease and identify suppression of the nuclear receptor Nor-1 as a previously unrecognized target for the treatment of cardiovascular diseases.

project_terms:
Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Blood Vessels;Breeding;Cardiovascular Diseases;Cell Cycle Progression;Cell Proliferation;Data;Development;ERG gene;Failure (biologic function);Figs - dietary;Functional disorder;Gene Expression;Gene Targeting;Growth Factor;Human;Inflammation;Injury;Ligands;Liver;Modeling;Molecular;Mus;Muscle Cells;Myocytes Smooth Muscle;Neurons;Nuclear;Nuclear Hormone Receptors;Nuclear Orphan Receptor;Nuclear Receptors;Numbers;Orphan;Pathogenesis;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Physiological;Play;Process;Role;Structure of femoral artery;Telomerase;Testing;Transcriptional Regulation;Treatment Failure;Vascular Diseases;base;member;neointima formation;novel;prevent;programs;receptor;research study;response;restenosis;transcription factor


application_id: 7387045
project_number: 1R21DE018177-01A1
project_title: Analyses of Host-Biofilm Interactions: A Novel Polymicrobial Model
administering_ic: NIDCR
award_notice_date: 2008-02-12
opportunity_number: PA-06-210
application_type: 1
activity_code: R21
ic: DE
serial_number: 018177
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2008-03-01
project_end_date: 2010-02-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1880406
contact_pi: NOVAK, KAREN F.
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
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis represents the most broadly distributed polymicrobial disease of mankind. The tissue destructive processes that lead to loss of function of periodontal soft tissues and alveolar bone result from a chronic polymicrobial biofilm activation of host inflammatory innate immune and adaptive immune responses in the local tissues. Development of the polymicrobial biofilm is a sequential process that begins with deposition of host and bacterial glycoproteins onto the clean tooth surface. Initial colonization by oral microorganisms occurs next with oral streptococci being the primary early colonizers. This initial colonization by streptococci is followed by increasing proportions of Actinomyces Veillonella and Fusobacterium spp. (middle colonizers) with subsequent colonization predominated by Gram-negative anaerobic bacteria (late colonizers). This shift from a predominance of Gram-positive facultative microorganisms to a microbiota dominated by Gram- negative anaerobic species is manifest clinically by inflammatory changes in the periodontal tissues as the host responds to this microbial challenge. It has been proposed that this multicellular bacterial-host interaction possesses unique features compared to planktonic bacterial infectious challenges; however there is little objective evidence to support this contention. This R21 exploratory/development grant will specifically focus on developing this evidence using a novel polymicrobial biofilm model. The General Hypotheses to be tested are: (1) Oral bacteria in biofilms will elicit different patterns of host responses from gingival epithelial cells; and (2) Host cells will respond differently to bacterial species present as monospecies versus multispecies biofilms. We have developed a novel in vitro biofilm-host cell model system using a rigid gas permeable contact lens material. In Specific Aim 1 we will determine the characteristics of single species and multispecies biofilms created on this material. The biofilms developed in this model system will then be used in Specific Aim 2 to challenge oral epithelial cells allowing us to characterize the patterns of responses elicited in these host cells by the bacterial challenge. In accomplishing these aims we will have developed a novel approach for evaluating host response patterns to planktonic single species biofilm and polymicrobial biofilm challenges. The results obtained will enable us to provide seminal data to enable a further exploration of host responses to biofilms of various compositions and complexities. The bacteria found in dental plaque biofilms interact with tissues supporting the teeth to initiate an inflammatory response. The clinical diseases associated with this inflammatory response are gingivitis and/or periodontitis. However the exact host responses elicited by this interaction have not been determined. We are developing an in vitro model of this interaction to gain a better understanding of the pathologenesis of gingivitis and periodontitis. This understanding is necessary to develop and evaluate new strategies for controlling the destructive features of these chronic inflammatory diseases.

project_terms:
Actinobacteria class;Actinomyces;Address;Adherent Culture;Area;Bacteria;Biological;Biological Markers;Biological Models;Biological Process;Body Surface;Cell Culture System;Cell model;Cells;Characteristics;Chronic;Clinical;Complex;Contact Lenses;Contact Lenses Extended-Wear;Coupled;DNA;Data;Dental Plaque;Deposition;Depth;Development;Disease;Disinfection;Disorder by Site;Documentation;Ecology;End Point;Epithelial;Epithelial Cells;Evaluation;Fibroblasts;Fusobacteria;Fusobacterium;Gases;Genes;Gingiva;Gingivitis;Glycoproteins;Gram-Negative Anaerobic Bacteria;Grant;Harvest;Health Transition;Human;Immune;Immune response;Immunity Natural;Immunologics;In Situ;In Vitro;Individual;Infection;Inflammatory;Inflammatory Response;Knowledge;Lead;Lesion;Literature;Lymphocyte;Metabolic;Microbial Biofilms;Microscopy Confocal;Modeling;Nature;Numbers;Nutrient;Oral;Oral cavity;Pattern;Periodontal Diseases;Periodontitis;Polymerase Chain Reaction;Polymers;Principal Investigator;Process;Proteins;Reproducibility;Research;Research Design;Resistance Antibiotic;Seminal;Silicones;Site;Standards of Weights and Measures;Stimulus;Streptococcus;Structure;Suspension substance;Suspensions;System;Testing;Time;Tissues;Tooth eruption;Tooth structure;Variant;Veillonella;alveolar bone;base;cell type;commensal microbes;copolymer;in vitro Model;innovation;lens;loss of function;macrophage;microbial;microorganism;novel;novel strategies;oral bacteria;oral biofilm;oral streptococci;pathogen;programs;quorum sensing;response;size;soft tissue;subgingival biofilm;theories;tooth surface


application_id: 7387025
project_number: 1R21AA016307-01A2
project_title: Neurogenesis and neurodegeneration in adolescent binge alcohol exposure
administering_ic: NIAAA
award_notice_date: 2008-03-18
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: AA
serial_number: 016307
suffix: A2
program_official: NORONHA, ANTONIO
project_start_date: 2008-03-20
project_end_date: 2010-02-28
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Adolescence is a time when many individuals begin to experiment with alcohol. Alcohol abuse and alcohol dependence collectively termed alcohol use disorders are diagnosed in ~6% of adolescents and result in significant neuropsychological and/or cognitive deficits. As many as half of all high school students may currently drink alcohol and up to 70% of those students are binge drinkers. Considering that binge drinking is one of the factors that predicts brain damage from alcohol understanding the impact of binge drinking on adolescent brain structure is an important public health concern. The neuroanatomical consequences of adolescent drinking are not well described though two studies have shown hippocampal volume reductions in adolescents with alcohol use disorders. This finding confirmed behavioral and neurophysiological work in animal models that the adolescent hippocampus is targeted by alcohol. However no one has examined whether alcohol directly produces neurodegeneration in the adolescent rat or the basic mechanism of cell or neuron reduction. The recent discovery that neural stem cells contribute to ongoing neurogenesis and to hippocampal structure suggests a novel potential mechanism of neurodegeneration alcohol-induced  
neurodegeneration. Thus this application will test the overall hypothesis that binge alcohol exposure in the adolescent rat alters neural stem cells and neurogenesis to produce neurodegeneration. Three specific aims will address this hypothesis in an in vivo rat model of an adolescent alcohol use disorder by (1) investigating the effects of adolescent binge alcohol administration on the components of neurogenesis (2) determining the mechanism by which alcohol intoxication inhibits neural stem cell proliferation and (3) evaluating whether changes in neurogenesis are associated with neurodegeneration (net reduction of cells) in the hippocampal dentate gyrus. Within each aim important questions regarding the contribution of alcohol dose or duration necessary to alter the components of neurogenesis and the contribution of cell death will be investigated. Understanding the mechanism of alcohol-induced effects on neural stem cells and dentate gyrus granule cell loss forms a solid foundation to investigate the differential sensitivity of the adolescent brain to alcohol effects and the dynamic role of both cell death and cell birth mechanisms in neurodegeneration.

project_terms:
Acute;Address;Adolescence;Adolescent;Adult;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic Intoxication;Alcohols;Animal Model;Area;Behavioral;Birth;Blood alcohol level measurement;Brain;Brain Injuries;Cell Cycle;Cell Death;Cell Death Inhibition;Cell Differentiation process;Cell Proliferation;Cell Survival;Cells;Chronic;Cognitive deficits;Condition;Data;Diagnosis;Dose;Ethanol;Exploratory/Developmental Grant;Fibrinogen;Foundations;Future;Generations;Hippocampus (Brain);Human;Impairment;Individual;Killings;Modeling;Mosses;Nerve Degeneration;Neurons;Numbers;Population;Process;Publishing;Rattus;Research;Rodent Model;Role;Science of Chemistry;Science of neurophysiology;Solid;Stem cells;Structure;Structure of dentate gyrus;Students;Testing;Time;Tissues;Uridine;Work;alcohol effect;alcohol exposure;alcohol use disorder;base;binge drinker;binge drinking;cognitive function;cooking;experience;granule cell;high school;in vivo;mature animal;migration;nerve stem cell;neurogenesis;neuron loss;neuropsychological;novel;problem drinker;public health medicine (field);research study;underage drinking


application_id: 7386754
project_number: 5R21HD050564-02
project_title: Urinary proteomics in aminoglycoside treated newborns
administering_ic: NICHD
award_notice_date: 2008-03-15
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: HD
serial_number: 050564
program_official: GIACOIA, GEORGE
project_start_date: 2007-04-01
project_end_date: 2009-03-31
study_section: Urologic and Kidney Development and Genitourinary Diseases Study Section[UKGD]
contact_pi_person_id: 7861170
contact_pi: KENNEDY, MARY JAYNE
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): Aminoglycosides (AG) are frequently administered to newborns for treatment of bacterial infection. Despite serum concentration monitoring and extended-interval dosing a significant number of newborns develop renal insufficiency as a consequence of AG therapy. The postnatal development of the kidney may also be impacted by AG-induced changes. Early identification of these changes is therefore important. While various urinary markers have been used to detect changes in tubular function they are neither sensitive nor specific for AG and development of additional biomarkers is needed. Proteomics is a tool to separate and identify differentially expressed proteins that may serve as candidate markers of toxicity and this technique can be used to investigate effects of AG on urinary protein expression. The broad long-term objective of this research is to develop a tool for early detection of nephrotoxicity in AG-treated newborns via a phased development program. The primary objectives of this application are to identify candidate urinary protein markers of AG-induced toxicity and prioritize candidates based on their discriminatory ability. An exploratory objective is to characterize potential long-term effects of early postnatal AG on renal function. The central hypotheses of this proposal are as follows: (1) The urinary protein expression profile in newborns with AG-induced nephrotoxicity differs from that in treated infants without nephrotoxicity and (2) Differentially expressed urinary proteins and/or protein groups can discriminate between AG-treated newborns with and without nephrotoxicity. These hypotheses will be tested by addressing the following specific aim: Characterize the urinary protein expression profile in AG-treated newborns with and without nephrotoxicity. We have developed techniques to isolate proteins from urine that are well suited for use in newborns and these techniques will be used to create databases of proteins expressed in AG-treated newborn urine. The outcomes of the proposed research will provide important new information regarding effects of the AG on the urinary proteome. Identification of regulated proteins may also reveal candidate markers that can be investigated as part of a phased development plan in further hypothesis-driven research (i.e. R01). If we identify discriminatory proteins we can develop a clinical assay to measure the protein(s) of interest and subsequently assess diagnostic performance. This information may allow us to develop a screening tool to facilitate early diagnosis of AG-induced toxicity that is superior to the current standards of care (serum creatinine and AG levels). The proposed research is directly responsive to the mission of the agency in that it utilizes an "innovative research strategy" to identify potential markers of AG-induced renal damage that may ultimately be used to protect infants. It is also relevant to public health given that the AG are among the most common drugs given to newborn infants. The results of this research may allow us to identify infants who are at risk for developing significant injury before it occurs.

