# projects

application_id: 7231294
project_number: 5R56DK063025-02
project_title: Mechanism of Diabetes-associated Hypertension
administering_ic: NIDDK
award_notice_date: 2006-05-12
application_type: 5
activity_code: R56
ic: DK
serial_number: 063025
program_official: JONES, TERESA L Z
project_start_date: 2005-04-15
project_end_date: 2007-03-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
The central hypothesis to be tested in this proposal is that diabetes-associated endothelial dysfunction is mediated in part by the interaction of modified HDL CD36 and caveolin-2 which results in the inhibition of endothelial nitric oxide synthase. One of the most prevalent and deadly complications of diabetes is cardiovascular disease. The recent "Atherosclerosis Risk in Communities Study" reported that the development of type II diabetes was nearly 2.5 times more likely in patients with hypertension than in normotensive patients. In addition the UK Prospective Diabetes Study and the Heart Outcomes Prevention Evaluation have demonstrated that lowering blood pressure in diabetic patients greatly lessens the risk of several cardiovascular diseases. Endothelial dysfunction is centrally involved in many of the complications caused by diabetes including hypertension. One of the mechanisms by which endothelial cells influence blood pressure is by the generation of nitric oxide. Previous studies have demonstrated that the ability of endothelial cells to generate nitric oxide is compromised when exposed either in vitro or in vivo to a diabetic environment.The mechanisms by which diabetes can inhibit nitric oxide generation and thus decrease thevasodilation of a vessel are not well understood. One intriguing possibility is that the diabetic serum may be acting through a cell surface receptor such as CD36. In addition preliminary data demonstrate that HDL isolated from the serum of diabetic humans or mice will inhibit the generation of nitric oxide in a CD36 and caveolin-2 dependent manner. The goal of the proposed studies is to determine the mechanism(s) whereby the interaction of diabetic HDL CD36 and caveolin-2 results in the inhibition of endothelial nitric oxide synthase. Aim 1: To determine the domain(s) within CD36 and caveolin-2 that permits the two proteins to associate and subsequently inhibit endothelial nitric oxide synthase. Aim 2: To determine the role of phosphorylation and acylation of caveolin-2 in the inhibition of endothelial nitric oxide synthase. Aim 3: To determine the mechanism(s) whereby diabetic HDL/CD36/caveolin-2 interaction inhibits endothelial nitric oxide synthase. Aim 4: To determine if the removal of CD36 orcaveolin-2 from leprdb null mice (a mouse model of type II diabetes) protects endothelial nitric oxide synthase activity and vascular responsiveness to agonists that stimulates nitric oxide generation.

project_terms:
CD antigens;caveolins;genetically modified animals;high density lipoproteins;hypertension;laboratory mouse;nitric oxide synthase;noninsulin dependent diabetes mellitus;pathologic process;phosphorylation;protein protein interaction;protein structure function;vascular endothelium


application_id: 7230906
project_number: 3R01AG019241-05S1
project_title: PREVENTION OF ALZHEIMER'S BY VITAMIN E AND SELENIUM
administering_ic: NIA
award_notice_date: 2006-05-30
application_type: 3
activity_code: R01
ic: AG
serial_number: 019241
suffix: S1
program_official: RYAN, LAURIE M
project_start_date: 2001-09-30
project_end_date: 2008-03-31
study_section: Epidemiology and Disease Control Study Section[EDC]
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: Alzheimer's disease (AD) is a major health problem in the United      States where it affects approximately four million older individuals. There is     no effective treatment of AD and prevention is the key to this disorder.            Oxidative stress in the form of lipid protein carbohydrate and DNA oxidation     plays a significant role in the pathogenesis of neuron degeneration in AD and       serves as a potential therapeutic target for slowing the onset or preventing        the disease. The present application termed PREADVISE is based on the             hypothesis that early treatment with vitamin E and selenium (Se) in the             presymptomatic stage of the disease may delay the onset or prevent AD. These        two agents have strong antioxidant properties and have not been used together       in a large human study. This proposed evaluation of AD prevention will be added     to the Selenium and Vitamin E Chemoprevention Trial (SELECT) a NCI-supported      phase III double-blind placebo-controlled 2X2 factorial study that assesses       the combined and single effect of these two antioxidants on the reduction of        the incidence of prostate cancer in 32400 healthy men 55 or older (50 or older     if African American). The duration of SELECT will be 12 years with a five-year      uniform accrual period. PREADVISE is open to men 65 or older (60 or older if a      minority) and it is estimated that 10368 participants will be enrolled. They       will be randomized to one of four arms: vitamin E plus Se vitamin E plus Se        placebo Se plus vitamin E placebo or vitamin E and Se placebos. They will         undergo a memory impairment screening examination as part of the initial and        annual SELECT evaluation and those that fall below the cutoff point will           undergo a more thorough cognitive evaluation using the Consortium to Establish      a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests.              Participants who fail the CERAD battery will receive a thorough dementia            medical evaluation for diagnosis and be reviewed in a consensus conference by       neurologists and a neuropsychologist with lengthy experience in dementia. It is     estimated that the relative risk for AD (relative risk 0.60) is detectable with     80 percent power in this trial. The study offers an inexpensive opportunity to      evaluate the long-term effect of two antioxidant agents in slowing the onset or     preventing AD in a large number of subjects. The study also will evaluate the       sensitivity and specificity of the screening measure in a matched sample of         normals. In addition it will evaluate the effect of antioxidant therapy in a       group of 200 elderly longitudinally followed normal controls.

project_terms:
Alzheimer&apos;s disease;aging;clinical trials;cognition disorders;combination therapy;dementia;diet therapy;dietary mineral;disease /disorder onset;disease /disorder prevention /control;genotype;human subject;human therapy evaluation;longitudinal human study;mental disorder diagnosis;neural degeneration;neuropsychological tests;nutrition related tag;outcomes research;patient oriented research;polymerase chain reaction;progressive supranuclear palsy;selenium;statistics /biometry;tocopherols;vitamin therapy


application_id: 7230383
project_number: 3R01GM074101-01S1
project_title: Intermolecular Activation of GPCR
administering_ic: NIGMS
award_notice_date: 2006-05-24
application_type: 3
activity_code: R01
ic: GM
serial_number: 074101
suffix: S1
program_official: DUNSMORE, SARAH
project_start_date: 2005-08-01
project_end_date: 2009-07-31
study_section: Physiological Chemistry Study Section[PC]
contact_pi_person_id: 8257380
contact_pi: JI, TAE H.
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): G protein coupled receptors (GPCRs) are the major hormone receptors constituting approximately 3 percent of the human genome. It has been a dogma that when a hormone1 binds to a GPCR the liganded receptor activates itself to generate hormone signals (cis-activation). In contrast to this dogmatic cis-activation the evidence is emerging that a liganded receptor molecule can intermolecularly activate nonliganded receptor molecules (trans-activation). There are only several reports on trans-activation of GPCRs: two on the thrombin receptors and our reports on the LH receptor (LHR). LHR consists of two equal halves the extracellular N-terminal exo-domain and the membrane associated heptahelical endo-domain. Hormone binds to the exo-domain whereas the endo-domain generates two distinct hormone signals: one for adenylyl cyclase to produce cAMP (cAMP signal) and the other for phospholipase cbeta to produce diacylglycerol and inositol phosphate (IP signal).    Trans-activation is difficult to test because it has to be differentiated from cis-activation and hormone binding needs to be distinguished from signal generation. LHR meets these requirements and offers a unique model to test trans-activation. We have established a large library of two mutant groups one deficient in hormone binding and the other deficient in signal generation. Co-expression of a binding deficient mutant and a signal deficient mutant in a cell rescues signal generation. Our preliminary data show that the trans-activation generates either the cAMP signal or IP signal but not both. Aim 1 will test the hypotheses that trans-activation occurs not only to the mutant receptor pairs but also to the wild type receptor and that the signal selection is specific. Aim 2 will define the mechanistics of the trans-activation and signal selection. These new paradigms will have broad implications on the mechanisms of GPCR signal generation and development of new receptor therapeutics particularly to control a specific signal without invoking other signals. Receptors generate multiple signals which is a source of undesirable/toxic side effects of hormone therapeutics.

project_terms:
G protein;SDS polyacrylamide gel electrophoresis;affinity labeling;binding proteins;binding sites;biological signal transduction;cell surface receptors;cyclic AMP;enzyme activity;follicle stimulating hormone;hormone binding protein;hormone receptor;inositol phosphates;intermolecular interaction;luteinizing hormone;mass spectrometry;organism;protein purification;protein sequence;receptor coupling;receptor expression;thyrotropin;tissue /cell culture;transfection


application_id: 7230194
project_number: 5R21NS052761-02
project_title: Genetic basis for alpha-synuclein toxicity
administering_ic: NINDS
award_notice_date: 2007-05-01
application_type: 5
activity_code: R21
ic: NS
serial_number: 052761
program_official: MURPHY, DIANE
project_start_date: 2006-05-15
project_end_date: 2007-12-31
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
project_abstract:
DESCRIPTION (provided by applicant): Mutations and environmental factors are known to induce various post-translational alterations in alpha- synuclein with alterations in alpha-synuclein playing an important role in the onset and progression of Parkinson's disease (PD). In particular increases in alpha-synuclein insolubility and alpha-synuclein aggregation appear to be central events in the pathogenesis and neurotoxicity observed in PD as well as experimental models of PD. Aging is a major risk factor for PD and related synucleinopathies although the underlying genetic basis for age-related alterations to alpha-synuclein is not currently known. Identifying each of the genes which negatively as well as positively regulate age-related changes in alpha-synuclein within post-mitotic neurons is likely to lead to a better understanding of the molecular basis for the onset and progression of pathogenesis in PD as well as potentially lead to the development of novel therapeutics for the treatment of PD. A number of mutations in alpha-synuclein have been identified in recent years with mutations in alpha-synuclein observed to promote some familial forms of PD. As with aging it is important to identify the genes which positively and negatively regulate the pathogenesis and toxicity associated with mutant alpha-synuclein in post-mitotic neurons. The Saccharomyces cerevisiae (S. cerevisiae) model system has been demonstrated to be useful for studying cellular aging with the stationary phase model of aging contributing to our understanding of post- mitotic cell aging. Additionally S. cerevisiae have proved useful in studying the biology of many human genes including mutant human genes associated with disease. The focus of the current proposal is to test the hypothesis that mutagenesis experimentation with the S. cerevisiae stationary phase model of aging aid in developing an understanding of the genetic basis for age-related alterations to wild-type and mutant alpha- synuclein aggregation/insolubility and age-related increases in wild-type and mutant alpha-synuclein toxicity. Studies will be conducted in cells expressing wild-type and mutant (A53T.A30P) alpha-synuclein. The specific aims are as follows: 1) To utilize mutagenesis to understand the genetic basis for the age-related alterations which occur to alpha-synuclein 2) To utilize mutagenesis to understand the genetic regulation of age-related increases in alpha-synuclein toxicity 3) To confirm the experimental validity and implications for PD each of the data obtained in the preceding specific aims.

project_terms:
Aging;Biological Models;Biology;Cell Aging;Cells;Data;Development;Disease;Environmental Risk Factor;Event;Genes;Genetic;Human;Lead;Mediating;Mitotic;Modeling;Models Experimental;Molecular;Mutagenesis;Mutation;Neurons;Numbers;Parkinson Disease;Pathogenesis;Phase;Play;Regulation;Risk Factors;Role;Saccharomyces cerevisiae;Study models;Testing;Toxic effect;age related;alpha synuclein;base;cell age;mutant;neurotoxicity;novel therapeutics;synuclein


application_id: 7230162
project_number: 5R21HL081614-02
project_title: The Role of O-GlcNAc in Platelet Activation
administering_ic: NHLBI
award_notice_date: 2007-04-11
opportunity_number: PA-03-015
application_type: 5
activity_code: R21
ic: HL
serial_number: 081614
program_official: SARKAR, RITA
project_start_date: 2006-04-01
project_end_date: 2008-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
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:
DESCRIPTION (provided by applicant): A platelet's role in hemostasis is to respond to lesions in the vasculature. Dysfunction leads to bleeding diatheses or to the pathogenic thrombosis that causes strokes heart attacks and other occlusive events which are major health issues in today's society. To understand hemostasis it is critical to understand platelet activation. This proposal focuses on a recently defined post-translational modification of platelet proteins that seems integral to activation. O-GlcNAcylation is not a standard form of glycosylation. It is the addition of a single N-acetylglucosamine to SER or THR residues. O-GlcNAc residues appear to be reciprocal with phosphorylation on a number of proteins and thus have been tied to key intracellular signaling events in other cell types. In platelets O-GlcNAc is present on as many as 100 proteins and its dynamic turnover is required for platelet function specifically granule release. When cyclical exchange of O-GlcNAc is blocked by a specific inhibitor that prevents its removal platelets fail to respond to thrombin collagen or A23187. The proposed experiments will expand these observations to determine which platelet proteins are modified and thus shed light on how O-GlcNAcylation affects platelet physiology. These studies will provide the initial data to directly address our long term hypothesis that dynamic changes in O-GlcNAcylation of specific platelet proteins are critical for platelet function. One Specific Aim is proposed: To identify platelet proteins which are modified with O-GlcNAc and to determine their site(s) of modification. This Aim will use O-GlcNAc-specific affinity chromatography techniques and mass spectroscopy-based proteomic analysis to identify O-GlcNAcylated proteins in both resting and stimulated platelets. Once completed/the experiments of this two year R21 application will provide the database needed to more fully understand the role of O- GlcNAcylation in platelet function. This information will further elucidate the events essential to the regulation of hemostasis and perhaps lead to a better understanding of how platelet function can be affected by metabolic syndromes such as diabetes.