project_terms:
Address;Age;Aminoglycosides;Animal Model;Antibiotics Aminoglycoside;Bacterial Infections;Biological Assay;Biological Markers;Caring;Clinical;Creatinine;Databases Protein;Development;Diagnosis;Diagnostic;Dose;Drug Kinetics;Early Diagnosis;Early identification;Evaluation;Failure (biologic function);Gene Proteins;Incidence;Infant;Infant Newborn;Injury;Intervention;Invasive;Kidney;Kidney Failure;Life;Long-Term Effects;Markers Biochemical;Measures;Mission;Mitochondria;Molecular Profiling;Monitor;Numbers;Outcome;Patients;Performance;Pharmaceutical Preparations;Phase;Phospholipid Metabolism;Plans Development;Polyacrylamide Gel Electrophoresis Two-Dimensional;Predictive Value;Process;Program Development;Protein Biosynthesis;Proteins;Proteome;Proteomics;Renal function;Research;Research Personnel;Respiration;Risk;Screening procedure;Serum;Severities;Spectrum Analysis Mass;Standards of Weights and Measures;Structure;Techniques;Testing;Tissues;Toxic effect;Tubular formation;Urine;base;comparative;innovation;interest;nephrogenesis;nephrotoxicity;postnatal;programs;prospective;protein expression;public health medicine (field);tool;urinary


application_id: 7386614
project_number: 5R21DE017160-02
project_title: Infrared spectroscopy as a novel diagnostic tool for periodontitis
administering_ic: NIDCR
award_notice_date: 2008-02-28
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: DE
serial_number: 017160
program_official: KUSIAK, JOHN W
project_start_date: 2007-03-20
project_end_date: 2009-08-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis is a common destructive disease of the supporting structures of the teeth; a risk factor for serious systemic diseases including vascular diseases and lung diseases; and an enormous consumer of American health dollars (>$14 billion / year). However diagnosis of periodontitis is problematic. Due to the complex nature of periodontitis we predict that a global approach to the measurement of disease processes may be required to provide a diagnostic solution. We hypothesize that (1) The combination of tissue hemoglobin oxygenated hemoglobin tissue oxygenation and perfusion tissue hydration and tissue temperature will provide a robust indicator of periodontal inflammation with site-specific diagnostic potential; and that (2) Global profiling of gingival crevicular fluid (GCF) constituents which reflect underlying periodontal disease processes will lead to the generation of accurate and testable diagnostic algorithms that will differentiate healthy gingivitis and periodontitis sites. Near Infrared Spectroscopy (NIRS) can simultaneously monitor multiple inflammatory indices non- invasively. Mid-Infrared spectroscopy (MIRS) can be used to generate molecular and sub- molecular profiles of biological fluids. Therefore we plan to use infrared technology to obtain diagnostic fingerprints of periodontal tissues and fluids. State-of-the-art approaches to the extraction of clinically significant data from IR spectra will allow us to (A) Correlate each principle component (source of spectral variation) to key clinical data (including standard inflammatory measurements and measurements of tissue destruction); and (B) Determine the percentage accuracy of NIRS- and MIRS-algorithms in diagnosing periodontal diseases along with the sensitivity specificity and positive and negative predictive values. The successful completion of this research plan will pave the way for the long-term goal of delivering IRS- based technology that reliably measures periodontal tissue status and represents a simple reproducible reagent-free real-time diagnostic device for the dental clinic or periodontal operatory. IR spectroscopy may also provide standardized inflammatory measurements - an invaluable but so far elusive research tool for periodontics. The successful development of IR-based imaging techniques can have a revolutionary effect on our approach to the diagnosis of periodontal diseases and a profound effect on the distribution of oral health expenditures. Diagnosis of periodontitis is problematic. Therefore we hope to test the potential of infrared spectroscopy as a diagnostic tool in periodontics. The long-term goal of this research project is to deliver an IRS-based technology that reliably measures periodontal tissue status and represents a simple reproducible reagent-free real-time diagnostic device for the dental clinic or periodontal operatory.

project_terms:
Address;Algorithms;American;Arts;Biological;Biological Markers;Bone and Bones;Burn injury;Carbohydrates;Classification;Clinical;Clinical Data;Collagen;Complex;Condition;Cytochromes;DNA;Data;Dental Clinics;Depth;Development;Devices;Diagnosis;Diagnostic;Diagnostic Procedure;Disease;Disease susceptibility;Economic Burden;Edema;Electromagnetics;Environmental Risk Factor;Enzymes;Fetal Lung;Fibronectins;Fingerprint;Forecast of outcome;Future;General Population;Generations;Genetic;Gingiva;Gingival Crevicular Fluid;Gingival Indexes;Gingivitis;Goals;Health;Health Expenditures;Hemoglobin;Hemorrhage;Hydration status;Imaging Techniques;Immune;In Vitro;Inflammation;Inflammatory;Invasive;Lead;Lesion;Lipids;Liquid substance;Lung diseases;Masks;Measurement;Measures;Mediator of activation protein;Metabolic;Methodology;Methods;Microbial Biofilms;Molecular;Molecular Profiling;Monitor;Myoglobin;Nature;Oral health;Pattern Recognition;Perfusion;Periodontal Diseases;Periodontal Pocket;Periodontic specialty;Periodontitis;Periodontium;Predictive Value;Process;Proline;Protein Structure Secondary;Proteins;RNA;Range;Reagent;Research;Research Project Grants;Risk Factors;Screening procedure;Secondary to;Sensitivity and Specificity;Severities;Site;Skin;Solutions;Source;Spectroscopy Near-Infrared;Spectrum Analysis;Standards of Weights and Measures;Surgical Flaps;System;Systemic disease;Techniques;Technology;Temperature;Testing;Time;Tissues;Tobacco smoking;Tooth Loss;Tooth Tissue;Upper arm;Variant;Vascular Diseases;Vibration - physical agent;Water;Wound Healing;alveolar bone;base;bone loss;clinically significant;data mining;functional group;hemodynamics;in vivo;indexing;infrared spectroscopy;innovation;mid infrared spectroscopy;novel diagnostics;pathogen;prognostic;research study;soft tissue;tissue oxygenation;tool


application_id: 7386602
project_number: 5R01AG025047-09
project_title: Neuroendocrine mechanisms of reproductive aging
administering_ic: NIA
award_notice_date: 2008-02-25
application_type: 5
activity_code: R01
ic: AG
serial_number: 025047
program_official: SUNEJA, SANOJ
project_start_date: 1999-06-01
project_end_date: 2010-03-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1891759
contact_pi: JENNES, LOTHAR H
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: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): The overall goals of the proposed research are to determine the changes that occur in the brain during reproductive aging and to reveal the underlying mechanisms that cause a gradual decline in the regularity of the estrous cycle which is followed by a complete cessation of cyclicity in the middle-aged female mouse. The central hypothesis to be tested is that while circulating estradiol levels are normal or slightly elevated in the middle-aged mouse the steroid signal does not reach the GnRH neurons which leads to a low preovulatory LH surge and to an irregular length of the estrous cycle. The present proposal focuses on the glutamatergic neurotransmitter system because it stimulates GnRH releaseit is at least in part regulated by estradiol and its activity or effectiveness is decreased in the middle-aged animal. In addition changes in gene expression in GnRH neurons will be determined during reproductive aging. Specifically  Aim 1: will test the hypothesis that the glutamatergic system does not respond to gonadal steroids during reproductive senescence;  Aim 2: will test the hypothesis that the glutamatergic innervation of GnRH neurons is altered or ineffective during reproductive senescence which leads to a reduced activation of the GnRH neurons during the steroid-induced surge;  Aim 3: will identify changes in gene expression of GnRH neurons changes during reproductive aging.   The proposed studies will provide comprehensive information on the changes that occur in the regulatory input to the GnRH neurons during reproductive aging and will determine which estradiol receptor mediates these changes. A detailed knowledge of these events will help to identify some of the basic mechanisms which underlie the inappropriate interactions between the brain and the ovaries and may provide clues for treatment of disorders that are caused by a central failure to maintain adequate GnRH release.