project_terms:
Acetylglucosamine;Address;Affect;Agonist;Antibiotic A23187;Blood Platelets;Blood Vessels;Blotting Western;Cataloging;Catalogs;Chemicals;Chromatography Affinity;Collagen;Cytoplasmic Granules;Data;Databases;Diabetes Mellitus;Disease;Disease susceptibility;Event;Excision;Functional disorder;Funding;Goals;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;Immunoprecipitation;Inhibitors Platelet;Lead;Lesion;Life;Light;Metabolic syndrome;Modification;Monosaccharides;Myocardial Infarction;Phosphorylation;Physiology;Platelet Activation;Platelet Count measurement;Play;Process;Protein Processing Post-Translational;Proteins;Proteomics;Regulation;Rest;Role;Serine;Signal Transduction;Site;Societies;Spectrum Analysis Mass;Standards of Weights and Measures;Stimulus;Techniques;Threonine;Thrombin;Thrombosis;Today;United States;base;cell type;extracellular;glycosylation;inhibitor/antagonist;numb protein;peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase;prevent;research study;stroke


application_id: 7228792
project_number: 3R21NS053593-01S1
project_title: Novel High Content Vascular Patterning Assay(RMI)
administering_ic: NINDS
award_notice_date: 2006-05-03
opportunity_number: RFA-RM-05-011
application_type: 3
activity_code: R21
ic: NS
serial_number: 053593
suffix: S1
program_official: SCHEIDELER, MARK A
project_start_date: 2005-09-30
project_end_date: 2008-08-31
study_section: ZNS1
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:
DESCRIPTION (provided by applicant): Angiogenesis the growth of new blood vessels occurs in a diverse array of human diseases. Even though anti-angiogenesis remains a large market for Pharmaceuticals high content high throughput cell based assays for angiogenesis inhibitor discovery remain to be developed for this application. It is our belief that developing new assays as screening tools for discovery of inhibitors that target endothelial cell differentiation can prove to be an efficient means of identifying new classes of anti-angiogenic drugs. Here we propose to develop 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 high throughput 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 through the 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 endothelial cell spheroids on microcarrier beads and array the spheroids in 3-D collagen matrix in 384 well optical screening plates. In addition these assays will be performed under hypoxic environment. In Specific Aim 2 we plan to develop and validate a high content (HC) image analysis platform for use with 3-D ECPA. This will be accomplished by developing software that identifies novel features of endothelial cell patterning in 3-D matrix and apply automated analysis to obtain morphogenic fingerprints. Finally we will validate the 3-DECPA and image analysis software for HTS application by screening a diversity set of natural products. We believe that this HC-HTS platform will offer unique opportunities to screen vast numbers of small molecule inhibitors of angiogenesis and assist in drug discovery.

project_terms:
angiogenesis inhibitors;bioassay;biomedical automation;biotechnology;computer program /software;digital imaging;drug discovery /isolation;high throughput technology;image processing;optics;technology /technique development;vascular endothelium


application_id: 7228478
project_number: 5R01HL071098-05
project_title: Group V Secretory Phospholipase A2 in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2007-03-21
application_type: 5
activity_code: R01
ic: HL
serial_number: 071098
program_official: LIU, LIJUAN
project_start_date: 2003-04-01
project_end_date: 2008-09-30
study_section: Pathology A Study Section[PTHA]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): A critical event in early atherogenesis is the retention of low-density lipoprotein (LDL) particles in the subendothelium through their binding to intimal proteoglycans. These retained lipoprotein particles are exposed to several modifying enzymes in the arterial wall including lipases oxidizing enzymes and proteases. A multitude of biological responses to such modified LDL including the recruitment and lipid loading of macrophages leads to the initiation and progression of atherosclerosis. The extracellular matrix (ECM) appears to play an active role in this process by not only mediating the retention of LDL particles but by also modulating the activity of various enzymes towards LDL. Thus in regions where LDL is being accumulated the co-localization of LDL ECM and LDL modifying enzymes leads to a self-perpetuating cascade of events that culminates in atherosclerosis. The identification and characterization of molecules and the manner in which they interact to contribute to this process is central to our understanding the mechanisms that underlie susceptibility to lesion formation. This proposal aims to study a novel form of secretory phospholipase A2 Group V sPLA2 which we now show is present in human and mouse atherosclerotic lesions specifically associated with macrophages. We hypothesize that Group V sPLA2and LDL in the proximity of macrophages leads to the localized production of aggregated and/or fused lipoprotein particles which consequently leads to foam cell formation. To test this hypothesis the following specific aims are proposed: Specific Aim 1): To test the hypothesis that Group V sPLA2 produces modifications in LDL particles that lead to increased uptake by macrophages. This will be accomplished by analyzing LDL particles after hydrolysis by Group V sPLA2 to determine particle composition density and extent of aggregation and/or fusion; quantifying the effect of Group V sPLA2 hydrolysis on the delivery of LDL lipid to macrophages and determining whether other factors in the arterial subendothelium namely sphingomyelinase and ECM promote Group V sPLA2-mediated effects. Specific Aim 2): To test the hypothesis that macrophage expression of Group V sPLA2 in the vessel wall results in increased atherosclerosis. This will be achieved by transplanting fetal liver hematopoetic stem cells over-expressing wild-type Group V sPLA2 or a mutant form of the enzyme that is deficient in proteglycan binding into LDL receptor-/- mice. Measuring lesion size and cholesterol/cholesterol ester content will assess the extent of atherosclerosis.

project_terms:
Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological;Blood Vessels;Cholesterol;Cholesterol Esters;Deposition;Diet;Endopeptidases;Enzymes;Event;Extracellular Matrix;Fetal Liver;Foam Cells;Genetic;Human;Hydrolysis;Lead;Lesion;Lipase;Lipids;Lipoproteins;Localized;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Measures;Mediating;Modification;Mus;Peptide Hydrolases;Play;Predisposition;Process;Production;Proteoglycan;Research Personnel;Role;Sphingomyelinase;Stem cells;Testing;Transplantation;atherogenesis;density;group V secretory phospholipase A2;macrophage;mutant;novel;particle;programs;response;size;uptake


application_id: 7228135
project_number: 5R01NR009280-03
project_title: BMI Nutrition Inflammation and Heart Failure Outcomes
administering_ic: NINR
award_notice_date: 2007-04-13
opportunity_number: PA-01-109
application_type: 5
activity_code: R01
ic: NR
serial_number: 009280
program_official: HUSS, KAREN
project_start_date: 2005-09-01
project_end_date: 2009-05-31
study_section: Nursing Science: Adults and Older Adults Study Section[NSAA]
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cardiac cachexia is an independent risk factor for morbidity and mortality in patients with heart failure (HF). In contrast obesity was recently reported to be associated with decreased risk of morbidity and mortality.  The finding that overweight and obese patients with HF have surprisingly better outcomes is in contrast to our current understanding of the relationships between obesity and HF and conflicts with the recommendation that these individuals should lose weight.  The biobehavioral mechanisms underlying the differences in outcomes between these groups of patients are not well understood.  Nutritional intake is a major contributor to body weight and may also play a crucial role in influencing HF outcomes.  Proinflammatory cytokines released as part of the systemic inflammatory response to both obesity and HF affect appetite food intake body composition myocardial function vascular epithelium and are predictors of patient outcomes.  The purpose of the proposed research is to examine the relationships among body fat content nutritional intake inflammation and patient outcomes in 300 patients with HF of ischemic origin that are equally distributed among four groups: underweight normal weight overweight and obese.  The primary aim of this prospective study is to determine the relationship between body fat mass and twelve-month patient outcomes (composite end-point of rehospitalization of death). Secondary aims are to examine how differences in body fat mass and distribution alter the effect nutritional deficiencies (four-day food diaries) and proinflammatory cytokine activity (tumor necrosis factor-alpha [TNFalpha] soluble TNF-alpha receptors interleukin-6 interleukin-1 receptor antagonist and interleukin-10) on patient outcomes.  Examination of the interactions among body fat content nutritional intake and proinflammatory cytokine activity will provide an understanding of the biobehavioral mechanisms underlying the improved patient outcomes observed in overweight and obese patients with HF.  This will assist with developing new nutrition and body weight guidelines for patients with HF who are overweight and obese.  An understanding of the underlying mechanisms may also allow application of these findings to underweight patients resulting in improved outcomes for these patients.

project_terms:
Abdomen;Address;Affect;Antilipemic Agents;Blood Vessels;Body Composition;Body Weight;Body Weight decreased;Body fat;Cachexia;Cardiac;Cessation of life;Chronic Disease;Class;Conflict (Psychology);Data;Death Cardiac;Desire for food;Development;Diagnosis;Diet Records;Eating;End Point;Endotoxins;Enrollment;Epithelium;Fatty acid glycerol esters;Goals;Guidelines;Health;Health Care Costs;Health Expenditures;Heart;Heart failure;High Density Lipoprotein Cholesterol;Hospitalization;Human;Individual;Inflammation;Inflammatory;Inflammatory Response;Intake;Interleukin 6 Receptor;Interleukin-10;Intervention;Knowledge;Lead;Lipoproteins;Longevity;Low-Density Lipoproteins;Malnutrition;Measurement;Measures;Mediator of activation protein;Medical;Modification;Morbidity - disease rate;Mortality Vital Statistics;Myocardial;New York;Numbers;Nutrient;Nutritional;Obesity;Outcome;Overweight;Patients;Pharmaceutical Preparations;Play;Population;Prospective Studies;Proteins;Protocols Treatment;Purpose;Rate;Recommendation;Recording of previous events;Recruitment Activity;Reporting;Research;Research Personnel;Research Priority;Risk;Risk Factors;Role;Science of nutrition;Serum;Shapes;Sodium Dietary;TNF gene;TNF protein human;Time;Tumor Necrosis Factor-alpha;Underweight;Visceral;Weight;Woman;anakinra;biobehavior;cytokine;day;improved;innovation;insight;men's group;novel;programs;therapy development


application_id: 7226633
project_number: 5U01DE014543-05
project_title: Multicenter Trial of CPE for Maxillofacial Prosthetics
administering_ic: NIDCR
award_notice_date: 2007-06-22
application_type: 5
activity_code: U01
ic: DE
serial_number: 014543
program_official: ATKINSON, JANE C
project_start_date: 2003-08-21
project_end_date: 2009-05-31
study_section: ZDE1-GH(08)
contact_pi_person_id: 1963729
contact_pi: GETTLEMAN, LAWRENCE M.
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-01
project_abstract:
DESCRIPTION (provided by applicant): Maxillofacial prosthetics is a subspecialty of prosthodontics providing the clinical rehabilitation treatment of patients who have lost parts of the face due to cancer trauma or birth defects. It is an orphan field a) offering fundamental rehabilitation and improvement in the quality of life to patients who may have exhausted personal or third party funding b) treating so few patients that it makes the field unprofitable for manufacturers and c) provides a dental solution to an essentially medical problem.  Silicone rubber materials have been used for facial rehabilitation for more than 4 decades with few improvements. There is a clear need for new alternative and more economic materials for extraoral maxillofacial prostheses. Research at Gulf South Research Institute in New Orleans by the Principal Investigator and others in the 1970s and 1980s developed an alternative low-cost thermoplastic material (chlorinated polyethylene CPE) that met all toxicological (safety) and physical (effectiveness) requirements.  A limited clinical trial at the time yielded equivocal results when compared to conventional but costly silicone rubber products.  This research will conduct a randomized single-crossover double-blinded Phase III clinical trial to evaluate a) experimental thermoplastic CPE and b) control silicone (Silastic Adhesive A/MDX4-4210) materials for non-inferiority of CPE based on functional & subjective characteristics and on the quality of life.  Both prostheses will be attached with a skin adhesive.   In the clinical trial the patient's missing anatomy will be sculpted and a gypsum mold made. The silicone and the CPE prosthesis will be fabricated and delivered in random order to 50 patients at M.D. Anderson Cancer Center University of Texas Houston 30 patients at Toronto Sunnybrook Regional Cancer Centre and 20 patients at J.G Brown Cancer Center University of Louisville (100 total) to be worn for 4 months each.  Detailed questionnaires will be filled out by the anaplastologist/laboratory technician clinicians before and after the prostheses are worn and the patient. Quality-of-life before and after wearing each prosthesis will be tested with the Toronto Outcomes Measure for Craniofacial Prosthetics. These methods were designed to test future materials and techniques.  The power analysis that determined that 100 patients would be needed used a non-inferiority approach from data in the previous study. The final analysis of the proposed clinical trial will also test for non-inferiority of CPE (experimental) compared to silicone rubber (control). The outcome will determine if the new material is at least equivalent to conventional silicone in important features. Longevity will be estimated by following patients. Material properties their cost and processing characteristics will affect use in underserved areas or developing countries.