project_terms:
Age;Aging;Agonist;Animals;Attenuated;Brain;Cells;Data;Diestrus;Disease;Effectiveness;Estradiol;Estradiol Receptors;Estrogen Receptors;Estrous Cycle;Event;Failure (biologic function);Female;Follicle Stimulating Hormone;Funding;Gene Expression;Gene Expression Profile;Genes;Glutamates;Goals;Gonadal Steroid Hormones;Gonadotropin Hormone Releasing Hormone;Hormones;Hypothalamic structure;Knowledge;Length;Literature;Luteinizing Hormone;Measures;Mediating;Mus;Neurons;Neurosecretory Systems;Neurotransmitters;Ovary;Ovulation;Pattern;Periodicity;Pituitary Gland;Proestrus;RNA Messenger;Research;Research Personnel;Rodent;Role;Signal Transduction;Steroids;System;Testing;base;juvenile animal;middle age;nerve supply;noradrenergic;programs;receptor;reproductive;research study;response;senescence


application_id: 7386484
project_number: 1R21HL089372-01A1
project_title: Oxidoreductase Activity of the Beta Subunit of Kv Channels
administering_ic: NHLBI
award_notice_date: 2008-01-08
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: HL
serial_number: 089372
suffix: A1
program_official: WANG, LAN-HSIANG
project_start_date: 2008-01-15
project_end_date: 2009-12-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 8759282
contact_pi: BARSKI, OLEG 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
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to define the catalytic properties of the -subunit of the voltage-sensitive potassium channel (Kv). The Kv channels regulate cell excitability and have been shown to play an important role in oxygen-sensing volume regulation memory and learning. The Kv proteins are ancillary proteins that associate with the cytoplasmic domain of Kv channels but no clear physiological function has been assigned to these proteins. Structural and sequence analyses show that Kv proteins are members of the aldo-keto reductase superfamily. Our central hypothesis is that the Kv proteins catalyze the reduction of endogenous carbonyls whereby they impart redox sensitivity to Kv currents. Such regulation may be an important feature of oxygen-sensing or metabolic dependence of Kv currents. To test this hypothesis we will measure the catalytic efficiency of Kv proteins with endogenous substrate series consisting of prostaglandins steroids metabolites of neurotransmitters and lipid peroxidation products. We will also test whether assembly of Kva- complexes enhance enzymatic activity of Kv and determine the sequence and rate-limiting step in its catalytic cycle (Aim 1). To determine whether the endogenous carbonyls utilized by Kv in biochemical experiments are also functionally active we will examine the ability of the most efficient series to alter the voltage-sensitivity and the kinetics of Kva- channels expressed in COS-7 cells (Aim 2). Results of these experiments will allow us to distinguish whether nucleotide binding itself catalytic cycle or binding of ligands which can serve as pharmacologic agents modulate Kv inactivation. Taken together the findings of this study will provide a better understanding of the catalytic and ligand binding properties of Kv and form the basis of a more in-depth project to examine the in vivo role of Kv catalysis and its putative role in regulating surface excitability oxygen-sensing or encoding memory. Results of these studies could also form the basis of developing pharmacological modulators of Kv-mediated changes in Kv current.

project_terms:
Action Potentials;Affinity;Apoptosis;Arrhythmia;Binding (Molecular Function);Biochemical;COS-7 Cell;Catalysis;Cells;Clinical;Complex;Cytoplasmic Tail;Dependence;Depth;Epilepsy;Foundations;Goals;Hypertension Pulmonary;Immune System Diseases;Investigation;Isotopes;Kinetics;Lead;Learning;Learning Disabilities;Ligand Binding;Lipid Peroxidation;Measures;Mediating;Membrane Potentials;Memory;Metabolic;Metabolism;Neurotransmitters;Nucleotides;Oxidation-Reduction;Oxidoreductase;Oxygen;Patch-Clamp Techniques;Physiological;Play;Potassium;Potassium Channel;Property;Prostaglandins;Proteins;Rate;Reaction;Reagent;Regulation;Research;Rest;Role;Sequence Analysis;Series;Steroids;Surface;System;Testing;Volumes Cell;analog;base;carbonyl reductase (NADPH);in vivo;member;memory encoding;novel;porin;pyridine nucleotide;research study;voltage


application_id: 7386390
project_number: 1R03AA015964-01A2
project_title: Drugged Driving in Alcohol-restricted Rural Appalachia
administering_ic: NIAAA
award_notice_date: 2008-05-09
opportunity_number: PA-06-180
application_type: 1
activity_code: R03
ic: AA
serial_number: 015964
suffix: A2
program_official: BLOSS, GREGORY
project_start_date: 2008-05-10
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZRG1 HOP-X (04)]
contact_pi_person_id: 8335129
contact_pi: WEBSTER, JOHN MATTHEW
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The literature on drug-impaired driving has not experienced the same growth as the alcohol-related DUI literature despite the early and continued recognition that drug-impaired driving is a major public health concern. This application proposes a study to examine alcohol-impaired and drug-impaired driving in rural Appalachia a group of DUI offenders who are virtually unstudied. Although some counties in rural Appalachia allow alcohol sales (wet counties) several do not allow alcohol to be sold (dry counties) or limit alcohol sales to certain towns (moist counties). DUI remains a frequent crime in rural Appalachia despite these differing levels of alcohol availability. The high rates of prescription drug abuse in rural Appalachia may contribute to the incidence of DUI in these areas. In this pilot study a sample of 120 rural Appalachian DUI offenders stratified by level of alcohol sales restriction (wet dry or moist county) will be interviewed. The specific aims for this project are to: (1) Describe individual characteristics of rural Appalachian DUI offenders including socio-demographic information alcohol and drug use histories attitudes and beliefs about alcohol and drug use and history of impaired driving; (2) Identify similarities and differences between individuals from rural Appalachian DUI offenders who have driven under the influence of drugs and rural Appalachian DUI offenders who have driven under the influence of alcohol but not drugs; and (3) Identify similarities and differences between rural Appalachian DUI offenders convicted in counties with varying levels of alcohol sales restriction. The overall aim of this project is to add to our understanding of alcohol- and drug-impaired driving in rural Appalachia. The long term objective of this project is to collect data to be used by this new investigator to develop a competitive R01 application to design and test a tailored intervention for rural Appalachian DUI offenders that equally addresses alcohol- and drug-impaired driving. More than 35 million Americans drive under the influence of alcohol or drugs per year. This project will collect information to compare alcohol-impaired drivers to drug-impaired drivers from rural Appalachia an understudied area yet known to have high levels of alcohol and prescription drug abuse. The long term objective of the project is to develop an intervention to reduce impaired driving in this area.

project_terms:
Address;Age;Alcohol consumption;Alcohols;American;Appalachian Region;Area;Attitude;Automobile Driving;Belief;Characteristics;Communities;County;Coupled;Crime;Data;Dependence;Depressed mood;Diet;Drug abuse;Drug abuser;Drug usage;Drunk driving;Educational aspects;Employment;Ethnicity aspects;Failure (biologic function);Gender;Growth;Health;Health Personnel;Health Services Accessibility;Health behavior;Incidence;Individual;Institutes;Intervention;Interview;Kentucky;Knowledge;Literature;Marital Status;Pain;Participant;Patient Self-Report;Pharmaceutical Preparations;Pilot Projects;Policies;Population;Population Density;Prevalence;Preventive;Publishing;Race;Rate;Readiness;Recording of previous events;Recruitment Activity;Reporting;Reporting Data;Research;Research Personnel;Rural;Rural Population;Safety;Sales;Sampling;Services;Substance abuse problem;Testing;Travel;United States Substance Abuse and Mental Health Services Administration;Urination;World Health Organization;alcohol abuse therapy;alcohol availability;alcohol measurement;base;convict;design;driving under influence;drug driving;experience;impaired driving performance;innovation;male;offender;prescription document;prescription drug abuse;prescription procedure;public health medicine (field);trafficking


application_id: 7385860
project_number: 5T32HL076138-05
project_title: Training Program in Transplantation
project_terms: Training Programs;Transplantation
administering_ic: NHLBI
award_notice_date: 2008-02-27
application_type: 5
activity_code: T32
ic: HL
serial_number: 076138
program_official: CHANG, HENRY
project_start_date: 2004-04-01
project_end_date: 2009-07-31
study_section: ZHL1-CSR-G(F1)
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Over the past 6 years a dynamic group of internationally recognized investigators in transplantation have been strategically recruited to the University of Louisville many as seasoned established teams.  This group is poised to establish a cutting-edge Postdoctoral Research Fellow gaining program in transplantation biology to educate the next generation of scientists.  This proposal directly addresses the mission of the NIH training grant program to help ensure that a diverse and highly trained workforce is available to assume leadership roles related to the nation's biomedical research agenda Trainees will undertake basic research with one or more faculty members and audit courses in immunology stem cell biology and transplantation.  Trainees must have either a Ph.D. in biochemistry immunology microbiology physiology genetics and related areas or a D.V.M. or M.D. and will be selected from applications received by faculty in this program.  Applicants will be required to submit a CV publication list 3 letters of recommendation and a statement of the specific research proposed.  A Training Committee comprised of the program Director and selected senior trainers will select the trainees from among these applications.  Trainees will prepare with their mentor a written training plan including coursework laboratory training and research description which will be reviewed and approved by the Training Committee.  The progress of trainees will be monitored by weekly meetings with one or more trainers presentation of the research results at the weekly seminar series and written annual reports for additional years of support.  Trainees will be expected to publish manuscripts regularly attend and present their work at research meetings and submit grant applications for external funding.  A central integrating focus of the training program will be the lecture series comprised of weekly laboratory seminars in transplantation immunology and stem cell biology; weekly joint immunology journal club; visiting professor series; transplant conference series; cancer center chemoattractant series; and the research seminar series.  These lectures not only provide an arena to develop presentation skills but also provide a venue in which experts in transplantation and related areas from throughout the world participate as speakers.      The faculty in this training program has the research background expertise and facilities to successfully conduct this program.  Well-equipped centrally-located laboratories exist at the Institute for Cellular Therapeutics Brown Cancer Center and Departments of Surgery Physiology Biophysics Medicine Molecular Biology Cardiology Pediatrics Biochemistry Pharmacology and Toxicology Ophthalmology Microbiology and Immunology Internal Medicine Pathology Neurological Surgery Anatomical Sciences Medical Ethics Biostatistics and Neurobiology.  Most trainers are also members of Institutes and Centers that serve to bring together multidisciplinary groups with interests that broadly complement transplantation. Postdoctoral fellows therefore have access to a wide variety of techniques and breadth of training experience. It is our goal that after 3 years of training trainees will be qualified to assume research positions related to transplantation and stem cell biology in industry academia and biotechnology.


application_id: 7385842
project_number: 5R01NS045734-05
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2008-03-10
application_type: 5
activity_code: R01
ic: NS
serial_number: 045734
program_official: KLEITMAN, NAOMI
project_start_date: 2004-05-03
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZRG1-CNNT(01)Q]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
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: 2008-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Contusive spinal cord injury (SCI) causes local endothelial cell damage resulting in vascular leakage and edema and the initiation of inflammation. These processes may lead to later tissue loss and functional deficits. Vascular endothelial growth factor (VEGF) is induced by SCI and may contribute to the leakage. VEGF may initiate detrimental processes as we have shown that VEGF injections after SCI in adult rats increases tissue loss seen at six weeks. Pharmacological inhibition of VEGF reduces edema inflammation and tissue loss in stroke models. Angiopoietin 1 (Ang1) induces vessel maturation and reduces leakage in many systems and is reduced after SCI. Therefore in aim la a VEGF trap and/or Ang1 will be administered early after SCI to test whether reduction of early leakage edema and inflammation reduces later loss of selected white matter tracts. In aim lb) the contribution of endothelial cell loss to secondary damage will be evaluated by protecting the cells with Ang1 plus VEGF or integrin agonist as these can promote endothelial cell survival in vitro. From 3-7 days after SCI an angiogenic response occurs in the injured cord. New vessels may counteract degeneration by increased tissue perfusion while their leakage may cause damage. Thus in aim 2a Ang1 will be administered during the angiogenic phase to promote maturation and maintenance of the new vasculature possibly resulting in better tissue protection. The new blood vessels regress between day 7 and 14 as secondary spinal tissue loss (cavitation) begins. This angiogenic failure may contribute to the secondary damage. In aim 2b the protective effects of maintaining the new blood vessels will be assessed by treating with Ang1 plus VEGF or Ang1 plus integrin agonist. The central hypothesis is that by enhancing stable and mature angiogenesis we will ultimately be able to reduce loss of important white matter tracts and improve functional sensory and motor outcome after SCI.