project_terms:
Adhesives;Affect;Area;Cancer Center;Characteristics;Clinic;Clinical;Clinical Trials;Clinical Trials Data Monitoring Committees;Clinical Trials Phase III;Congenital Abnormality;Data;Dental;Developed Countries;Developing Countries;Double-Blind Method;Economics;Effectiveness;Evaluation;Face;Funding;Future;Gypsum;Inferior;Laboratories Dental;Longevity;Malignant Neoplasms;Manufacturer Name;Maxillofacial Prosthesis;Medical;Methods;Molds;Multicenter Trials;Orphan;Outcome;Outcome Measure;Patients;Polyethylene;Polyethylenes;Principal Investigator;Process;Property;Prosthesis;Prosthodontic specialty;Quality of life;Questionnaires;Randomized;Recruitment Activity;Regional Cancer;Rehabilitation therapy;Research;Research Institute;Safety;Science of Anatomy;Silastic;Silicone Elastomers;Silicones;Skin;Solutions;Technicians Laboratory;Techniques;Testing;Time;Training;Trauma;Universities;University of Texas M D Anderson Cancer Center;base;cost;craniofacial;design;exhaust;maxillofacial


application_id: 7225914
project_number: 5R44EY014728-04
project_title: A Real Time Monitoring System to Measure IOP in Glaucoma
administering_ic: NEI
award_notice_date: 2007-04-13
application_type: 5
activity_code: R44
ic: EY
serial_number: 014728
program_official: WUJEK, JEROME R
project_start_date: 2003-05-01
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-F(12)]
contact_pi_person_id: 7678043
contact_pi: JACKSON, DOUG J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 602020195
duns_number: 602020195
fips: US
organization_id: 10000059
organization_name: ASSENTI, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402170191
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
budget_end_date: 2009-04-30
assistance_listing_number: 93.867
project_abstract:
DESCRIPTION (provided by applicant): Assenti LLC is a 10-person start-up company formed out of collaborative research teams from the University of Louisville's Speed School of Engineering and the Department of Ophthalmology & Visual Sciences along with key industry partners. Assenti's enclosed SBIR Phase II application will allow us to continue our significant progress and momentum towards becoming the first company to bring a MEMS (Micro-Electrical-Mechanical Systems) based device to market for treating glaucoma patients. This revolutionary technology has the potential to eliminate the root cause of blindness for patients with glaucoma by providing continuous non-invasive monitoring of Intra-Ocular Pressure (IOP). Our near term goal for commercialization is to develop our Gen I "Smart IOP" monitor that will strictly monitor IOP so patients can self-administer eye drops to reduce pressure which will lead to the elimination of optic nerve damage and hence prevention of blindness from glaucoma. However our eventual longer term goal is to develop a self contained system that will either release hypotensive medication to reduce IOP or use a switch controlled MEMS valve to create a totally autonomous system requiring no patient intervention. Recent studies have shown that applying topical ocular hypotensive medication was effective in delaying or preventing the onset of primary open-angle glaucoma [12]. Assenti has met or exceeded all three specific aims from our funded SBIR Phase I and we anxiously look forward to build upon this progress in Phase II. We have identified the following three specific aims to accomplish for Phase II: 1. Develop a reliable production ready battery-free IOP monitoring system using an ultra-miniature MEMS pressure sensor as well as a telemetry 1C whose combined size measures less than 2mm x 2mm x 0.5mm (75% volume reduction from the phase I device) for FDA animal and eventual human trials. 2.Implementation of our strategic FDA test plan developed by Arkios LLC to obtain our IDE and lead Assenti towards a PMA of our Smart IOP monitor. S.Research into our longer term goal of combining Assenti's Smart IOP monitor with an invivo IOP reducing mechanism that can lead to autonomous control of the entire system and completely eliminate patient intervention.

project_terms:
Animal Model;Animal Testing;Animals;Antihypertensive Agents;Blindness;Communication;Condition;Custom;Data;Deposition;Development;Devices;Electronics;Electrostatics;Engineering;Eyedrops;Film;Funding;Glass;Glaucoma;Goals;Gold;Growth;Housing;Human;Immune response;In Vitro;Industry;Inflammatory Response;International;Intervention;Investigation;Lead;Magnetism;Marketing;Measures;Mechanics;Medicine;Methodology;Monitor;Object Attachment;Operative Surgical Procedures;Ophthalmology;Optic Nerve;Oryctolagus cuniculus;Patients;Performance;Persons;Pharmaceutical Preparations;Phase;Plant Roots;Pressure- physical agent;Prevention;Primary Open Angle Glaucoma;Process;Production;Reports Progress;Research;Research Personnel;Risk;Scheme;Schools;Self-Administered;Semiconductors;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Source;Speed (motion);Strategic Planning;System;Technology;Telemetry;Testing;Time;United States Food and Drug Administration;Universities;base;biomaterial compatibility;commercialization;concept;design;in vivo;non-invasive monitor;novel;ocular hypotensive;performance tests;pre-clinical;prevent;programs;protein degradation;response;sensor;size;vision science


application_id: 7225556
project_number: 5R01NS037717-08
project_title: Molecular/genetic control of oligodendrocyte development
administering_ic: NINDS
award_notice_date: 2007-03-13
application_type: 5
activity_code: R01
ic: NS
serial_number: 037717
program_official: UTZ, URSULA
project_start_date: 2000-03-01
project_end_date: 2009-02-28
study_section: Molecular, Cellular and Developmental Neurosciences 2[MDCN-2]
contact_pi_person_id: 1906514
contact_pi: QIU, MENSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of oligodendrocytes. Although considerable insights have been gained into the molecular mechanisms that control the initial specification of oligodendrocytes it is still not clear how the terminal differentiation and myelination of oligodendrocytes are regulated during animal development. Recently we have demonstrated that oligodendrocyte progenitor cells start to acquire the expression of Nkx2.2 homeodomain transcription factor during their migration to their destination sites and expression of Nkx2.2 is required for oligodendrocyte differentiation and myelin gene expression. Here we hypothesize that Nkx2.2 plays a key role in controlling the timing of oligodendrocyte differentiation and myelination during animal development and the expression and activity of Nkx2.2 are tightly regulated by both intracellular and extracellular factors.  Specific aim 1 of this proposal is to test the hypothesis that Nkx2.2 and Sox10 interact physically and have synergistic actions on activating myelin gene expression and oligodendrocyte differentiation. Specific aim 2 is to test the hypothesis that Nkx2.2 expression in oligodendrocyte progenitor cells can be induced by extracellular factors (thyroid hormone) that promote oligodendrocyte differentiation. Specific aim 3 is to test the hypothesis that the Notch pathway controls the timing of oligodendrocyte differentiation by regulating Nkx2.2 expression in oligodendrocyte progenitor cells. Specific aim 4 is to test the hypothesis that Nkx2.2 regulates oligodendrocyte myelination at later stages of animal life in collaboration with Nkx6.2.  Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of oligodendrocytes and may provide theoretic basis for design of novel therapeutic approaches for prevention and treatment of motor neuron and oligodendrocyte atrophies.

project_terms:
Animals;Atrophic;Cells;Collaborations;Destinations;Development;Gene Expression;Genetic;Goals;Life;Molecular;Molecular Genetics;Motor Neurons;Myelin;Oligodendroglia;Pathway interactions;Play;Prevention approach;Process;Role;Signal Transduction;Site;Staging;Stem cells;Testing;Thyroid Hormones;Time;base;design;extracellular;homeodomain;insight;migration;myelination;notch protein;novel therapeutics;oligodendrocyte lineage;transcription factor


application_id: 7224428
project_number: 1R21CA123867-01A1
project_title: Phase I and Biological Studies of DB67 - A Blood Stable Camptothecin
administering_ic: NCI
award_notice_date: 2007-01-26
opportunity_number: PAR-04-155
application_type: 1
activity_code: R21
ic: CA
serial_number: 123867
suffix: A1
program_official: XIE, HENG
project_start_date: 2007-01-26
project_end_date: 2008-12-30
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): As a class the camptothecins have been widely recognized for their therapeutic potential which for many reasons including the instability of the lipophilic lactone moiety has not been fully realized. DB-67 (7-t- butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog that was engineered to be blood stable and highly potent on the basis of structure-activity relationship studies. The camptothecins have a labile a-hydroxy-5-lactone ring which hydrolyzes to yield the negatively charged carboxylate form. Compared to the uncharged lactone the negatively charged carboxylate is less likely to diffuse into cells and is often considered "inactive." Based on its blood stability and anti-tumor activity DB-67 was selected by the NCI for development through three cycles of the RAID program. Data from NCI studies and from collaborative efforts revealed impressive in vitro and in vivo anti-tumor activity particularly in glioma models but also in melanoma and colon xenograft models. Currently DB-67 formulation and toxicology studies have been completed and clinical grade material is available through the NCI. Based on the extensive formulation toxicology and pharmacokinetic profile observed in preclinical models and its potential to exert a potent anti-tumor effect in humans we hypothesize that DB-67 will be well-tolerated and efficacious in clinical trials. This grant application outlines the clinical studies and the correlative pharmacokinetic studies that will define DB-67 disposition and toxicity in patients with refractory solid tumors. The following specific aims will be accomplished: 1.1) To estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of intravenous DB-67 administered once daily for 5 days every 21 days to adults with recurrent or refractory solid tumors in which standard therapies are not effective; 1.2) To characterize the plasma pharmacokinetics of DB-67 and metabolites after intravenous administration and relate DB-67 pharmacokinetics and toxicity. Ultimately the objective is to use DB-67 as a single agent or in combination with other molecular-targeted therapies or cytotoxics in frontline therapy with the goal to improve overall patient outcome.

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


application_id: 7223466
project_number: 5R01DE012205-08
project_title: Selective Aggregation and Sorting of Salivary Proteins
administering_ic: NIDCR
award_notice_date: 2007-04-20
application_type: 5
activity_code: R01
ic: DE
serial_number: 012205
program_official: SHUM, LILLIAN
project_start_date: 1999-08-01
project_end_date: 2009-04-30
study_section: Oral Biology and Medicine Subcommittee 1[OBM-1]
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
project_abstract:
DESCRIPTION: The long-term goal of this research is to determine the mechanisms for sorting and storage of regulated secretory proteins in salivary glands. The answer to this question is important for our understanding of the regulation of protein secretion from salivary glands and hence the composition of saliva. Significant progress towards this goal was made in the first grant period. It was shown that calcium- and pH-mediated aggregation do not contribute significantly to the storage of secretory proteins in parotid secretory granules suggesting that sorting in this gland differs from that of other endocrine and exocrine glands. Indeed it was demonstrated that sulfated proteoglycans are necessary for efficient storage of secretory proteins in secretory granules of rat parotid acinar cells. The sulfated proteoglycan appears to buffer the internal pH of secretory granules. These results led to the hypothesis that sulfated proteoglycans act as buffering agents that regulate protein sorting and storage in parotid acinar cells. Specific Aim 1 will test if sulfated proteoglycans act as buffering agents in parotid secretory granules. Aim 2 will test if expression and) post-translational modification of the proteoglycan core proteins regulates the sorting and storage of other) parotid secretory proteins. These Aims will employ isoproterenol treatment to overexpress acidic and basic PRPs in rat parotid glands combined with in vitro tissue culture approaches. As an alternative we will use transgenic mice that overexpress PRPs in salivary glands. In Aim 3 it will be tested if sulfated proteoglycans play a role in protein or membrane binding of PSP. Specific Aim 4 will test if sulfated proteoglycans or other acidic proteins are involved in sorting and storage of secretory proteins in the submandibular gland a current target for gene therapy protocols. The proposed research will use cell biological and molecular methods in salivary cells and protein expression experiments in intact animals. The results of this research will provide insight into the unique sorting mechanisms that function in salivary glands. This will lead to a better understanding of the formation of saliva and provide the basis for efficient delivery of therapeutic proteins from salivary glands.

project_terms:
Acinar Cell;Animals;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Buffers;Calcium;Cells;Cellular biology;Cytoplasmic Granules;Endocrine;Exocrine Glands;Foundations;Gland;Goals;Grant;In Vitro;Isoproterenol;Lead;Mediating;Membrane;Methods;Mice Transgenic;Molecular;Neuroendocrine Cell;Parotid Gland;Play;Protein Overexpression;Protein Processing Post-Translational;Protein Secretion;Protein Sortings;Proteins;Proteoglycan;Protocols documentation;Rattus;Regulation;Research;Role;Saliva;Salivary;Salivary Glands;Salivary Proteins;Secretory Vesicles;Sorting - Cell Movement;Submandibular gland;Sulfates Inorganic;Sulfates Unspecified or Sulfate Ion;Testing;Tissues;Transfection;base;crosslink;gene therapy;in vivo;inhibitor/antagonist;innovation;insight;parotid secretory;parotid secretory protein;protein expression;protein protein interaction;proteoglycan core protein;research study;saliva composition;salivary acinar cell;salivary cell;secretory protein;therapeutic protein;tissue culture


application_id: 7223190
project_number: 3R01NS048191-03S1
project_title: Mitochondrial Uncoupling as a Therapeutic Target in TBI
administering_ic: NINDS
award_notice_date: 2006-04-17
application_type: 3
activity_code: R01
ic: NS
serial_number: 048191
suffix: S1
program_official: HICKS, RAMONA R
project_start_date: 2004-02-01
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1]
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
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;brain injury;calcium flux;cyanides;cytoprotection;electron transport;fasting;free radical oxygen;functional ability;genetically modified animals;hypoketonemic hypoglycemia;insulin;laboratory mouse;laboratory rat;membrane potentials;mitochondria;mitochondrial membrane;neuroprotectants;nutrition related tag;oxidative phosphorylation;trauma


application_id: 7221940
project_number: 5R01DE010729-12
project_title: Control of A actinomycetemcomitans Leukotoxin Expression
administering_ic: NIDCR
award_notice_date: 2007-04-20
application_type: 5
activity_code: R01
ic: DE
serial_number: 010729
program_official: LUNSFORD, DWAYNE
project_start_date: 1994-04-01
project_end_date: 2009-04-30
study_section: Oral Biology and Medicine Subcommittee 1[OBM-1]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
project_abstract:
DESCRIPTION: A. actinomycetemcomitans is associated with human periodontal disease and expresses a leukotoxin (ItX) that kills human cells that are required for the immune response against infection. Most A. actinomycetemcomitans strains express low levels of this toxin but some strains contain alterations in the ltx promoter and exhibit a hyper-leukotoxic phenotype. These strains exhibit altered regulation of the Itx genes and are associated with localized juvenile periodontitis. We will determine how the ltx genes are regulated in minimally leukotoxic organisms and how the regulatory processes are altered in hyper-leukotoxic organisms. We have identified a c/s-acting negative regulator of toxin expression that interacts with a trans-acting protein. This protein will be isolated and we will determine how this interaction reduces ltx expression. We will also determine if the acquisition of an insertion element (IS) leads to increased toxin expression by displacing this c/s-acting negative regulator upstream from the ltx genes. We will also determine if IS introduces an outwardly directed promoter that transcribes the ltx genes. We have also shown that ltx expression is induced during anaerobic growth. A c/s-acting sequence and a trans-acting polypeptide that may play a role in anaerobic regulation have been identified. We will determine if this sequence functions as an UP element that interacts with the ltx-subunit of RNA polymerase. Finally the ltx operon possesses a fifth gene orphan that resides upstream from IXC. Frame shift mutations in orfA reduce ltx expression. Therefore we will determine if the OrfA polypeptide is involved in the regulation of It expression and whether a naturally occurring deletion in orfA leads to the hyper-leukotoxic phenotype. It is clear that the leukotoxin is an important virulence determinant of A. actinomycetermcornitans and thus it is important to understand the mechanisms that lead to the hyper-leukotoxic phenotype. These studies will determine how/Ix expression is regulated in A. actinomycetemcomitans and will identify mechanisms that contribute to hyper-expression of the toxin. The cis- and/or transacting components that are found to differ in ltx hyper-expressing strains may represent new diagnostic targets to detect hyper-virulent A. Actinomycetemcomitans. It is also possible that the regulatory processes themselves may represent targets that can be exploited for the development of local or systemic therapies Aimed at affecting leukotoxin expression in vivo.

project_terms:
Actinobacillus actinomycetemcomitans;Aerobic;Affect;Binding (Molecular Function);Binding Sites;Biological Models;Cells;Codon Initiator;Condition;Consensus;DNA Insertion Elements;DNA-Directed RNA Polymerase;Development;Disease;Disruption;Distal;Down-Regulation;Elements;Exhibits;Frameshift Mutation;Gene Mutation;Genes;Genes Regulator;Genomics;Growth;Human;Immune response;Infection;Killings;Lead;Localized;Mediating;Mouth Diseases;Mutation;Nucleotides;Operon;Organism;Orphan;Periodontal Diseases;Periodontitis;Periodontitis Juvenile;Phenotype;Play;Polymerase;Population;Process;Promotor (Genetics);Proteins;Regulation;Role;Systemic Therapy;Toxin;Trans-Activators;Transact;Transcription Genetic;Virulence;Virulent;early onset;in vivo;leukotoxin;novel diagnostics;polypeptide;research study


application_id: 7221923
project_number: 5R01CA115197-02
project_title: EGFR Targeted Nanoparticles to Overcome Paclitaxel Resistant Breast Cancer
administering_ic: NCI
award_notice_date: 2007-02-08
opportunity_number: PAR-03-045
application_type: 5
activity_code: R01
ic: CA
serial_number: 115197
program_official: FU, YALI
project_start_date: 2006-04-12
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-BCMB-R(50)R]
contact_pi_person_id: 7876835
contact_pi: MUMPER, RUSSELL J
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this proposal is to utilize a targeted nanosystem to overcome and treat multi-drug resistant breast cancer. Breast cancer like many cancers are highly prone to multi-drug resistance due to the overexpression of p-glycoprotein (p-gp). The main hypothesis is that paclitaxel containing lipid nanoparticles (NPs) targeted to the epidermal growth factor receptor (EGFR) using transforming growth factor-alpha (TGF-???w-coated nanoparticles may advantageously overcome resistance in human breast cancer cells over Taxol or untargeted NPs.  Preliminary in-vitro and in-vivo supports that these NPs may overcome resistance and thus forms the basis of this proposal.  The EGF-receptor is present in the majority of breast cancers and is present at very high levels as compared to normal cells.  TGF-?? has been shown to bind to a single class of high-affinity EGFR binding sites with dissociation constant <5.3 nM.

The four year proposal has three Specific Aims as follows:

Specific Aim #1: Develop two improved pegylated (PEG) paclitaxel NP formulations; one being untargeted (PEG-NPs) and the other being targeted (TGF-?? PEG-NPs) 
Specific Aim #2: Perform pharmacokinetic biodistribution and organ toxicity studies in mice 
Specific Aim #3: Perform tumor efficacy studies with both untargeted PEG-NPs and targeted (TGF-???n PEG-NPs) formulations versus Taxol in a nude mouse xenograft model bearing sensitive and resistant human MDA-MB-231 breast cancer cells that overexpress the EGF-receptor (EGFR)

A highly interdisciplinary team providing expertise in nanotechnology/drug delivery clinical oncology and tumor biology has been assembled.  Dr. Mumper!|s labs at the University of Kentucky will develop and characterize all NP formulations and perform in-vitro cytotoxicity in-vivo pharmacokinetic biodistribution and tumor efficacy studies.  Dr. Adams!| labs at the University of Kentucky will develop paclitaxel-resistant breast cancer cells assist with in-vitro cytotoxicity studies and in-vivo studies and assess EGFR expression both in-vitro and in-vivo.  Dr. Tseng!|s labs at the University of Louisville will perform all structural analysis experiments relating to histocompatibility and the mechanisms of action of NPs in the breast cancer cells. 

The innovation of this proposal relates to nanotemplate engineering of biocompatible nanoparticles overcoming multi-drug resistance and the use of nanotechnology to engineer a cell-targeted cancer therapy.

project_terms:
Affinity;Albumin-Stabilized Nanoparticle Paclitaxel;Alcohols;Antineoplastic Agents;Attributes of Chemicals;Back;Binding (Molecular Function);Binding Sites;Biocompatible;Biodistribution;Biological Assay;Biology;Blood;Breast Cancer Cell;Breast Cancer Treatment;Brij-78;Cancer Patient;Cell Line;Cell surface;Cells;Chromatography High Pressure Liquid;Class;Clinical;Clinical Oncology;Colorectal Adenocarcinoma;Data;Development;Dissociation;Dose;Doxorubicin;Drug Delivery Systems;Drug Kinetics;Elements;Engineering;Environment;Enzymes;Epidermal Growth Factor Receptor;Exotoxins;Folate;Formulations Drug;Gadolinium;Glycoproteins;Goals;Histocompatibility;Histology;Human;In Vitro;KB Cells;Kentucky;Knowledge;Lead;Ligands;Lipids;Literature;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Neoplasms;Methods;Mice Inbred BALB C;Mice Nude;Multi-Drug Resistance;Mus;Nanotechnology;Neurons;Normal Cell;Normal tissue morphology;Oils;Organ;Outcome;Paclitaxel;Patients;Pharmaceutical Preparations;Phase;Phospholipids;Plague;Polysorbates;Principal Investigator;Protein Overexpression;Pseudomonas;Publishing;Purpose;Rate;Research;Research Personnel;Research Proposals;Resistance;Resistance development;Sensory;Solid;System;Tail;Testing;Therapeutic;Therapeutic Effect;Tissues;Toxic effect;Toxin;Toxins Targeted;Transforming Growth Factor alpha;Tumor Biology;Tumor Tissue;Universities;Vascular Endothelial Growth Factors;Veins;Water;Work;Xenograft Model;Xenograft procedure;base;biomaterial compatibility;cancer cell;cancer therapy;cetyl alcohol;cytotoxic;cytotoxicity;folate-binding protein;improved;in vivo;innovation;melting;mouse model;nanoparticle;nanoscience;nanosystems;neoplastic cell;novel;programs;prototype;receptor;receptor binding;receptor expression;receptor recycling;research study;size;surfactant;tumor;uptake


application_id: 7220400
project_number: 1F31MH077450-01A1
project_title: Determinants of Reward Value
administering_ic: NIMH
award_notice_date: 2006-09-22
opportunity_number: PA-04-032
application_type: 1
activity_code: F31
ic: MH
serial_number: 077450
suffix: A1
program_official: PINARD, COURTNEY ROSE
project_start_date: 2006-09-29
project_end_date: 2008-09-28
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8194588
contact_pi: SINGER, REBECCA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed experiments will examine an effect reported by Clement Feltus Kaiser and Zentall (2000) in which a preference was found for stimuli that followed greater effort over those that followed less effort. When such effects are found in humans they are attributed to cognitive dissonance the discrepancy between beliefs and behavior. Clement et al. interpreted this behavior as a form of contrast in which stimuli that follow greater effort appear to have more value when compared to the aversive event that preceded it. However their design does not rule out an account based on delay to reinforcement. The first set of proposed experiments will distinguish experimentally between contrast and delay reduction accounts. The next proposed experiment will examine whether a shift in food preference can result from requiring greater effort to obtain it an application that could be used in treating eating disorders such as obesity. A final experiment will examine whether a direct manipulation of hedonic state can produce a similar effect. Autism centers in the United States are applying this research to behavior management plans (how effort and subject reward value are related). This model is also used to study risk-taking and gambling behavior.

project_terms:
autogenic training;behavioral /social science research tag;discrimination learning;food;motivation;pigeons;predoctoral investigator;preference;psychological values;reinforcer;stimulus /response


application_id: 7219730
project_number: 1P01HL086670-01
project_title: Analytical and Preparative Core
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 086670
project_start_date: 2006-12-01
project_end_date: 2011-11-30
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-12-01
budget_end_date: 2008-03-31
project_terms:
Collaborations;Fluorescent Dyes;High Density Lipoproteins;Individual;Isoelectric Focusing;Label;Lipids;Lipoproteins;Plasma;Production;Protein Isoforms;Proteins;Purpose;Quality Control;Radioisotopes;Research;Resources;Services;Standardization;defective adenoviral vector;experience;helper-dependent adenoviral vector;particle;programs


application_id: 7219668
project_number: 1R44HD055019-01
project_title: Adaptive High Intensity Electrical Stimulation for Post-Surgical Rehabilitation
administering_ic: NICHD
award_notice_date: 2007-04-15
opportunity_number: PA-06-120
application_type: 1
activity_code: R44
ic: HD
serial_number: 055019
program_official: SHINOWARA, NANCY
project_start_date: 2007-05-01
project_end_date: 2008-02-29
study_section: Special Emphasis Panel[ZRG1 MOSS-L (10)]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
budget_end_date: 2008-02-29
project_abstract:
DESCRIPTION (provided by applicant): Recovery of quadriceps muscle force following post-surgical knee immobilization is a significant therapeutic aim which is associated with quality of gait and the ability to perform activities of daily living. Several studies from various research groups have shown that neuromuscular electrical stimulation (NMES) used in conjunction with a comprehensive post-surgical rehabilitation program is a safe and highly effective method for achieving quadriceps strengthening. The most profound results have been demonstrated with use of high intensity NMES technique in which a few very strong isometric contractions of the quadriceps muscle were performed several times per week during a physical therapy session in which the patient was seated on a biomechanical dynamometer. Efficacy of this technique has been demonstrated for individuals undergoing rehabilitation following surgical reconstruction of the anterior cruciate ligament (ACLR); however widespread clinical acceptance of the technique has been limited. We assert that this high intensity electrical stimulation technique would be more widely practiced: 1) if a low cost practical cohesive system were available to replace costly and loosely connected research-based apparatus and 2) if the system involved an NMES unit that controlled stimulation automatically using an outcome-based paradigm that did not require incessant involvement of the therapist. We propose a novel rehabilitation system indicated for quadriceps strengthening during post-surgical knee immobilization in which the knee joint will be stabilized using an instrumented post-surgical knee brace and stimulation is delivered by a high output portable NMES unit with autonomous adaptive stimulation control capabilities. The target markets for this device would be clinics who serve patients undergoing rehabilitation following ACLR or total knee arthroplasty (TKA). The target price for the system will be $4000. The goals of this FastTrack SBIR project are therefore to demonstrate feasibility of the adaptive stimulation control approach in Phase I using laboratory-based apparatus. We will interface our adaptive stimulator to the KinCom dynamometer and show that the stimulator can elicit a contraction of sufficient strength that function outcomes could be expected and demonstrate that the adaptive controller can develop appropriate stimulation patterns for use in this low-cycle count application. The Phase II goals will be: 1) to develop an instrumented knee brace capable of stabilizing the knee during near maximal isometric contractions and obtaining measurements of the resulting torque; 2) to implement a rapid training version of our adaptive stimulation controller that is suited for use in this low cycle count application; 3) to implement an alternate fundamental stimulation waveform that may be more comfortable to some users; and 4) to demonstrate efficacy of the proposed system for quadriceps strengthening following ACLR or TKA. / Relevance The proposed work may benefit public health through development of an electrical stimulation exercise device indicated for quadriceps strengthening during post-surgical immobilization following surgical repair of the anterior cruciate ligament (ACLR) or total knee arthroplasty (TKA). Quadriceps strengthening has been shown to improve gait and improve performance of activities of daily living (ADLs). There are approximately 100000 ACLR and 400000 TKA surgeries per year in the United States.