project_terms:
Acute;Adult;Agonist;Angiogenic Factor;Angiopoietin-1;Blood Vessels;Brain Ischemia;Cell Death;Cell Survival;Cells;Chest;Contusions;Drug Delivery Systems;Early treatment;Edema;Endothelial Cells;Event;Evoked Potentials;Extravasation;Failure (biologic function);Fiber;Growth Factor;In Vitro;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Integrins;Lead;Location;Maintenance;Modeling;Molecular;Monitor;Motor;Outcome;Perfusion;Phase;Process;Rattus;Secondary to;Sensory;Signal Pathway;Spinal;Spinal Cord;Spinal cord injury;System;Testing;Tissues;VEGF Trap;Vascular Endothelial Growth Factors;Week;angiogenesis;cell injury;day;dorsal column;functional loss;improved;injured;neuron loss;prevent;protective effect;response;sensory system;stroke;therapeutic target;white matter


application_id: 7385707
project_number: 7R01AI057808-04
project_title: Role of RANTES in Pneumococcal Immunopathogenesis
administering_ic: NIAID
award_notice_date: 2007-08-21
application_type: 7
activity_code: R01
ic: AI
serial_number: 057808
program_official: KHAMBATY, FARUKH M
project_start_date: 2004-08-01
project_end_date: 2008-05-31
study_section: Bacteriology and Mycology Subcommittee 2[BM-2]
contact_pi_person_id: 1860389
contact_pi: LILLARD, JAMES W
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-11-01
project_abstract:
DESCRIPTION (provided by applicant): Streptococcus pneumoniae infections are becoming increasingly difficult to manage due to the inability of susceptible individuals to mount appropriate anti -polysaccharide and to a lesser degree -surface protein antibody responses as well as increasing antibiotic resistance. Hence new prophylactic interventions and understanding of pneumococcal immunopathogenesis are greatly needed. This proposal stems from and focuses on our recent findings that RANTES (regulated on activation normal T cell expressed and secreted) significantly yet differentially enhances mucosal and systemic immunity. We present preliminary data that RANTES mRNA mucosal expression is elevated during the primary inflammatory/adaptive recognition response to pneumococcal carriage which suggests that RANTES is essential for protective mucosal immunity to S. pneumoniae infections. RANTES MIP-1alpha and CCR5 polymorphisms resulting in diminished expression are also associated with increased susceptibility to- and progression of- other mucosal pathogens in man. In this regard our preliminary results show that RANTES blockade leads to the transition of pneumococcal carriage to lethal pneumonia in a mouse model of carriage using S. pneumoniae strain EF3030. These findings provide the rationale to support the hypothesis that RANTES is essential for the induction of protective mucosal and systemic adaptive immunity against S. pneumoniae.  We have emphasized in vivo approaches using mouse models of pneumococcal -carriage and -pneumonia to test this hypothesis. Aim One will assess the recognition phase host immune response to EF3030 challenge in normal RANTES- or T cell- blocked mice. Aim Two will characterize the adaptive (activation/effector phase) mucosal and systemic immune responses to the phosphorylcholine determinant of C-polysaccharide (PC) and pneumococcal surface adhesin A (PsaA) during pneumococcal disease in control Ab-treated or RANTES-inhibited mice. Aim Three will ascertain the role of RANTES in protection against carriage and/or pneumonia induced by wild type mutant surface protein (e.g. psaA-) and rough EF3030 strains. This study will provide important and new information regarding the cellular and molecular mechanisms that RANTES uses to induce protective immunity against pneumococci.

project_terms:
Streptococcus pneumoniae;adhesin;bactericidal immunity;chemokine;cytotoxic T lymphocyte;enzyme linked immunosorbent assay;flow cytometry;genetically modified animals;helper T lymphocyte;humoral immunity;immune response;immunoglobulin A;immunopathology;interleukin 10;laboratory mouse;mucosal immunity;phosphorylcholine


application_id: 7385025
project_number: 5R01NS035102-14
project_title: Genotype/Phenotype Correlations in Williams Syndrome
administering_ic: NINDS
award_notice_date: 2008-09-18
application_type: 5
activity_code: R01
ic: NS
serial_number: 035102
program_official: MAMOUNAS, LAURA
project_start_date: 1996-05-17
project_end_date: 2010-03-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): Williams syndrome (WS) is a complex neurodevelopmental disorder characterized by mild to moderate mental retardation (MR) a distinctive personality profile an unusual cognitive profile infantile hypercalcemia dysmorphic facial features and supravalvar aortic stenosis (SVAS). Our research has demonstrated that WS is a contiguous gene disorder resulting from submicroscopic deletions of chromosome 7ql 1.23 including deletion of the elastin gene (causing SVAS connective tissue abnormalities and some facial features of WS) the LIM-kinase 1 gene (contributing to the visuospatial constructive cognitive difficulties of WS) and the GTF21 gene (implicated in the reduced general intellectual ability in WS). In addition we have identified a region of the WS deletion that is likely to include gene(s) that contribute to the WS personality profile. The overall goal of the proposed research is to create a medical and behavioral profile for WS that will then be used to examine genotype/phenotype correlations. We have three specific aims: 1) Ascertain and phenotypically characterize individuals who have WS and individuals who have features that overlap with WS. 2) Identify and characterize the cardinal features of the phenotype of classic WS. The medical phenotype will be characterized based on dysmorphology examination review of medical records and echocardiographic analysis. The neurobehavioral phenotype will be characterized based on psychological tests designed to measure general intelligence including strengths and weaknesses in particular aspects of cognition; specific tests of language memory and visuospatial abilities; and measures of personality temperament and adaptive behavior. 3) Identify genes responsible for specific phenotypic features of WS. Genetic analysis will include defining atypical deletion breakpoints screening genes in the region for mutations in specific populations (e.g.GTF21 mutations in nonspecific MR) determining parent of origin and inversion status to investigate the roles of these variables on the phenotype and testing of candidate genes for involvement in the pathogenesis and phenotypic variability of particular WS features. We expect to identify genes involved in WS personality characteristics and hypercalcemia and to characterize genetic modifying factors. The long term objective is to provide a better understanding of mechanisms underlying cognitive and personality development. The findings will be of immediate use to practitioners who provide educational and therapeutic services to individuals with WS and their families.

project_terms:
Affect;Aortic Valve Stenosis;Behavior;Behavioral;Behaviors Adaptive;Biological Assay;Candidate Disease Gene;Cardiovascular Surgical Procedures;Characteristics;Chromosome Deletion;Chromosomes;Clinical;Cognition;Cognitive;Complex;Connective Tissue;Correlation Studies;Development;Disease;Dysmorphology;Echocardiography;Elastin;Equilibrium;Face;Family;Fluorescent in Situ Hybridization;Foundations;Gene Deletion;Gene Expression;Gene-Modified;General Population;Genes;Genetic;Genetics Other;Genotype;Goals;Grant;Hypercalcemia;Hypertension;Individual;Infantile hypercalcemia;Intelligence;LIM Domain Kinase 1;Language Tests;Lead;Location;Maps;Measurement;Measures;Medical;Medical Records;Memory;Mental Retardation;Moderate Mental Retardation;Modification;Mutation;Neurodevelopmental Disorder;Parents;Pathogenesis;Personality;Personality Development;Phenotype;Physiology;Play;Point Mutation;Population;Psychological Tests;Reporting;Research;Role;Sampling;Screening procedure;Services;Temperament;Testing;Therapeutic;Visuospatial;Williams Syndrome;base;chromosome mutation;design;genetic analysis;insight;instrument;interest;neurobehavioral;research study;success;trait


application_id: 7385015
project_number: 5R01AI067869-02
project_title: YopM and protective innate defenses against plague
administering_ic: NIAID
award_notice_date: 2008-03-10
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 067869
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2007-03-16
project_end_date: 2012-02-29
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
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_terms:
Biology;CD8B1 gene;Cells;Classification;Cytokine Signaling;Data;Dendritic Cells;Down-Regulation;Effector Cell;Exposure to;Foundations;Human;Immune;Immune response;Infection;Interleukin-1;Interleukin-12;Interleukin-15;Interleukin-18;Lung;Maps;Mediating;Mice Knockout;Mus;Natural Killer Cells;Numbers;Parents;Pathway interactions;Plague;Pneumonic Plague;Population;Predictive Value;RNA Messenger;Reporting;Resistance;Signal Pathway;Signal Transduction;Spleen;T-Lymphocyte;T-Lymphocytes Cytotoxic;Testing;Therapeutic Intervention;Time;Toxin;Virulence;Virulent;Yersinia pestis;cDNA Arrays;chemokine;cytokine;insight;mRNA Expression;macrophage;microbial host;mouse model;mutant;neutrophil;pathogen;prevent;research study


application_id: 7383903
project_number: 5R01AI049367-07
project_title: Blockade of host apoptosis by Toxoplasma gondii
administering_ic: NIAID
award_notice_date: 2008-03-10
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 049367
program_official: WALI, TONU M
project_start_date: 2001-03-01
project_end_date: 2011-02-28
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Toxoplasma gondii infected cells exhibit a profound blockade of apoptosis that manifests at multiple points inthe apoptotic cascade. Our studies have shown an essential role for the hose transcription factor NFKB in theestablishment of the parasite-directed anti-apoptotic state. Activation of NFxB by diverse cellular pathwaysoccurs via the phosphorylation of specific Ser residues on its inhibitor kB. This phosphorylation event iscatalyzed by a unique cellular kinase complex defining the kB kinase signalosome (IKK). In T.gondiiinfected cells Phospho-kB localizes at the parasitophorous vacuole membrane (PVM) the oraganelledefining the intracellular replication-permissive niche. The detection of P-kBat the PVM in cells devoid of allIKK activity suggested the presence of a parasite-encoded kinase (TglKK) is responsible. We find just suchan activity in parasite extracts and PVM-enriched fractions. We focus here on identifying the gene(s)encoding the TglKK activity and examining its role both in NFxB activation and the blockade of apoptosis.Our data indicate that TglKK activity alone is not sufficient to drive NFKB gene expression in cells withdefects in IKK. Initial studies examining the temporal nature of NFxB activation reveal a biphasic pattern ofNFKB expression suggesting independent but temporally linked contributions of the host and parasite IKKactivities. We propose to use host cell lines with specific lesions in patheways upstream of IKK as well ascell lines "locked" into a defined expression profile to better characterize the pertinent cellular pathwayssubverted by T.gondii infection. Finally we have developed a genetic screen to identify parasite genesinvolved in NFKB activation. Initial results bear out the evidence that the mechanism to subvert NFKB ismultifactorial. Identification of these parasite genes and the elucidation of their roles in NFKB activation in thecontext of the studies on the cellular components will help define the signaling networks subverted by theparasite. Dissection of these pathways is particularly important given the targets of NFKB many of thecytokines implicated both in the pathogenesis of acute toxoplasmosis and the development of immunity tothe parasite.

project_terms:
Acute;Apoptosis;Apoptotic;Appendix;Arts;Biochemical Genetics;Biological;Biphasic Pattern;Cell Line;Cells;Complex;Cytoplasm;Data;Defect;Detection;Development;Dissection;Event;Exhibits;Gene Expression;Generations;Genes;Genetic Screening;I Kappa B-Alpha;IkappaB kinase;Immunity;Infection;Knock-out;Lesion;Link;Localized;Maps;Membrane;Molecular;Molecular Profiling;NF-kappa B;Nature;Organelles;Parasites;Pathogenesis;Pathway interactions;Phosphorylation;Phosphotransferases;Protein Isoforms;Regulation;Role;Signal Transduction;Technology;Toxoplasma gondii;Toxoplasmosis;Ursidae Family;Vacuole;base;cytokine;inhibitor/antagonist;mutant;pathogen;research study;success;transcription factor


application_id: 7383898
project_number: 5K02AI059023-05
project_title: T CELL ADJUVANTS FOR BIODEFENSE
administering_ic: NIAID
award_notice_date: 2008-03-03
application_type: 5
activity_code: K02
ic: AI
serial_number: 059023
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2004-03-01
project_end_date: 2009-02-28
study_section: Allergy, Immunology, and Transplantation Research Committee[AITC]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
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: 2008-03-01
project_abstract:
DESCRIPTION (provided by applicant): Significance of the research. Vaccination with recombinant proteins is the safest way to immunize people against biological weapons and infectious diseases. However the use of mild adjuvants with low levels of inflammatory side effects that make subunit vaccines desirable for immunization may also be responsible for their relatively poor efficacies. This is true because inflamed environments help promote the survival of activated T cells which in turn promote long-term immunity. It is proposed that identification and description of adjuvant mechanisms that promote T cell survival will improve biodefensive vaccine design by favoring ways to maximize antigen-specific T cell yield while limiting inflammation. Research goals. This K02 application is organized around two research goals to be pursued in tandem over the next five years. The award will make possible Dr. Mitchell's scientific direction of experiments designed to determine i) the mechanisms by which Toll-like receptor (TLR) adjuvants promote T cell immunity via interactions with antigen-presenting cells and ii) the signaling pathways in T cells that result from upstream interactions and that cause prolonged cellular survival. The hypothesis that TLR adjuvants boost the numbers of antigenspecific T cells by improving their survival through activities of the NF-kappaB/IkappaB factor Bcl-3 will be tested.  Multiple aspects of this hypothesis will be tested using mouse models of T cell responses and infectious disease microarray analyses retroviral gene transfer and biochemical analyses of experimentally modified T cells in order to rationally enhance the establishment of immunity. Career development. Dr. Mitchell was first trained as a virologist and then as a T cell immunologist. He has an eight year history of studying the effects of adjuvants on T cells and is poised to make significant advances in this subdiscipline. Career development will occur at the University of Louisville's Department of Microbiology and at the Institute for Cellular Therapeutics a center of excellence where the Mitchell laboratory is housed. The University of Louisville is a state-supported institution with a rapidly expanding basic research program. External salary support will lessen the load of non-research duties such that conceptual advances in vaccine design for biodefense can be made.

project_terms:
Adjuvant;Adverse effects;Antibodies;Antigen-Presenting Cells;Antigens;Award;Basic Science;Biochemical;Biological;Cell Survival;Cell division;Cells;Class;Clonal Expansion;Communicable Diseases;Condition;Development;Environment;Gene Transfer;Generations Future;Genetic;Goals;Growth Factor;Housing;I Kappa B-Alpha;Immune response;Immunity;Immunization;Immunologic Adjuvants;Immunologist;Infection;Inflammation;Inflammatory;Institutes;Institution;Laboratories;Ligands;Molecular;Mus;NF-kappa B;Numbers;Pathway interactions;Pattern;Property;Proteins;Receptors Immunologic;Recombinant Proteins;Recombinant Vaccines;Recording of previous events;Research;Research Personnel;Science of Microbiology;Signal Pathway;Signal Transduction;Specific qualifier value;T-Lymphocyte;Testing;Therapeutic;Toll-like receptors;Training;Universities;Vaccination;Vaccine Design;Vaccines;Vaccines Subunit;Vaccinia virus;Virus Diseases;Wages;Withdrawal;base;biodefense;career;daughter cell;design;improved;mimetics;mouse model;novel;pathogen;programs;receptor;research study;response;toll-like receptor 4


application_id: 7383824
project_number: 5R03DC007315-03
project_title: Neural Substrates of Component Lexical Semantic Processes
administering_ic: NIDCD
award_notice_date: 2008-03-12
opportunity_number: PAR-04-062
application_type: 5
activity_code: R03
ic: DC
serial_number: 007315
program_official: COOPER, JUDITH
project_start_date: 2006-04-01
project_end_date: 2010-03-31
study_section: ZDC1-SRB-Y(56)
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Extracting meaning from words (lexical semantics) is critical to normal language functioning. Lexicalsemantic impairment can result from a variety of causes including developmental abnormalities stroke anddegenerative diseases but may reflect damage to one or more component processes. Current languagemodels have identified two qualitatively different components of the lexical semantic system. (1) Anautomatic component enables rapid access to semantics within milliseconds of lexical input; (2) a controlledcomponent evolves more slowly and guides strategic retrieval of semantic information not recoveredautomatically. In addition some processes associated with these components are thought to depend uponthe modality of incoming stimuli. The objective of the project is to identify the neural correlates of thesebehaviorally separable automatic and controlled components of the lexical semantic system within andacross visual and auditory modalities. In a preliminary study we identified dissociable neural correlates ofvisually cued automatic and controlled lexical semantic processing in healthy volunteers using event-relatedfMRI and a primed lexical decision task. A series of similar studies are proposed to characterize moreprecisely the roles of several frontal and temporal lobe brain regions in components of the lexical semanticsystem. The design is novel in that automatic and controlled semantic priming conditions will becompareddirectly using randomized designs identical to those used in behavioral research. There are three goals. Thefirst goal is to characterize more precisely the role of a left frontal region in visually cued controlled retrievalof lexical semantic information. The second goal is to characterize more precisely the role of a left temporalregion in visually cued automatic lexical semantic processing. The third goal is to identify neural regionsinvolved in auditorily cued lexical semantics that overlap and are dissociable from those involved in visuallycued lexical semantics. Identifying neural systems associated with component processes involved inextracting meaning from words is of central importance to understanding the structure and organization ofthe lexical semantic system and should aid diagnosis and rehabilitation of language disorders.

project_terms:
Alzheimer's Disease;Anterior;Aphasia Wernicke;Auditory;Behavioral;Behavioral Research;Brain Injuries;Brain region;Condition;Cues;Degenerative Disorder;Development;Diagnosis;Event;Fusiform gyrus;Goals;Image;Impairment;Inferior;Knowledge;Language;Language Disorders;Left;Literature;Magnetic Resonance Imaging Functional;Modality;Modeling;Mosses;Occipital lobe;Patient observation;Patients;Prefrontal Cortex;Process;Randomized;Reading;Receptive aphasia (finding);Rehabilitation therapy;Research;Retrieval;Role;Semantic Dementias;Semantics;Series;Stimulus;Strikes Employee;Structure;System;Techniques;Temporal Lobe;Testing;Thinking function;Visual;auditory comprehension;base;design;healthy volunteer;hemodynamics;interest;lexical;lexical retrieval;millisecond;novel;relating to nervous system;response;semantic processing;stroke


application_id: 7383123
project_number: 5R01AI044254-08
project_title: Analysis of Borrelia burgdorferi Erp Proteins
administering_ic: NIAID
award_notice_date: 2008-03-28
application_type: 5
activity_code: R01
ic: AI
serial_number: 044254
program_official: BREEN, JOSEPH J
project_start_date: 2000-03-01
project_end_date: 2011-02-28
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-03-01
project_abstract:
Lyme disease is a significant threat to human health throughout many parts of the USA. The causativeagent Borrelia burgdorferi is maintained in nature by infectious cycles involving ticks and many species ofvertebrates with humans being incidental hosts. Understanding the mechanisms by which B. burgdorferiinfects humans and is transmitted from vector ticks will be important in development of improvedmethodologies to prevent and treat this disease. During transmission from tick to mammal 6. burgdorferisignificantly increases expression levels of the Erp family of outer surface proteins. Expression of Erpproteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferiencode multiple Erp lipoproteins a ubiquity that is highly suggestive of important roles for these proteins inB. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulatorfactor H in vitro raising the possibility that these proteins may function in vivo to protect the bacteria fromkilling by the host's innate immune system. Based on results of our previous studies we hypothesizethat Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processesand that these functions necessitate the bacteria regulate Erp expression. To test this hypothesiswewill (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erpmutants for their abilities to bind factor H resist complement-mediated killing and infect mice and ticks; (2)examine mechanisms by which B. burgdorferi controls Erp expression including innovative analyses oftranscription throughout mammalian and tick infection; and (3) characterize functions of the novelDMAbinding proteins we discovered that specifically bind to erp operator DMA. Results of our studies will provideimportant insight into the mechanisms by which B. burgdorferi infects humans.