project_terms:
Activities of Daily Living;Algorithms;Anterior Cruciate Ligament;Arthroplasty Replacement Knee;Biomechanics;Braces-Orthopedic appliances;Client;Clinic;Clinical;Count;Databases;Degenerative polyarthritis;Delaware;Development;Devices;Electric Stimulation;Exercise;Gait;Goals;Government;Immobilization;Individual;Isometric Contraction;Isometric Exercise;Knee;Knee joint;Laboratories;Lead;Leg;Marketing;Measurement;Methods;Muscle;Operative Surgical Procedures;Outcome;Output;Patients;Pattern;Performance;Phase;Physical therapy;Pilot Projects;Postoperative Period;Price;Protocols documentation;Ramp;Recovery;Recruitment Activity;Regulation;Rehabilitation therapy;Reporting;Research;Safety;Signal Transduction;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Speed (motion);Staging;System;Techniques;Therapeutic;Time;Torque;Training;Transducers;United States;Universities;Week;Work;analog;base;cost;desire;improved;instrument;novel;programs;prototype;public health medicine (field);reconstruction;repaired;tool


application_id: 7219521
project_number: 5R25HL084695-02
project_title: Summer Undergraduate Experiences In Biomedical Research
administering_ic: NHLBI
award_notice_date: 2007-04-01
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_abstract:
DESCRIPTION (provided by applicant):   
  
The primary goal of this program is to provide minority and disadvantaged undergraduate students with an initial exposure to basic science and clinical researchers and their areas of cardiovascular research at the University Of Louisville School Of Medicine. It is anticipated that significant number of minority undergraduate students will elect to enter into graduate research programs at either this university or others around the country as a results of the experiences in our program. We also expect a limited number of medical students to participate in this program. It is hoped that these students will either pursue a research experience during their residency or in a few cases pursue a combined degree in medicine and research (Ph.D. or M.S.). Specifically the program will emphasize the following: a. To develop an appreciation for the scientific method of investigation. Emphasis will be placed on exposing students to literature-based hypothesis generation proper experimental design and appropriate data analysis procedures. b. Exposure to a biomedical research environment that emphasizes collaboration between basic science and clinical researchers and that clearly demonstrates the clinical relevance of cardiovascular research that is being conducted at this university. c. To provide an accurate perception of the importance of animal research with emphasis on proper use of animals and an initial exposure to ethics in the conducting of these types of research studies; (End of Abstract)

project_terms:
Animal 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;abstracting;base;clinically relevant;experience;programs;research study


application_id: 7218851
project_number: 1R43NS057890-01
project_title: Stimulation Augmented Recumbent Stepper for Stroke Rehabilitation
administering_ic: NINDS
award_notice_date: 2007-04-06
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: NS
serial_number: 057890
program_official: CHEN, DAOFEN
project_start_date: 2007-04-06
project_end_date: 2008-03-31
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-06
budget_end_date: 2008-03-31
project_abstract:
DESCRIPTION (provided by applicant):  Among the most significant goals of therapeutic exercise following stroke are maintaining strength and endurance of paretic muscles and aiding in restoration of functional use of the affected limbs. One relatively new and promising device that may address these aims is the NuStep TRS4000 recumbent cross trainer which provides a coupled reciprocal leg/arm extension exercise movement against graded loads while the subject remains seated for safety and comfort. We propose to augment the TRS4000 with functional electrical stimulation (FES) which has the potential to produce the required reciprocal stepping pattern thereby exercising the lower extremity musculature providing a cardiorespiratory exercise opportunity and providing the spinal cord and brain with targeted afferent feedback that may aid in restoration of function of the affected limbs. We hypothesize that the FES component may improve both efficacy and availability of TRS4000 exercise for a significant percentage of potential users. We anticipate that successful implementation would lead to a viable commercial product which would meet a clinically relevant need and build upon existing clinical acceptance of the NuStep device. The goals of this Phase I project are: 1) to modify and instrument a TRS4000 device for interface to a proprietary 2-channel adaptive stimulator; 2) to develop NuStep-specific adaptive stimulation control algorithms; 3) to validate controller design through simulation studies; and 4) to demonstrate feasibility of the approach through a pilot study that will be performed at the University of Cincinnati's Neuromotor Recovery and Rehabilitation Laboratory at Drake Rehabilitation Center (Cincinnati OH) under the direction of Stephen Page PhD. The feasibility study will include recruitment of three (3) subjects that have experienced a stroke who will each participate in 3 sessions of FES-augmented NuStep exercise. Sessions will be managed and patients continually monitored by an Exercise Physiologist to assure their safety. Feasibility will be defined as the ability for the adaptive stimulator to develop client-specific stimulation patterns to elicit the proposed recumbent stepping movement across subjects and visits without intervention of therapists or research engineers. Phase II work may include stimulator modifications to simplify instrumentation and to stimulate a larger number of muscles mechanical modifications to the TRS4000 to improve efficacy in motor reeducation applications and a clinical trial of sufficient sample size to demonstrate efficacy of the FES-enabled TRS4000 for exercise with the potential for motor re-education improvements. The target market for the device will be rehabilitation clinics that provide care to individuals following stroke. customKYnetics Inc. will seek a Strategic Alliance partnership with NuStep Inc. for manufacturing marketing sales and distribution of the FES-augmented TRS4000 with the goal of achieving a price point of $5000. / Relevance Stimulation Augmented Recumbent Stepper for Stroke Rehabilitation Applicant Institution: customKYnetics Inc. (PI: Hartman Eric C.) The proposed work may benefit public health through development of an electrical stimulation augmented recumbent stepping machine (TRS4000 NuStep Inc.) indicated for exercise and motor reeducation following stroke (700000 cases per year) or spinal cord injury (11000 cases per year). Compared to the stand-alone NuStep device the electrical stimulation component may improve efficacy of the exercise for users with marginal volitional control and may improve availability of the exercise for individuals with insufficient volitional control to otherwise participate.

project_terms:
Address;Affect;Algorithms;Bilateral;Biomechanics;Brain;Caring;Client;Clinic;Clinical;Clinical Trials;Computer Simulation;Coupled;Development;Devices;Doctor of Philosophy;Educational aspects;Electric Stimulation;Engineering;Exercise;Feasibility Studies;Feedback;Goals;Government;Individual;Institution;Intervention;Intervention Studies;Laboratories;Lead;Leg;Limb structure;Lower Extremity;Marketing;Mechanics;Modification;Monitor;Motor;Movement;Muscle;Numbers;Outcome;Patients;Pattern;Phase;Pilot Projects;Price;Recovery;Recruitment Activity;Rehabilitation Centers;Rehabilitation therapy;Research;Safety;Sales;Sample Size;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Spinal Cord;Spinal cord injury;Surface;Survivors;Technology;Therapeutic;Training;Universities;Upper arm;Visit;Work;base;chronic stroke;clinically relevant;concept;day;design;desire;experience;functional restoration;improved;instrument;instrumentation;motor control;post stroke;prototype;public health medicine (field);research study;restoration;simulation;stroke;stroke rehabilitation


application_id: 7217908
project_number: 5F30NS051998-03
project_title: Role of Hsp90 Interactions in PC-12 Survival to Hypoxia
administering_ic: NINDS
award_notice_date: 2007-03-13
opportunity_number: PA-01-100
application_type: 5
activity_code: F30
ic: NS
serial_number: 051998
program_official: GOLANOV, EUGENE V
project_start_date: 2005-04-01
project_end_date: 2008-03-31
study_section: ZNS1-SRB-M(13)
contact_pi_person_id: 8088892
contact_pi: WIEGAND, CHRISTINA B
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):    Hypoxia is a primary factor in ischemic diseases such as stroke and traumatic brain disease. PC-12 cells have been widely used as a model to study signaling pathways of neuronal sensitivity to hypoxia notably the PI3K/Akt survival pathway. Hypoxia induces heat shock protein response in ischemic brain as well as in PC- 12 cells and HspQO has been implicated in the regulation of Akt activity. Thus hypoxia-induced HspQO may modulate PC-12 cell survival via protein binding regulated by phosphorylation. Proteomic techniques SDS-PAGE and MALDI-MS as well as site-directed mutagenesis translation co-immunoprecipitation and GST pull-down methods will be used to: (i) identify HspQO binding proteins in normoxic and hypoxic cells and determine their role in PC-12 survival to hypoxia; (ii) determine whether Akt and Akt-mediated phosphorylation events regulate HspQO protein binding and cell survival to hypoxia; (iii) determine whether HspQO regulation of cell survival to hypoxia involves shuttling its binding proteins to various subcellular compartments in an Akt dependent or independent manner. These studies will provide the groundwork for future intervention strategies aiming to prevent neuronal cell loss in diseases associated hypoxia.

project_terms:
Binding Proteins;Brain;Brain Diseases;Cell Survival;Cells;Co-Immunoprecipitations;Complex;Disease;Event;Future;Glutathione S-Transferase;Heat shock proteins;Hypoxia;Intervention;Mediating;Methods;Modeling;Mutagenesis Site-Directed;Neurons;PC12 Cells;Pathway interactions;Phosphorylation;Protein Binding;Proteomics;Regulation;Role;Signal Pathway;Signal Transduction;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Techniques;Translations;prevent;response;stroke


application_id: 7217422
project_number: 5R01ES011594-05
project_title: Metabolism and Detoxification of Base Propenals
administering_ic: NIEHS
award_notice_date: 2007-04-18
application_type: 5
activity_code: R01
ic: ES
serial_number: 011594
program_official: THOMPSON, CLAUDIA L
project_start_date: 2003-06-01
project_end_date: 2009-03-31
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the metabolic pathways that regulate the cytotoxic and mutagenic potential of base propenals (BP) generated from oxidant-induced DNA damage. BP are derived from selective hydrogen abstraction from C4' of the deoxyribose ring and their formation leads to strand scission. High concentrations of BPs are generated by anticancer drugs such as bleomycin and environmental agents such as Cr (VI). BPs have also been detected in normal untreated human cells suggesting that they are produced from background DNA damage. The BPs are highly reactive unsaturated aldehydes which readily attack cellular nucleophiles such as glutathione and guanine. At high concentrations BPs are cytotoxic and cytostatic whereas at low concentrations they form potentially mutagenic DNA adducts. Propenal-derived DNA adducts have been detected in high abundance in normal and cancerous human tissues and it has been suggested that they are derived mainly from BPs originating from oxidant-mediated DNA damage. Nonetheless the metabolic processes that regulate the cytotoxic and mutagenic potential of BPs are not well understood. Based on our preliminary data and literature evidence we propose that glutathione S-transferase (GSTP1-1) and aldose reductase (AR) are the major enzymes that participate in the metabolism of base propenals and that the sequential biotransformation by these enzymes prevents the toxicity and mutagenicity of base propenals. To test this hypothesis we will identify the major cellular and urinary metabolites of base propenals generated by COS-7 and HepG2 cells or mice exposed to radiolabeled adenine and thymine propenals (Aim 1). Next we will delineate the contribution of AR and GSTP1-1 to the overall metabolism of base propenals using pharmacological and molecular strategies and elucidate the metabolism of propenal in AR-inhibitor treated or GSTP1-1 null mice (Aim 2). To test the catalytic efficiency of AR and GSTP1-1 we will examine their steady-state kinetic properties and determine whether product or substrate inhibition limits propenal metabolism via this pathway (Aim 3). Finally to delineate the role of GSTP1-1 and AR in preventing the acute toxicity of base propenals and their ability to form DNA adducts (Aim 4) we will test whether inhibition or overexpression of these enzymes prevents base propenal cytotoxicity and adduct formation and whether the mutagenic burden due to base propenal exposure is altered in GSTP1-1-null or AR inhibitor-treated mice. The results of these studies will provide a better understanding of the cytotoxic effects of DNA degradation products and the mechanism by which they indirectly induce potentially mutagenic DNA lesions. Our results may also help in designing more effective and targeted anticancer interventions and could lead to the identification of organ systems and individuals more sensitive to endogenous and environmental oxidants.