project_terms:
Acute;Address;Animals;Area;Arthropods;Bacteria;Binding (Molecular Function);Binding Proteins;Biology;Borrelia burgdorferi;Chronic;Complement;Complement Factor H;Congenic Strain;DNA;DNA Sequence;DNA-Binding Proteins;Development;Disease;Environment Controlled;Family;Gene Expression;Genes;Health;Human;Immune system;Immunocompetent;In Vitro;Infection;Ixodes (genus);Killings;Lipoprotein (a);Lipoprotein (a-);Lyme Disease;Mammals;Maps;Mediating;Membrane Proteins;Methodology;Morbidity - disease rate;Multigene Family;Mus;Nature;Numbers;Operon;Order Spirochaetales;Pathogenesis;Plasmids;Process;Production;Protein Binding;Proteins;Regulation;Reporting;Research Design;Resistance;Rest;Role;Series;Signal Transduction;Techniques;Testing;Ticks;Tissues;Transcription Genetic;United States;Variant;Vertebrates;base;genetic manipulation;genetic regulatory protein;improved;in vivo;innovation;insight;member;mutant;prevent;tool;transmission process;vector


application_id: 7383113
project_number: 5R01AI065974-03
project_title: Molecular pathogenesis of Francisella tularnesis
administering_ic: NIAID
award_notice_date: 2008-03-28
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 065974
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2006-03-01
project_end_date: 2011-02-28
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The causative agent of the fatal disease Tularemia Francisella tularensis (Ft) is a gram negative highlyinfectious intracellular bacterium that is classified as a Category A Select Bioterrorism Agent. Intracellularreplication of Ft within macrophages is essential for disease manifestation. It is rather astonishing therelative paucity of knowledge about the molecular and cellular aspects of pathogenesis of this versatile andextremely virulent pathogen. Our preliminary data indicate that upon entry into macrophages Ft-containingphagosome (FCP) evades lysosomal fusion. The organism escapes from the phagosome into the cytoplasmby 2-12h post-infection. Our hypothesis is that specific modes of entry of Ft into macrophages allow theorganism to modulate biogenesis of its phagosome by specific exported bacterial effectors into a niche thatdoes not fuse to the lysosomes and allow subsequent escape of the organism into the cytoplasm where itreplicates. To test this hypothesis our specific aims are: I. To dissect the cell biology of intracellular F.tularensis and the unique mechanisms that halt phagosome biogenesis at a non-acidified late endosome-likestage. II. To identify mutants defective in arresting phagosome biogenesis and escape into the cytoplasm. . To characterize the bacterial factors involved in arresting phagosome biogensis and escape into thecytoplasm. Significance: Pathogenesis of the Category A Select Bioterrorism Agent Ft is one of the leaststudied and understood among intracellular bacterial pathogens. Understanding how this organism exploitsmacrophages for proliferation and disease manifestation is fundamental to our knowledge of tularemia. Thebacterial effectors involved in exploiting the macrophage are potential targets for treatment as well aspotential vaccine candidates.

project_terms:
Abbreviations;Adenylate Cyclase;Bacteria;Biogenesis;Biological;Bioterrorism;Categories;Cellular biology;Cytoplasm;Data;Degradation Pathway;Disease;Francisella;Francisella tularensis;Human;Infection;Knowledge;Lactate Dehydrogenase;Lactate Dehydrogenases;Lysosomes;Molecular;Nuclear;Organism;Ovalbumin;Pathogenesis;Pathogenicity Island;Phagosomes;Relative (related person);Route;Staging;Testing;Texas red;Therapeutic Intervention;Transmission Electron Microscopy;Tularemia;Vaccines;Vaccines Attenuated;Vacuole;Virulent;design;late endosome;lysosomal proteins;macrophage;monocyte;mutant;novel;pathogen;pathogenic bacteria;vaccination strategy


application_id: 7382504
project_number: 5R21AG029268-02
project_title: Mechanisms and use of antidiabetic agents in brain aging and Alzheimer's disease
administering_ic: NIA
award_notice_date: 2008-03-26
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AG
serial_number: 029268
program_official: PETANCESKA, SUZANA
project_start_date: 2007-04-01
project_end_date: 2010-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(91)S]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) the third most costly disease in the United States after cardiac disease and cancer has shown an increase in incidence recently moving from 7th to 5th as a leading cause of death among the elderly. Currently available medical strategies treat the symptoms rather than address the underlying processes responsible for the progressive decline in cognitive function seen in AD patients. However results from both clinical and basic science research suggest that antidiabetic agents (e.g. thiazolidinediones - TZDs) may be beneficial in the treatment of AD and a few human and animal studies have shown that use of rosiglitazone (a TZD) can improve memory and lead to cognitive improvements. These results appear to provide compelling preliminary evidence to support the use of antidiabetic drugs to combat the cognitive impairment associated with AD. However little is known about the underlying molecular mechanisms or about the identity of the CNS targets of TZDs. Some of the proposed beneficial effects of TZDs include reestablishment of insulin sensitivity and associated peripheral and/or CNS glucose utilization along with reductions in inflammatory cytokines Ab1-42 deposits microglial activation and intracellular Ca2+ levels. Given that Ca2+ dysregulation is considered a hallmark of brain aging and AD and is also present in animal models of diabetes we propose that some Ca2+ biomarkers of brain aging may be targets for intervention with TZDs. Using electrophysiological molecular and Ca2+ imaging techniques along with a team of qualified scientists this project will test the overall hypothesis that some TZDs can improve cognitive status in aged animals by reducing key biomarkers of brain aging and neurodegeneration in the hippocampus. We will determine the molecular bases underlying the potential use of TZDs for the treatment of AD by the following Specific Aims: 1) to test the hypothesis that TZDs act as neuroprotective agents by normalizing Ca2+ levels within neurons and/or glial cells; and 2) to test the prediction that in vivo TZD treatment can improve cognition in aged animals and restore Ca2+ homeostasis. Results form our studies may provide support for the therapeutic application of TZDs in preventing/retarding the cognitive decline seen in AD. Furthermore these studies will contribute to future drug discovery efforts to generate new TZD-derived or similar drugs for the treatment of AD.

project_terms:
24-thiazolidinedione;Action Potentials;Address;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Animal Model;Animals;Animals Laboratory;Anti-Inflammatory Agents;Anti-inflammatory;Antidiabetic Drugs;Basic Science;Biological Markers;Blood Vessels;Brain;Calcineurin;Cause of Death;Cell Survival;Clinical;Clinical Trials;Cognition;Cognitive;Condition;Cues;Cultured Cells;Deposition;Diabetes Mellitus;Diet;Disease;Elderly;Future;Glucose;Glutamates;Heart Diseases;Hippocampus (Brain);Homeostasis;Human;Image;Imaging Techniques;Impaired cognition;Incidence;Inflammation;Inflammatory;Insulin;Insulin Resistance;International;Intervention;Lead;Learning;Long-Term Potentiation;Malignant Neoplasms;Measures;Mediating;Medical;Memory;Modeling;Molecular;Molecular Target;Monitor;Nature;Nerve Degeneration;Neuroglia;Neurons;Neuroprotective Agents;Outcome;Pathway interactions;Patients;Performance;Peripheral;Permeability;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Pioglitazone;Pliability;Population;Process;Property;Qualifying;Rats Inbred F344;Recruitment Activity;Reporting;Research;Research Personnel;Risk;Risk Factors;Role;Ryanodine Receptor Calcium Release Channel;Scientist;Slice;Source;Specificity;Streptozocin;Symptoms;Techniques;Testing;Tests Mental;Therapeutic;Thiazolidinediones;Tissues;Toxic effect;United States;aged;aging brain;base;cell type;cellular targeting;cognitive function;cytokine;drug development;drug discovery;improved;in vivo;insight;insulin sensitivity;insulin sensitizing drugs;interdisciplinary approach;mature animal;mild cognitive impairment;morris water maze;neurotransmission;novel;novel therapeutics;prevent;programs;research study;rosiglitazone;symposium;synaptic function;young adult


application_id: 7382503
project_number: 5R01HL080609-03
project_title: Oxidant Mediated Diaphragm Dysfunction in Diabetes
administering_ic: NHLBI
award_notice_date: 2008-03-06
application_type: 5
activity_code: R01
ic: HL
serial_number: 080609
program_official: CROXTON, THOMAS
project_start_date: 2006-04-01
project_end_date: 2010-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-E(02)]
contact_pi_person_id: 6210708
contact_pi: CALLAHAN, LEIGH A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure aheightened risk of postoperative respiratory complications and a greater need for prolonged mechanicalventilation. However it is not known how diabetes produces these problems. One potential explanation isthat uncontrolled diabetes alters respiratory muscle function reducing the capacity of the respiratory pump.The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlleddiabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in thefollowing groups of studies. Aim I studies will characterize the effects of uncontrolled diabetes on diaphragmspecific force generation changes in muscle mass and diaphragm endurance testing the hypothesisdiabetes induced alterations in diaphragm performance are related to increases in free radical generation.Aim II studies will interrogate a number of free radical generating pathways in muscle (including the cellsurface NADPH oxidase) and determine which pathways are responsible for increased free radicalgeneration in the diaphragm in diabetes. Aim III studies will determine if iNOS is upregulated in thediaphragm in diabetes and will test the hypothesis that iNOS acts as an upstream modulator of free radicalgeneration. Aim IV studies will examine several downstream targets of diabetes induced free radicalgeneration in the diaphragm that are responsible for reductions in diaphragm performance includingcontractile protein alterations calpain mediated reductions in muscle mass and alterations in mitochondrialATP generating capacity. A variety of physiologic biochemical proteomic fluorogenic pharmacologic andgenetic techniques will be used to test these hypotheses. Our preliminary data represent the firstdemonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease processand suggest that iNOS regulates NADPH oxidase activity and free radical generation in the diaphragm indiabetes. These new data should provide important information regarding the pathogenesis of diabetesinduced diaphragm dysfunction and uncover pathways which could provide novel therapeutic targets fortreatment of respiratory muscle weakness in this condition.