project_terms:
Acute;Adenine;Affect;Aldehyde Reductase;Aldehydes;Amino Acids Basic;Animals;Antineoplastic Agents;Biochemical Pathway;Biological;Bleomycin;Cancerous;Catalysis;Cells;Chromium;Chronic;Class;Cultured Cells;Cytostatics;DNA;DNA Adducts;DNA Damage;DNA lesion;Data;Deoxyribose;Disease;Doctor of Philosophy;Enzymes;Future;Generations;Genes;Glutathione;Glutathione S-Transferase;Goals;Guanine;Human;Hydrogen;In Situ;Individual;Inflammation;Intervention;Investigation;Kinetics;Lead;Literature;Malignant Neoplasms;Mediating;Metabolic;Metabolic Biotransformation;Metabolic Detoxication Drug;Metabolic Pathway;Metabolism;Metals;Mice Knockout;Modification;Molecular;Mus;Nature;Oxidants;Oxidation-Reduction;Pathway interactions;Peroxonitrite;Pharmaceutical Preparations;Polymorphism Genetic;Population Study;Predisposition;Property;Protein Isoforms;Protein Overexpression;Radiolabeled;Recombinant Proteins;Relative (related person);Research Personnel;Role;Site;Sites Active;Specificity;Testing;Thymine;Tissues;Toxic effect;Urine;adduct;base;body system;carcinogenesis;catalyst;chromium hexavalent ion;cytotoxic;cytotoxicity;design;environmental agent;enzyme activity;gain of function;human tissue;inhibitor/antagonist;molecular modeling;novel;prevent;programs;radiotracer;research study;toxicant;urinary


application_id: 7217265
project_number: 5T35ES014559-02
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2007-04-04
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: 2007-04-01
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 environmental health sciences. This application addresses 2 specific aims:  Aim 1: To provide hands-on training in basic and clinical environmental health sciences-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 environmental health sciences-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 NIEHS-funded investigators and collaborating faculty. These faculty members 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. The investigators 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 Environmental Health Sciences-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;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: 7216998
project_number: 1P20RR023572-01
project_title: University of Kentucky Clinical Translational Science
administering_ic: NCRR
award_notice_date: 2006-09-18
opportunity_number: RFA-RM-06-001
application_type: 1
activity_code: P20
ic: RR
serial_number: 023572
program_official: TALBOT, BERNARD
project_start_date: 2006-09-18
project_end_date: 2008-09-17
study_section: Special Emphasis Panel[ZRR1 CR-1 (01)]
contact_pi_person_id: 1901564
contact_pi: BALKE, C WILLIAM
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal outlines a comprehensive planning process for the design and implementation of a Clinical and Translational Science Award (CTSA) Program at the University of Kentucky (UK). The plan will align UK's ongoing restructuring of its clinical and translational research enterprise with the goals and objectives of the National Institutes of Health's (NIH) Roadmap CTSA initiative to improve the quality and accelerate the pace of the University's clinical and translational discovery. As such the goals of UK's CTSA Program are:  
1. The establishment of the UK Center for Clinical and Translational Science (the UK Center) which will serve as the "academic home" for the distinct discipline of clinical and translational research. The UK CTSA Program will include dedicated faculty and staff who will conduct original research develop graduate and postgraduate training curricula and lead programs that integrate clinical and translational science across multiple UK departments colleges institutes and centers and hospitals.  
2. The aggregation and integration of the essential infrastructure and core services required for the efficient and ethical conduct of first-rate clinical and translational research by investigators in the UK Center. The co-localization of these key resources in the UK Center will lead to natural synergies of existing resources and talent thereby furthering the Center's overall function.  
3. The development of integrated training mechanisms required for the adequate preparation of future generations of clinical and translational scientists at multiple levels of career development. The specific objectives of the planning process for the UK Center include: (1) Identifying clinical and translational science communities served; (2) Cataloging existing mechanisms for the conduct of and training in clinical and translational research; (3) Identifying strengths and weaknesses of each existing mechanisms;(4) Identifying new programs to meet the aforementioned goals of the UK Center; (5) Developing the UK Center's content governance administration and evaluation; and (6) Managing the institutional and cultural changes as a bonafide UK Center for Clinical and Translational Research is established.   
  
The CTSA planning process will expand and extend the planning process begun at UK in 2004 when were cognized that consistent with the NIH Roadmap a new and quantitatively different structure was needed for the governance support and facilitation of clinical and translational research. UK is now well along in the transformation of its clinical and translational research activities into a new and distinct discipline of clinical and translational science. The planning process described in this application will complete this transformation and will thereby change for the better the University's entire discovery mission.

project_terms:
NIH Roadmap Initiative tag;career;clinical research;education evaluation /planning;educational resource design /development;health science profession;health science research;health science research analysis /evaluation;health science research potential;interdisciplinary collaboration;postgraduate education;training;university


application_id: 7216779
project_number: 5R01EY016724-02
project_title: Neuroplasticity Genes in Visual Cortex
administering_ic: NEI
award_notice_date: 2007-03-23
application_type: 5
activity_code: R01
ic: EY
serial_number: 016724
program_official: AGARWAL, NEERAJ
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: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): 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 means to 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 of normal 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 Mund 3-3 ("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 project will address the following specific aims: 1. To test the hypothesis that CPG gene mutation will alter the time course of the physiologically defined critical period in mouse visual cortex. Electrophysiological and immediate early gene expression methodologies will determine the effect of Mund 3-3 and Dab-1 mutation on susceptibility to monocular deprivation. 2. To test the hypothesis that "plasticity" and "anti-plasticity" CPGs will show distinct temporal associations with known laminar specific developmental events during the critical period 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 function of age and dark rearing. 3. To verify the identity of previously unsuspected CPGs indicated by the gene screen. Our screen has implicated novel CPGs with documented neurological functions. In addition to Mund 3-3 and Dab-1 Plasticity Related Gene 1 (PRG-1) which influences axonal outgrowth and two genes associated with Ras mediated cytoskeletal reorganization (Chimaerinl and Abl interacting protein 2) are tentatively identified. The identification of effector genes which control the visual cortical critical period would be a major step in unraveling molecular mechanisms of neuronal plasticity. Such information is essential to understanding processes such as neuronal development regeneration learning and memory and would further 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: 7216725
project_number: 5R01GM047915-13
project_title: Modified Photoproteins as Labels and Molecular Switches
administering_ic: NIGMS
award_notice_date: 2007-03-30
application_type: 5
activity_code: R01
ic: GM
serial_number: 047915
program_official: EDMONDS, CHARLES G
project_start_date: 1995-01-01
project_end_date: 2009-01-14
study_section: Special Emphasis Panel[ZRG1-BECM(01)S]
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Bioluminescent photoproteins afford high sensitivity of detection and have been employed as labels in bioanalysis. We propose to further expand the applications of these photoproteins by modifying them to possess unique bioluminescence properties. One of the goals of this work is to alter the electronic and H-bonding network within the chromophore-binding pocket of these photoproteins in order to shift their emission wavelengths. This will be achieved by incorporation of non-natural amino acids into the aequorin structure and by performing site-directed mutagenesis. The resulting proteins will be characterized in terms of their activity and structure-function relationship. We also propose to mimic the natural phenomenon that occurs in the jellyfish Aequorea Victoria where transfer of energy from aequorin to GFP results in the emission of green light. For that we propose to prepare protein-based "artificial jellyfish" by attaching a fluorophore to unique sites on aequorin close to  the coelenterazine binding pocket. This will allow transfer of energy from aequorin to the fluorophore thus shifting the wavelength of emission of the protein. "Molecular switches" that can be "turned on" in the presence of a target analyte will be prepared by constructing hybrid proteins between aequorin variants and a binding protein for a specific analyte. The hybrid proteins will be constructed by inserting the gene of the binding protein into the gene of aequorin. The conformational changes that occur in the binding protein upon ligand binding will bring the two parts of aequorin together allowing for the emission of bioluminescence. In addition "molecular switches" will be constructed by preparing fusion proteins of a dissected aequorin and genes that code for a pair of poplypeptides that can form a leucine zipper. The leucine zipper allows for aequorin to re-assembly and bioluminescence emission. When target DNA is present the leucine zipper is pulled apart; aequorin is disassembled with the subsequent loss of light. Applications of the above modified photoproteins in bioanalysis will be demonstrated by developing highly sensitive assays for panels of analytes that are important in disease diagnosis. Furthermore these assays based on aequorin variants with different emission wavelengths will be incorporated into a microcentrifugal microfluidic platform which should result in multiplex analysis with applications in point-of-care diagnostics and HTPS.

project_terms:
Accident and Emergency department;Aequorin;Affect;Age;Amino Acid Sequence;Amino Acids;Antibodies;Binding (Molecular Function);Binding Proteins;Biochemical Genetics;Biochemical Reaction;Biological Assay;Bioluminescence;Characteristics;Chimeric Proteins;Code;Compact discs;Culture Media;DNA;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Electronics;Energy Transfer;Enzymes;Fluorescence;Funding;Genes;Goals;Green Fluorescent Proteins;Hybrids;Jellyfish;Label;Leucine Zippers;Ligand Binding;Ligands;Light;Liquid substance;Location;Luminescent Proteins;Methods;Methyl Green;Microfluidics;Miniaturization;Molecular;Molecular Biology;Mutagenesis Site-Directed;Mutation;Nanotechnology;Nature;Numbers;Object Attachment;Organism;Physiological;Property;Proteins;Purpose;Radiation Visible;Sampling;Signal Transduction;Site;Sites Active;Solutions;Structure;Structure-Activity Relationship;Techniques;Time;Variant;Victoria Austrailia;Work;base;chromophore;coelenterazine;design;desire;feeding;fluorophore;high throughput screening;hybrid protein;interest;light emission;luminescence;micro-total analysis system;miniaturize;molecular modeling;molecular recognition;mutant;oxidation;point of care;protein protein interaction;protein structure;quantum


application_id: 7216510
project_number: 1S10RR023684-01
project_title: Applied Biosystems 4800 MALDI TOF/TOF Mass Spectrometer
administering_ic: NCRR
award_notice_date: 2007-02-15
opportunity_number: PAR-06-093
application_type: 1
activity_code: S10
ic: RR
serial_number: 023684
program_official: TINGLE, MARJORIE
project_start_date: 2007-02-15
project_end_date: 2008-02-14
study_section: Special Emphasis Panel[ZRG1 BCMB-A (30)]
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:
DESCRIPTION (provided by applicant): The Proteomics Core Facility at the University of Kentucky (UK) College of Medicine requests $416290 to acquire a matrix-assisted laser desorption ionization (MALDI) tandem time-of-flight (TOF/TOF) mass spectrometer. The goal of this application is to provide advanced mass spectrometry capabilities to meet the proteomics needs of 18 highly productive NIH-funded investigators at UK. Compared to an older model the Applied Biosystems 4800 MALDI-TOF/TOF mass spectrometer offers 10x better sensitivity enhanced precursor ion selection and more efficient fragmentation of singly charged precursor ions generated by MALDI using high energy (2 KeV) collision-induced dissociation. Its superior mass accuracy and resolution in both MS and tandem MS/MS modes enable powerful proteomics capabilities. This equipment will provide state-of-the- art capabilities to the Proteomics Core Facility and enhance the ability of the facility to meet an ever-increasing volume and intensity of research support. This equipment is essential to these ongoing research programs and to stimulating and enabling new collaborative research initiatives on protein identification posttranslational modification characterization gene discovery and functional proteomics. Currently there is no MALDI- TOF/TOF mass spectrometer at UK or any universities in the Commonwealth of Kentucky. The purchase of the MALDI-TOF/TOF mass spectrometer is critical to the continuing expansion and enhancement of the proteomics research program in human disease and basic research at UK. As described in this application 18 NIH-funded investigators from 10 different departments have specific needs for this mass spectrometer which will be a shared research resource. Indeed due to the lack of a more sensitive and high throughput MALDI- TOF/TOF mass spectrometer on campus and the current usage saturation of the other instruments some of these research projects are seriously delayed or compromised. Thus the purchase of the MALDI-TOF/TOF mass spectrometer will have a major impact on research capabilities at our institution. Relevance The research to be supported by this instrument spans a wide spectrum of biological and biomedical research including cutting-edge programs focused on neurological disorders such as Alzheimer's disease Parkinson's disease and Lou Gehrig's disease; cancer biology including DNA repair gene regulation and apoptosis in prostate breast and skin cancers; and diabetes and cardiovascular disease. Other programs explore fundamental questions in signaling pathways and gene transcription regulation that are critical to the pathogenesis of multiple major diseases such as cancer diabetes and neurological disorders or study the role of metalloproteases in ovarian function and women's health. The addition of this instrument to the Proteomics Core Facility at UK Medical Center will significantly enhance the productivity and progress of these research programs thus advancing the NIH mission to improve public health.