project_terms:
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one;AKAP13 protein human;Ablation;Admission activity;Angiotensin II;Animal Model;Animals;Biochemical;Biological Assay;Blotting Western;Calpain;Caring;Cell Culture Techniques;Cell surface;Cells;Cessation of life;Chemicals;Complement;Condition;Contractile Proteins;Coronary Arteriosclerosis;Coronary Artery Bypass;Critical Illness;Data;Databases;Development;Diabetes Mellitus;Diaphragm (Anatomy);Disease;Electron Transport;Endothelin-1;Environmental air flow;Fiber;Free Radical Scavengers;Free Radicals;Frequencies (time pattern);Functional disorder;Gel;Generations;Genetic Techniques;Glucose;Goals;Hand;Health;Hospitalization;Hospitals;Hyperglycemia;In Situ;In Vitro;Incidence;Injection of therapeutic agent;Interleukins;Ketones;Kidney Diseases;Knock-out;Link;Lipid Peroxidation;Measures;Mechanical ventilation;Mediating;Medical;Medicare;Membrane;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;NADP;NADPH Oxidase;Neuropathy;Nitric Oxide Synthase;Numbers;Operative Surgical Procedures;Oxidants;Oxygen Consumption;Pathogenesis;Pathway interactions;Patients;Performance;Phosphorylation;Physiological;Postoperative Period;Principal Investigator;Process;Production;Protein Overexpression;Protein Subunits;Proteins;Proteomics;Pump;Purpose;Rate;Rattus;Research;Research Design;Research Personnel;Respiratory Failure;Respiratory Muscles;Respiratory System;Respiratory Tract Infections;Respiratory physiology;Retinal Diseases;Review Literature;Risk;Role;Series;Signal Transduction;Skeletal muscle structure;Skin;Source;Streptozocin;Structure;Superoxide Dismutase;Superoxides;Techniques;Testing;Transgenic Animals;Transgenic Organisms;Up-Regulation (Physiology);Weaning;Work;Workload;Xanthine Oxidase;calpastatin;chemical genetics;diabetic;hospital admission rate;improved;inhibitor/antagonist;mitochondrial dysfunction;non-diabetic;novel therapeutics;oxidation;prevent;programs;protein function;protein structure function;research study;respiratory;response;theories;therapeutic target


application_id: 7382167
project_number: 5P20RR020171-03
project_title: ROLE OF CALCINEURIN IN ASTROCYTE ACTIVATION ASSOCIATED WITH ALZHEIMER?S DISEASE
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7558
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Alzheimer?s Disease (AD) and other neurodegenerative syndromes are accompanied by a pronounced immune/inflammatory response (e.g. activated neuroglia and elevated cytokine levels) that could contribute significantly to widespread neuronal death and deterioration. In lymphocytes and other cell types the Ca2+/calmodulin dependent protein phosphatase calcineurin along with its target transcription factor NFAT (nuclear factor of activated T cells) have long been recognized to induce numerous immune/inflammatory signaling cascades. As such it is somewhat surprising that the calcineurin/NFAT pathway has not been investigated extensively for a similar role in neuro-immune/inflammatory signaling. Recently we showed that calcineurin immunostaining is markedly upregulated in activated astrocytes in hippocampus and neocortex of transgenic AD model mice (Norris et al. J Neurosci 25:4649 2005). Moreover overexpression of activated calcineurin in mixed (neuronal and glial) hippocampal cultures induced ?activation-like? changes in astrocytes (i.e. pronounced hypertrophy of soma and processes) and also triggered the expression of most genetic markers for the activated phenotype including numerous immune/inflammatory factors. The results suggest that similar to its well-known role in lymphocytes calcineurin also may serve as a critical upstream regulator of immune/inflammatory signaling cascades associated with astrocyte activation and AD.  Using astrocyte-enriched cell cultures and viral-mediated gene transfer the proposed research will extend our earlier work by determining whether endogenous inflammatory mediators recruit the calcineurin/NFAT pathway in astrocytes en route to the expression of a panel of molecular markers for the activated astrocyte phenotype. Furthermore adeno-associated viruses encoding an astrocyte-specific promoter will be used to determine if calcineurin/NFAT activity in astrocytes contributes significantly to the neuropathological changes and cognitive deficits found in amyloid-bearing AD model mice.


application_id: 7382166
project_number: 5P20RR020171-03
project_title: KY COBRE:THERAPEUTICS IN A MOUSE MODEL OF INCLUSION BODY MYOSITIS
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7557
contact_pi_person_id: 1937719
contact_pi: MURPHY, MICHAEL P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Inclusion body myositis (IBM) is a common degenerative muscular disease afflicting a significant proportion of the elderly. It has no effective treatment. A hallmark of IBM pathology is an accumulation of amyloid precursor protein (APP) derived peptides such as the 40 or 42 amino acid A? peptide or 83 or 99 residue C-terminal fragments (CTFs). IBM parallels AD with regards to the presence of A? although in AD the peptide is deposited extracellularly instead of intracellularly which is the case in IBM. In collaboration with Dr. Frank LaFerla at UC Irvine we recently reported the development of a transgenic mouse model of IBM made by overexpressing APP in skeletal muscle via a creatine kinase promoter. To our knowledge this is the only mouse model of IBM to utilize full length APP and therefore offers a unique opportunity to study both the development of IBM pathology and to evaluate possible treatment strategies. One of the strengths of our group has been the development of potential AD therapeutics. We now propose to apply our resources and knowledge to test three distinct approaches in the IBM mouse model each targeting a specific aspect of APP processing: treatment with (i) typical and atypical NSAIDs (which reduce production of A?42) (ii) a potent global inhibitor of the ?-secretase enzyme (which reduces the production of all forms of A? and causes C-terminal fragments of APP to accumulate) or (iii) passive immunization with anti-A? antibodies (which target extracellular A?). These approaches are either currently available for patient use or are currently in clinical trial and may thus be available within a few years as potential IBM therapies. In addition to answering important questions about potentially effective therapeutics this study will also directly address several theoretical issues about the development of IBM pathology. Is A? production in general required for the development of the pathology or is the longer more amyloidogenic A?42 the critical factor (as it is in AD)? Alternatively are the presence of intracellular APP CTFs responsible? Is the presence of secreted or extracellular A? important? A careful comparison of the outcomes of each aim will help to elucidate these issues hopefully helping to resolve these long standing debates regarding IBM pathogenesis.


application_id: 7382165
project_number: 5P20RR020171-03
project_title: MOLECULAR MECHANISMS INVOLVING THE DOPAMINE D4 RECEPTOR IN ADHD
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7556
contact_pi_person_id: 1915629
contact_pi: GLASER, PAUL E A
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. The primary goal of Dr.Glaser's COBRE proposal is to investigate the molecular mechanism behind the difference in monoaminergic activity evoked by different alleles of the dopamine D4 receptors (D4R) implicated in human beings with ADHD. Specific experiments will target the effect of the 4R-D4R (4 repeat allele of the dopamine D4 receptor) and 7R-D4R receptors on dopamine norepinephrine serotonin and their metabolites in the striatum nucleus accumbens and prefrontal cortex in transgenically modified mice. The research outlined in this proposal by Dr.Glaser will allow him to develop pilot data that will give him a better chance of obtaining R01 level funding. By establishing himself as an independent investigator Dr.Glaser can better dedicate himself to the understanding of the molecular basis of ADHD which will lead to better understanding and superior treatments for ADHD thus reducing its burden on today's schools health systems and society.


application_id: 7382164
project_number: 5P20RR020171-03
project_title: KY COBRE: PROTEOMICS CORE
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7555
contact_pi_person_id: 8336117
contact_pi: VANAMAN, THOMAS C
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. The proteomics core is designed to provide quantitative and qualitative protein profiling and identification analysis as well as post-translational modification and sequence analysis through a combination of 2D gel mass spectrometry and Edman sequencing analysis services. The core is equipped with Bio-Rad IPG and SDS-PAGE apparatus for 2D gel analysis a Typhoon phosphorimager/scanner system for detection and quantitation of fluorescent protein dyes (Cy-dyes) and stains (SYPRO-Ruby Pro-Q Diamond) used to analyze 1D and 2D gels a Ciphergen SELDI-TOF protein profiling system an ABI QSTAR II Q-TOF Mass Spectrometer with both MALDI and LC/ESI source capabilities Waters HPLC systems and multiple PCs for data acquisition and analysis including a site license for PDQuest software and a 5 station site license for Ciphergen software. Fully trained technical staff will assist investigators with the full range of proteomics analytical services. The staff will instruct investigators and their laboratory staff (students post-doctoral fellows and technicians) in sample preparation 2D gel analysis and quantitation by fluorescent staining methods. Protein fragmentation mass peptide mapping and protein sequencing by both MS/MS mass spectrometry and chemical sequencing will be performed by Dr. Beach on samples provided by individual investigators. Preparation and analysis of samples with the Ciphergen system will be facilitated by automated robotic work stations. Data analysis will be performed by investigators and their colleagues through multiple distant work stations connected to the Ciphergen system via the web.


application_id: 7382163
project_number: 5P20RR020171-03
project_title: KY COBRE: IMAGING CORE
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7554
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. The imaging core facility houses three epifluorescence microscopes (Nikon Eclipse 600 Zeiss Axiovert 100 and 200M) with digital image capture capability (Spot CE and Orca ER digital cameras with Metaview and Open Lab software). The Eclipse 600 will allow the high resolution imaging of cells and sub-cellular compartments. This instrument can be used for detailed analysis of various cellular structures. The core also contains two inverted epifluorescence microscopes. The Axiovert 200M is equipped with stage controllers to allow long term analysis of live cells. The Axiovert 100 can be used for analysis of cells in tissue culture dishes or fixed samples on slides. The flexibility of the instruments in the facility will enable the core users a wide range of analytical techniques with which to pursue their individual projects. The facility contains two computers for image processing. The computers have complete Internet access and network access to color printers and to data storage. The core director Dr. Whiteheart will be available to offer advice on sample preparation on data analysis and on imaging procedures. In addition Dr. Whiteheart will also advise in the preparation of figures and selection of images for publication.


application_id: 7382162
project_number: 5P20RR020171-03
project_title: KY COBRE: TISSUE CULTURE & PROTEIN PRODUCTION CORE
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7553
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. The Tissue Culture and Protein Production Core is designed to facilitate cell culture and recombinant protein production by the COBRE investigators key components of their proposed projects. It will make available well-maintained equipment and instrumentation that would not normally be found within individual laboratories particularly those of junior investigators. The approach is to provide training and priority access to members of the investigators'' teams rather than maintaining the personnel required to accomplish the tasks on a service basis. In this way costs will be kept to a minimum. The Core will provide tissue culture hoods and incubators for mammalian cell culture. In addition fermenters bioreactors cell cracking equipment and chromatography instrumentation will be available for production of recombinant proteins. Instrumentation to characterize recombinant proteins will also be available in the Core. A single staff member will maintain the Core equipment provide training to new users and oversee scheduling.


application_id: 7382161
project_number: 5P20RR020171-03
project_title: KY COBRE: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7552
contact_pi_person_id: 7875201
contact_pi: HERSH, LOUIS B
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. The Administrative Core is designed to facilitate and coordinate the research and training objectives of the Molecular Basis of Human Disease (MBHD)-COBRE. This core will provide the organizational and administrative structure needed to insure that the faculty members to be mentored have access to an environment that will facilitate their success in obtaining independent ROl-type research funding. This core will: 1) Provide administrative leadership and coordination of the overall research effort. 2) Provide support for grants accounting preparation of progress reports and grant writing. 3) Insure that the trainees have access to state-of-the-art training 4) Provide a mentoring environment that will enhance the ability of the junior faculty to obtain grant funding 5) Facilitate the use of modern research core facilities and provide funds to enhance and utilize the services of these research cores. 6) Fund pilot projects to expand research efforts in studying human disease at the molecular level. 7) Facilitate the hiring of new faculty to increase the critical mass of investigators conducting research on the molecular basis of human disease. 8) Oversee a website dedicated to the program.