project_terms:
Alzheimer's Disease;Amyotrophic Lateral Sclerosis;Apoptosis;Arts;Basic Science;Biological;Biomedical Research;Breast;Cancer Biology;Cardiovascular Diseases;Charge;Core Facility;DNA Repair Gene;Diabetes Mellitus;Disease;Dissociation;Equipment;Funding;Gene Expression Regulation;Goals;Institution;Ions;Kentucky;Malignant Neoplasms;Medical center;Medicine;Metalloproteases;Mission;Modeling;Ovarian;Parkinson Disease;Pathogenesis;Productivity;Prostate;Protein Processing Post-Translational;Proteins;Proteomics;Research;Research Personnel;Research Project Grants;Research Support;Resolution;Resources;Role;Signaling Pathway Gene;Skin Cancer;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spectrum Analysis Mass;Time;Transcription Genetic;Transcriptional Regulation;United States National Institutes of Health;Universities;Women's Health;college;gene discovery;human disease;improved;instrument;mass spectrometer;nervous system disorder;programs;public health medicine (field)


application_id: 7216470
project_number: 1P20RR023523-01
project_title: Planning Grant for Louisville Clinical and Translational Science Award
administering_ic: NCRR
award_notice_date: 2006-09-26
opportunity_number: RFA-RM-06-001
application_type: 1
activity_code: P20
ic: RR
serial_number: 023523
program_official: TALBOT, BERNARD
project_start_date: 2006-09-25
project_end_date: 2008-09-24
study_section: Special Emphasis Panel[ZRR1 CR-1 (01)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The NIH has recently completed the process of doubling its budget which resulted in many important basic discoveries which need to be applied to clinical practice. As affirmed by Dr. Zerhouni "It is the responsibility of those of us involved in today's biomedical research enterprise to translate the remarkable scientific innovations we are witnessing into health gains for the nation". In order to address this challenge in 2003 the NIH road map for medical research was developed having three fundamental themes: (1) new pathways to discovery (2) research teams of the future and (3) re-engineering the clinical research enterprise. To help achieve the goals of the road map the NIH has launched a new program that will fund institutional Clinical and Translational Science Awards (CTSAs). The CTSA will serve as an institutional 'home' that will provide integrated physical and academic resources unique to an individual institution which will facilitate the conduct of original clinical and translational research. During this exciting time of NIH funding doubling the University of Louisville (U of L) and its partners initiated policies and programs that are completely harmonious with the NIH road map. In conjunction with the state of Kentucky the U of L generated new funds for professorships and endowed chairs. Our NIH funding more than quadrupled new research buildings were built clinical research training programs were developed and research translated into health benefits for our patients. These health advances ranged from 'high technology' procedures such as the first hand transplant in the United States and the first implantable artificial heart to wellness programs for employees with U of L health insurance focusing on obesity exercise and lifestyle  
spear headed by U of L President James Ramsey. With the support of a CTSA the long-range goals of U of L and its partners are to create transforming clinical and translational research that will benefit the  
community. The specific objectives of this CTSA planning grant are to:  
1. Provide evidence of institutional support and an organizational framework for the LICTS;  
2. Expand and develop the clinical and translational educational opportunities and degrees offered  
through the LICTS and the Graduate School at U of L;  
3. Develop novel clinical and translational methodologies and resources;  
4. Integrate campus-wide activities in bioinformatics clinical informatics statistical and regulatory  
support into a central cohesive unit to promote the clinical and translational science enterprise at Louisville;  
5. Expand and integrate a clinical and translational research resources and outreach network.

project_terms:
NIH Roadmap Initiative tag;biomedical facility;clinical research;education evaluation /planning;health science research potential;health science research support;science education


application_id: 7214704
project_number: 5K08EY016120-03
project_title: PROTEOMIC ANALYSIS OF AGE-RELATED MACULAR DEGENERATION
administering_ic: NEI
award_notice_date: 2007-03-29
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: EY
serial_number: 016120
program_official: MARIANI, ANDREW P
project_start_date: 2005-04-01
project_end_date: 2008-03-31
study_section: ZEY1-VSN(06)
contact_pi_person_id: 7936607
contact_pi: TEZEL, TONGALP H
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): Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population in the Western world. So far several "destructive" treatment modalities have been tried in vain to improve the central vision in patients with AMD. The failure of developing effective treatment stems from the inadequacy of our knowledge of cellular mechanisms in AMD pathogenesis. Several epidemiological studies indicate aging as the predominant risk factor for AMD. Experimental data suggest that post-translational modifications of cellular proteins by glycation phosphorylation or oxidation may be responsible for age related retinal cell loss. However the exact mechanisms involved in age-related retinal cell loss and macrostructural alterations leading to AMD have not yet been identified. Identification of these pathogenetic pathways will help us to develop rational strategies to block the cellular events leading to AMD. Proposed experiments aim to identify the differential in situ protein expressions of RPE choriocapillaris and photoreceptor cells in the macula and periphery of the (1) young (<50) normal donors (2) normal old (>65) donors without any retinal pathology (3) old donors with age-related maculopathy (ARM) and (4) old donors with AMD. Comparison of these proteome maps will reveal the topographical and age-related variations in protein expression of each cell type. Such proteome maps will also be useful in detecting the differentially expressed proteins in ARM and in AMD. Using bioinformatic techniques possible pathological events and related pathways will be identified. Proposed studies will also yield topographical and age-correlated specific proteome maps of each tissue which can be used for future research in the field. Results of this proposal will undoubtedly improve our understanding of the precise mechanisms of cell death in AMD and facilitate efforts to develop more specific treatment techniques aimed at identified pathological pathways.

project_terms:
Age;Age related macular degeneration;Aging;Alzheimer's Disease;Apoptotic;Atherosclerosis;Bioinformatics;Blindness;Cell Death;Cells;Condition;Data;Dermal;Disease;Elderly;Endothelium Vascular;Epidemiologic Studies;Epithelium;Event;Eye;Failure (biologic function);Functional disorder;Future;Glomerulonephritis Membranoproliferative;In Situ;Knowledge;Lead;Maps;Modality;Numbers;Oxidative Stress;Pathogenesis;Pathology;Pathway interactions;Patients;Phosphorylation;Photoreceptors;Photoreceptors Retinal;Population;Protein Processing Post-Translational;Proteins;Proteome;Proteomics;Pulmonary Emphysema;Research;Research Personnel;Retinal;Retinal Pigments;Risk Factors;Signal Transduction;Signal Transduction Pathway;Techniques;Tissues;Variant;Vision;Western World;age related;attenuation;cell type;glycation;improved;macula;oxidation;programs;protein expression;research study;response;stem;stressor


application_id: 7214449
project_number: 1R03CA125781-01
project_title: Chemopreventive properties of aryl hydrocarbon receptor antagonists
administering_ic: NCI
award_notice_date: 2006-09-18
opportunity_number: PAR-04-147
application_type: 1
activity_code: R03
ic: CA
serial_number: 125781
program_official: STEELE, VERNON E
project_start_date: 2006-09-18
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZCA1 SRRB-F (O1)]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The aryl hydrocarbon receptor (AHR) may play in important role in the etiology of tobacco smoke induced lung cancer and may also be an important target for effective chemopreventive approaches. Our initial data performed in human lung epithelial cells indicates that constituents present in cigarette smoke condensate can act as AHR agonists and that several dietary flavonoids in particular apigenin emodin and kaempferol appear to act as effective AHR antagonists. The hypothesis to be tested in this proposal is that the AHR is an important pharmacological target of dietary flavonoids that will be effective for chemoprevention of tobacco smoke induced lung cancer. Specific Aims: (1) Determine the extent to which cigarette smoke condensate activates and flavonoids inhibit the AHR and cell transformation. (2) Determine whether apigenin inhibits cigarette smoke condensate-induced malignant transformation of human lung epithelial cells in vivo.

project_terms:
aromatic hydrocarbon receptor;flavonoids;gene targeting;human;lung;neoplasm /cancer;smoking;tobacco abuse


application_id: 7214056
project_number: 5R01NS047395-04
project_title: Focal Brain Ischemia in the TNF-alpha-Transgenic Rat
administering_ic: NINDS
award_notice_date: 2007-02-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 047395
program_official: JACOBS, TOM P
project_start_date: 2004-02-01
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-3(01)Q]
contact_pi_person_id: 1859648
contact_pi: PETTIGREW, L. CREED
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-02-01
project_abstract:
DESCRIPTION (provided by applicant): Tumor necrosis factor-alpha (TNFalpha) is a pleotrophic cytokine secreted by astroglia macrophages and other cells participating in the inflammatory reaction initiated by cerebral infarction. Levels of TNFalpha rise sequentially in the infarct core the ischemic penumbra and in unaffected tissue in human brain damaged by stroke and may persist up to 40 days afterward. The Overall Goal of this R01 proposal is to establish the TNFalpha-transgenic rat as a new model for investigation of TNF receptor (TNFR)-mediated signal transduction and cell death pathways activated during brain infarction in man. This animal was constructed to overexpress the murine TNFalpha gene with its own promoter and has never been used to investigate the pathophysiology of any brain disorder. Cerebral tissue obtained from the transgenic rat shows elevated levels of TNFalpha mRNA and protein. When subjected to middle cerebral artery occlusion transgenic animals have larger mean percent infarct volume than wild type controls. We will employ this unique animal to test our principal Hypothesis: Upregulated synthesis of TNFalpha in ischemic brain augments neuronal apoptosis by receptor-mediated activation of signal transduction cascades. We propose to accomplish the following Specific Aims: 1) to characterize the neurochemical and cerebrovascular anatomy physiology and cognitive function of the TNFalpha-transgenic rat under normal conditions and in response to ischemic brain injury 2) to identify the cellular origin of TNFalpha and define the immune response to cerebral ischemic injury in the TNFalpha-transgenic rat 3) to use the transgenic animal to simulate how elevated TNFalpha levels affect TNFR number or distribution and modulate signal transduction cascades in ischemic human brain 4) to use the transgenic animal to simulate how elevated TNFalpha levels influence apoptotic neuronal degeneration in ischemic human brain and 5) to assess the research utility of the TNFalpha-transgenic rat as a model for therapeutic intervention by determining if pre- or post-ischemic inhibition of TNFalpha synthesis attenuates ischemic injury.

project_terms:
Acids;Affect;Animals;Animals Wild;Apoptosis;Apoptotic;Astrocytes;Attenuated;Behavior;Binding (Molecular Function);Biochemical;Biological Assay;Brain;Brain Diseases;Brain Infarction;Brain Injuries;Brain Ischemia;Cell Death;Cell Line;Cells;Cerebral Infarction;Cerebrovascular Circulation;Cerebrum;Cessation of life;Clinical Management;Cognitive;Complement;Condition;Coupled;Cysteine;Data;Death Domain;Electrophoretic Mobility Shift Assay;Endopeptidases;Enzyme-Linked Immunosorbent Assay;Family;Feedback;Functional disorder;Gel;Genes;Goals;Human;Imines;Immune;Immune response;Immunoassay;Infarction;Inflammatory;Injury;Intervention;Investigation;Ischemia;Ischemic Brain Injury;Ischemic Penumbra;JUN gene;Label;Link;MAPK14 protein human;MPP1 protein human;Measurement;Measures;Mediating;Methods;Microglia;Microscopy Confocal;Mitogen-Activated Protein Kinases;Modeling;Molecular Weight;Mus;NF-kappa B;Necrosis;Nerve Degeneration;Neuroglia;Neurons;Nuclear;Numbers;Occlusion Middle Cerebral Artery;Pathway interactions;Peptide Hydrolases;Performance;Phosphorylation;Physiological;Physiology;Principal Investigator;Promotor (Genetics);Protein Overexpression;Proteins;RNA Messenger;Rattus;Reaction;Receptor Mediated Signal Transduction;Research;Sampling;Science of Anatomy;Science of neurochemistry;Signal Transduction;Simulate;Stress;Support of Research;Surveys;TNF gene;TNF protein human;Techniques;Testing;Thalidomide;Therapeutic;Therapeutic Intervention;Time;Tissues;Transgenes;Transgenic Animals;Transgenic Organisms;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;acute stroke;caspase;caspase-8;cerebrovascular;cognitive function;cytokine;day;design;immunoregulation;inhibitor/antagonist;intercellular cell adhesion molecule;iodoantipyrine;macrophage;man;member;monocyte;neuron apoptosis;p65;programs;prototype;receptor;research and development;research study;response;spatiotemporal;stress activated protein kinase;stress-activated protein kinase 1;stroke;transcription factor;transcriptional coactivator p75


application_id: 7213463
project_number: 5R01AA013168-05
project_title: Alcohol apoptosis and lung opportunistic infection
administering_ic: NIAAA
award_notice_date: 2007-03-07
application_type: 5
activity_code: R01
ic: AA
serial_number: 013168
program_official: JUNG, KATHY
project_start_date: 2003-04-01
project_end_date: 2010-03-31
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
contact_pi_person_id: 8535326
contact_pi: D'SOUZA EL-GUINDY, NYMPHA BRUNA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of this proposal is to elucidate the mechanisms by which chronic alcohol (EtOH) ingestion predisposes the host to pulmonary infections.  In spite of years of extensive research the precise mechanisms whereby pulmonary infections develop in alcoholics are not fully elucidated.  Therefore novel approaches need to be undertaken to further our understanding of how these infections develop.  Based on the gaps in our understanding of why alcoholics have a greater propensity to acquire lung infections and the recently discovered pivotal role for apoptosis in health and diseases the project proposes to test three hypotheses: 1) EtOH alters basal rate of lung apoptosis.  The primary targets of this EtOH effect are the alveolar macrophages (AM) and during an infection also infiltrating cells; 2) EtOH alters apoptosis of lung immune cells by modulating the amount and interaction of apoptotic protein adapters; and 3) The EtOH-induced apoptotic death of lung cells overwhelms the inherent clearance mechanisms in the lung. As a result the uncleared dead cells undergo secondary necrosis leading to persistent lung inflammation.  Accordingly the proposal has four specific aims: 1) to determine the temporal relationship between EtOH-altered rate of lung apoptosis and severity of infection; 2) to determine the lung cell types undergoing apoptosis following EtOH ingestion and infection; 3) to determine the mechanism(s) underlying EtOH effects on lung immune cell apoptosis and 4) to determine the temporal relationship between EtOH-induced alterations in the kinetics of lung apoptosis and the ability of AM to remove apoptotic cells. To achieve these goals mice will be fed EtOH for various periods and infected with Streptococcus pneumoniae (SP).  These mice will be used to assess the apoptotic and pathologic state of the lung.  To evaluate the potential deleterious effects of EtOH enhanced lung cell apoptosis the lung propensity to clear an SP infection will be evaluated in presence and absence of apoptosis inhibitors.  By applying biochemical molecular and cell biology techniques the steps of apoptotic signaling pathway where EtOH acts will be established.  Finally the project will determine if there is a correlation between EtOH-induced apoptosis decreased phagocytosis and increased inflammation.  The project will provide essential and novel information to: 1) broaden our understanding of how EtOH increases the hosts' susceptibility to pulmonary infections and 2) pave the way to developing therapeutic interventions to control pulmonary infections.