application_id: 7382160
project_number: 5P20RR020171-03
project_title: KY COBRE: DISSECTING THE CELL SURFACE PROTEOME OF PROSTATE CANCER
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7551
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Prostate cancer is a major contributor to cancer related mortality in American men of all ages causing the death of approximately 30000 men each year. Prostate cancer frequently metastasizes to the bone and lymph nodes resulting in mortality. No effective treatment for metastatic prostate cancer is available. The long-term objective of this project is to understand the role of cell surface proteins in prostate cancer metastasis. Cell surface proteins play vital roles in multiple steps of prostate cancer metastasis such as detachment of tumor cells from the extracellular matrix resistance of tumor cells to the detachment-induced apoptosis adhesion of tumor cells to endothelial cells and angiogenesis to support tumor growth. The hypothesis of this project is that there are cell surface proteins either uniquely or differentially expressed in both epithelial and endothelial cells that are important for individual processes of prostate cancer metastasis. At present no proteomic approaches are readily available to characterize the cell surface proteome. Specific Aim 1 is to develop innovative approaches to specially characterize cell surface proteomes using a combination of new methods targeting and labeling cell surface proteins and cutting-edge mass spectrometry technologies. A comprehensive understanding of the cell surface proteomes will be achieved by specific cell surface protein targeting and high accuracy protein identification and quantification. Specific Aim 2 is to use these proteomic approaches to identify uniquely or differentially expressed cell surface proteins in cancerous prostate epithelial cells by comparing them to normal prostate epithelial cells. Multiple strategies will be used to select a limited number of proteins that will be the focus of functional studies. The selected cancer-associated proteins will be either suppressed or overexpressed using siRNA or transfection techniques respectively to determine their role in cell adhesion/detachment and apoptosis. Specific Aim 3 is to identify unique cell surface proteins in endothelial cells from bone marrow where prostate cancer metastasis frequently occurs. Several those unique endothelial cell surface proteins will be selected. Using the siRNA technique to suppress the expression of the selected proteins we will focus on determining their functional roles in carcinoma-endothelial cell-cell interaction and angiogenesis. The studies proposed herein will determine an array of cell surface proteins potentially involved in prostate cancer metastasis and open new avenues for therapeutic intervention of the advanced metastatic disease.


application_id: 7382159
project_number: 5P20RR020171-03
project_title: KY COBRE: PDGF SIGNAL TRANSDUCTION ROLE FOR ABI FAMILY KINASES IN CELL MIGRATIO
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7550
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Growth factors induce cell proliferation differentiation migration apoptosis and angiogenesis. Regulation of these processes is extremely important as deregulation contributes to the induction and progression of malignancy. In particular cell motility is critical for tumor invasion and metastasis hallmarks of aggressive cancers. Growth factors control cellular events by activating proteins in a complex web of signaling pathways. Previously we found that c-Abl a kinase involved in the development of leukemia is activated by platelet-derived growth factor (PDGF) and is required for mitogenesis cytoskeletal reorganization and migration downstream of PDGF. Signaling pathways that control cell migration are beginning to be identified however the pathways are not completely characterized and cross-talk between the pathways is only beginning to be elucidated. The overall goal of this proposal is to define Abl kinase-dependent PDGF signaling pathways that control cell migration. We aim to: 1) Determine the functional significance of PDGFR-Abl kinase bidirectional signaling. 2) Identify downstream targets of Abl kinases involved in PDGFinduced cell motility. 3) Determine whether Abl kinase activity is upregulated in non-hematopoeitic cancer cell lines and whether Abl kinases function to promote motility and/or invasion in these ce_ls. Results from these experiments will provide us with mechanistic insight into how Abl kinase deregulation contributes to cancer formation/progression which will aid in the discovery of new drug combinations for cancer treatment.


application_id: 7382158
project_number: 5P20RR020171-03
project_title: KY COBRE: TALIN-1 METASTISIS SUPPRESSOR IN LUNG CANCER
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7549
contact_pi_person_id: 8345406
contact_pi: MCCANN, RICHARD O.
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Lung cancer is a multifactorial disease caused by a cascade of genetic events including changes in cell cycle checkpoint and progression cell proliferation and chromosome stability which leads to the development of a primary carcinoma. After establishment of the primary tumor changes in normal cell adhesion and motility subsequently allow these tumor cells to escape from the original tumor migrate to secondary sites and grow anew. The acquisition of this capacity in the primary tumor frequently results in clinically incurable disease and these secondary tumors or metastases are a significant contributor to mortality and morbidity in lung cancer patients. Several genetic lesions on chromosome 9 at position 9p21 have been associated with lung cancer. Among these is the focal adhesion protein Talin-1 which is involved in cell adhesion and motility. Talin-1 levels are decreased in certain lung cancer cells. The HYPOTHESIS to be evaluated is that dysregulation of Talin-1 leads to altered cell adhesion leading to anchorage-independent growth of cells in the primary tumor. Acquisition of this phenotype then increases the invasiveness of these cells and results in the development of metastatic lung cancer. SPECIFIC AIMS. This hypothesis will be addressed by (1) determining the molecular basis for the Talin-1 deficiency at the gene mRNA and protein levels in lung cancer cells; (2) determining the role of Talin-1 in lung cancer cell adhesion migration and invasion with particular emphasis on the behavior of lung cancer cells in three-dimensional culture matrices that mimic the cellular environment in vivo; and (3) extending these studies to a broad panel of lung cancer cell lines representing each histological class of lung cancer so that previously unknown general features of metastatic lung cancer will be identified. SIGNIFICANCE. These studies will provide insight into the molecular and cellular mechanisms of lung cancer progression and determine whether Talin-1 is a suppressor of metastasis in lung cancer. These studies will also lead to the development of new prognostic indicators and therapeutic strategies for treatment of metastatic lung cancer.


application_id: 7382157
project_number: 5P20RR020171-03
project_title: KY COBRE: MECHANISM OF TRANSCRIPTIONAL CONTROL BY TWO DIABETES GENE PRODUCTS
administering_ic: NCRR
award_notice_date: 2006-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7548
contact_pi_person_id: 8224062
contact_pi: CHI, YOUNG-IN
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:
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Gene-specific transcription factors initiate transcription by specifically recognizing promoter regions of the target genes and mediating interactions with coregulators to recruit the remainder of the main transcriptional machinery. A large number of Mendelian human diseases have been linked to the mutations in genes encoding these transcription factors and in fact a recent complete human genome analysis revealed that transcription factors represent one of the four major functional groups of proteins whose germline mutations result in various human diseases. Our long-term goal is to understand the molecular mechanisms of gene regulation by these transcription factors and the molecular basis of disease-causing mutations found in them. This project focuses on diabetes. The transcription factors HNFI alpha and HNF4c alpha play vital roles in organ development and adult homeostasis and have been identified as culprit gene products for the monogenic dominant inherited forms of diabetes. Despite their similar physiological roles they belong to completely different transcription factor families and possess distinctive mechanisms of gene regulation through their unique structures and interactions with different sets of coregulators. Detailed structural information on how the molecular interactions occur during the multicomplex formation is not completely known. Therefore we propose to (1) solve the crystal structure of HNFlc alpha and HNF4a in complex with its target DNA and other functional partners and (2) examine the effects of diabetes-causing mutations on protein stability DNA binding protein-protein interaction in vitro and overall transcriptional activity in vivo to understand the molecular basis of gene regulation complex formation and functional loss by mutations. These findings should aid in the overall understanding of transcription control involved in insulin action and secretion and rational targeting of these transcription factors in order to modulate their activities and reverse the adverse effects by mutations thus potential treatment for diabetes.


application_id: 7382120
project_number: 5P20RR020145-03
project_title: SMOKING: EFFECTS OF GENOTYPE ON PERIODONTITIS
administering_ic: NCRR
award_notice_date: 2006-07-31
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2006-08-01
project_end_date: 2007-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7511
contact_pi_person_id: 8534338
contact_pi: AL-SABBAGH, MOHANAD
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 subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. Smoking: Effect of Genotype on Periodontitis; Mohanad Al-Sabbagh DDS MS (Division of Periodontics College of Dentistry); Mentors: Mark V. Thomas DMD MS (Associate Professor & Chief Division of Periodontics Peter Wedlund PhD Associate Professor Department of Pharmaceutical Sciences College of Pharmacy) Periodontitis is a polygenic multifactorial disease which is the result of complex interactions between oral bacteria and host response. Bacteria are necessary but not sufficient to cause the soft and hard tissue destruction that is the hallmark of periodontal disease(s). Genetic background diabetes age and smoking have been demonstrated to increase susceptibility to periodontal diseases with smoking being an especially strong risk. Genetic factors have also been identified to confer risk with some studies estimating the heritable risk at nearly 50%. After sequencing of the human genome the data indicates that the genome of the population is nearly 99.9% identical across individuals which allows for ~3 million bp differences between individuals; nearly 90% of the variation is determined by single nucleotide polymorphisms (SNPs). Interestingly certain polymorphisms have been associated with severe periodontitis eg. genes that code for inflammatory mediators/cytokines and/or produce cell receptors for innate/immune signaling. Although smoking is a strong risk factor for periodontitis not all smokers are equally susceptible to periodontal tissue destruction as noted by the extent of disease variation in the smoking population. This suggests that other factors including genetic polymorphisms may alter risk in response to smoking and result in differential susceptibility and/or disease expression. The objective of this proposal is that for more effective management of periodontitis it would be desirable to identify subsets of individuals at greatest risk for developing smoking-related periodontitis. Identification of genetic markers that confer increased risk to periodontitis in smokers would permit more effective allocation of healthcare resources and permit targeted interventions. It would also contribute to our general understanding of the mechanisms by which smoking confers risk. The hypotheses tested include: (1) SNP that increase production of select pro-inflammatory mediators would be related to periodontitis; (2) SNP that decrease production of anti-inflammtory biomolecules would be related to periodontitis; and (3) SNP that affect the production of enzymes required for detoxification of various noxious products of smoking would be related to periodontitis. We propose to conduct a case-control study of 500 smokers with or without periodontitis. We will compare these groups with regard to certain genetic polymorphisms that may be associated with increased risk for periodontitis.  This project originally was initiated as a potential YIP pilot project; however with the graduation of Dr. Kesavalu?s Project #3 from the CBBO/SD we solicited the ability of Dr. Al-Sabbagh and his mentors to develop a full project. This has been accomplished during the 01 year. The proposal has been submitted to the SAC for review and the reviews are currently be gathered to submit to NCRR for a start time within the next 3 months.