project_terms:
Affect;Alcohol abuse;Alcohol consumption;Alcohols;Alveolar;Animals;Apoptosis;Apoptosis Inhibitor;Apoptotic;Area;Attenuated;Bacterial Infections;Biochemical;Cell surface;Cells;Cellular biology;Cessation of life;Chemical Agents;Chronic;Disease;Dose;Excision;Goals;HIV;Health;Immune;Immunologic Surveillance;In Vitro;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Kinetics;Lung;Lung Inflammation;Macrophages Alveolar;Measures;Mediator of activation protein;Medical History;Mice Knockout;Mitochondria;Molecular;Mus;Natural immunosuppression;Necrosis;Numbers;Opportunistic Infections;Organ;Organism;Pathologic;Pathway interactions;Phagocytosis;Phase;Play;Pneumococcal Infections;Pneumonia;Predisposition;Process;Proteins;Rate;Recurrence;Research;Research Design;Risk;Rodent Model;Role;Severities;Signal Pathway;Source;Streptococcus pneumoniae;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Work;adapter protein;alcohol effect;base;caspase;cell type;chronic alcohol ingestion;feeding;in vivo;inhibitor/antagonist;mRNA Expression;macrophage;microbicide;neutrophil;novel;novel strategies;novel therapeutics;pathogen;problem drinker;receptor;research study;time use


application_id: 7211611
project_number: 2R01EY012974-05A2
project_title: The role of costimulatory molecules in uveitis
administering_ic: NEI
award_notice_date: 2007-01-26
application_type: 2
activity_code: R01
ic: EY
serial_number: 012974
suffix: A2
program_official: SHEN, GRACE L
project_start_date: 2000-01-01
project_end_date: 2011-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: The identification of costimulatory molecules has provided important insights into molecular mechanisms for the regulation of the immune response and more importantly into several novel approaches for autoimmune or tumor immunotherapy. The growing number of known T cell costimulatory pathways together with the dynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatory molecules regulating responses of naive effector and memory T cells. With the support of the current grant my laboratory has made significant progress in understanding the role of costimulatory molecules in autoimmune uveitis. However our studies have also raised two important questions: (1) why are effector uveitogenic T cells more resistant than naive T cells to treatment by costimulatory molecule blockers? (2) Do pathogenic and regulatory T cells rely on different costimulation so that a specific treatment regimen can be identified to maximally suppress the pathogenic response with a minimal inhibitory effect on regulatory T cell activation? For human disease immunotherapies that can interfere with an ongoing autoimmune disease are more important than those preventing the development of disease since disease has already started by the time the patient visits the doctor. Thus the long-term goal of this proposal is to explore therapeutic approaches inhibiting already activated autoreactive effector T cells. We will therefore determine whether CD28/B7 costimulatory molecules are crucial for the pathogenic effect of uveitogenic T cells specifically: (1) whether effector and regulatory T cells use CD28/B7 differently in terms of time and quantity and whether blockade of a combination of costimulatory molecules favors the treatment of ongoing autoimmune disease; (2) whether we can identify therapeutic regimens that have a limited impact on regulatory T cell activity while inhibiting pathogenic activity; and (3) whether a combined treatment acting on costimulation of autoreactive T cell and ocular inflammation can provide better control of ongoing disease. To provide a working model that will allow better understanding of the pathogenesis of recurrent uveitis we have established chronic recurrent models in the rat and mouse. These studies should provide insights into the pathogenic mechanism leading to disease progression and help in the development of supplementary therapies for this devastating disease.

project_terms:
Acute;Animals;Anti-Inflammatory Agents;Antibodies;Autoimmune Diseases;Autoimmune Process;CTLA4-Ig;Cells;Chronic;Clinical Treatment;Combined Modality Therapy;Complex;Data;Development;Disease;Disease Progression;Disease model;Disease remission;Dose;Environmental Risk Factor;Eye;Generations;Genetic;Goals;Grant;Guanine Nucleotide Dissociation Inhibitors;Human;Immune response;Immunotherapy;Inflammation;Inflammatory;LTB4R gene;Laboratories;Leukotriene B4;Ligation;Lymphoid;MHC antigen;Mediating;Modeling;Molecular;Mus;Nature;Numbers;Onset of illness;Pathogenesis;Pathway interactions;Patients;Pattern;Phase;Protocols Treatment;Rattus;Reaction;Recruitment Activity;Recurrence;Regulation;Relapse;Research Personnel;Resistance;Rodent;Role;Signal Transduction;Study models;T memory cell;T-Cell Activation;T-Lymphocyte;Therapeutic;Therapeutic Effect;Time;Uveitis;Visit;Work;autoimmune uveitis;autoreactive T cell;cell motility;chemokine;cytokine;disorder control;human disease;insight;novel strategies;prevent;programs;protective effect;receptor;response;treatment effect;tumor


application_id: 7211504
project_number: 5K23AA014235-05
project_title: Suppression of CYP2E1 in drug induced liver injury
administering_ic: NIAAA
award_notice_date: 2007-03-28
application_type: 5
activity_code: K23
ic: AA
serial_number: 014235
program_official: RADAEVA, SVETLANA
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: ZAA1-DD(01)
contact_pi_person_id: 6807001
contact_pi: LINDER, MARK W
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant):   The long-term career goals are to develop the clinical discipline of pharmacogenomies and the short-term goal is to develop an independent patient-oriented research career focusing on the validation and development of pharmacogenentic diagnostics. Environment: The University of Louisville has adopted pharmacogenetics as one of seven key areas for development. The Pharmacogenetic Diagnostics Laboratory (founded by Dr's Valdes and Linder) is one of the first CLIA certified clinical pharmaeogenetic laboratories in the world. Dr C. McClain (Co-mentor) is Director of the newly established Clinical Research Center at the University of Louisville Hospital. Preliminary findings: Within the proximal promoter of the CYP2E1 gene is a nucleotide sequence (cytokine response element) responsible for gamma-interferon (gamma-IFN)-dependent suppression of gene transcription. A naturally occurring polymorphisrn G(-71)T within this sequence renders the CYP2E1 promoter insensitive to suppression by gamma-IFN. Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter. Polymorphism within the promoter sequence interrupts this feedback and leads to increased toxicity from reactive intermediate products. Approach: To test this hypothesis we will; i) Investigate  the mechanism of IFN-gamma mediated CYP2E1 suppression in humans ii) Evaluate the influence of IFN-gamma on the LD 50 of CYP2E 1 substrates which undergo metabolic bioactivation iii) Characterize the molecular detail of IFN-gamma dependent suppression of CYP2E1 and iv) Evaluate the relationship between the CYP2E1*7B allele and selected human diseases influenced by the catalytic properties ofCYP2E1. Significance: This research will identify a novel mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1. These findings may lead to development of a diagnostic test for identifying susceptible individuals and provide insight into potential therapeutic or preventive approaches.

project_terms:
Adopted;Alleles;Area;Base Sequence;CYP2E1 gene;Clinical;Clinical Research;Cytochromes;Development;Diagnostic;Diagnostic tests;Discipline;Elements;Environment;Enzymes;Exposure to;Failure (biologic function);Feedback;Goals;Hospitals;Human;Individual;Inflammation;Inflammatory Response;Injury;Interferon Type II;Interferons;Laboratories;Laboratory Finding;Lead;Liver;Mediating;Mediator of activation protein;Mentors;Metabolic;Metabolism;Molecular;Pharmaceutical Preparations;Pharmacogenetics;Phase;Physiological;Polymorphism Genetic;Predisposition;Preventive;Production;Prohibit;Promotor (Genetics);Property;Recovery;Regulation;Research;Response Elements;Risk;Structure;Testing;Therapeutic;Time;Toxic effect;Transcription Genetic;Universities;Validation;Variant;Work;career;cell injury;cytokine;enzyme activity;human disease;insight;novel;patient oriented research;response


application_id: 7211371
project_number: 5R01HL076794-04
project_title: Hematopoietic Stem Cell Therapy for Myocardial Regeneration
administering_ic: NHLBI
award_notice_date: 2007-04-12
application_type: 5
activity_code: R01
ic: HL
serial_number: 076794
program_official: BUXTON, DENIS B
project_start_date: 2004-04-01
project_end_date: 2009-03-31
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Recent reports that HSCs can regenerate infarcted myocardium have unleashed a tidal wave of enthusiasm for translating these findings to the clinical arena.  A number of institutions have already initiated studies of cytokine or HSC therapy in patients with acute MI.  It is our opinion that this rush to clinical trials is not only premature but possibly counterproductive and that further careful preclinical investigation is necessary to establish the efficacy of various treatment protocols and the underlying mechanisms.  For example nothing is currently known regarding whether i.v. HSC administration is effective which cytokine or combination of cytokines is more likely to succeed how long the window of efficacy is and whether HSCs are effective in the context of reperfusion.  Similarly nothing is known regarding the nature of the integrin/adhesion molecule interactions that underlie the homing of HSCs or the potential synergistic role of accessory calls specifically the FCs.  Our fundamental hypothesis is that both i.v.  injected and cytokine-mobilized HSCs can regenerate infarcted myocardium and that this process is mediated by a well-defined cascade of molecular interactions that involve specific adhesion molecules (ICAM-1 VCAM-1 P-selectin and E-selectin) integrins (VLA-4 VLA-5 and LFA-1) chemokines (SDF-1) and chemokine receptors (CXCR-4).  We further propose that FCs exert an important potentiating effect on HSC-dependent cardiac reqeneration and that this process can be further enhanced by FL These hypotheses will be tested in a well-established murine model using a broad multidisciplinary approach that will encompass diverse techniques (integrative physiology protein chemistry biochemistry pathology confocal microscopy immunohistochemistry molecular immunology molecular biology and gene therapy).  Aim I will assess the effectiveness of two clinically-relevant forms of HSC therapy (i.v.  HSCs and cytokines) in two different models designed to simulate reperfused and nonreperfused MI and will define the time-window of efficacy.  Three clinically-applicable cytokines (G-CSF SCF FL) will be tested alone or in combination.  Using gene targeted mice and immunologic blockade of integrins Aim 2 will systematically investigate the role of four specific adhesion molecules (VCAM-1 ICAM-1 P-selectin and E-selectin) and three specific integrins (VLA-4 VLA-5 and LFA-1) in HSC migration to the infarcted myocardium.  Aim 3 will decipher the role of SDF-1/CXCR-4 interactions in HSC homing and infarct repair using adenovirus-mediated gene transfer of SDF-1 and CXCR-4.  Aim 4 will explore the differential regenerative capacity of HSCs and FCs harvested from bone marrow vis-a-vis peripheral blood and the underlying mechanisms.  Aim 5 will determine whether FCs induce allogeneic graft tolerance to HSCs via a Th2 cytokine (IL-4 and IL-10)-dependent mechanism.  This proposal will yield novel information regarding the ability of i.v.  HSCs and various cytokine regimens to regenerate infarcted myocardium the molecular mechanisms for HSC homing the potential role of FCs and the beneficial effects of FL. The results may eventually lead to the development of novel therapeutic strategies in patients with ischemic heart disease.

project_terms:
Abbreviations;Ablation;Acute myocardial infarction;Adenoviruses;Adult;Allogenic;Animals;Area;Arts;Binding (Molecular Function);Biochemistry;Blood Cells;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cardiac;Cell Adhesion Molecules;Cell Survival;Cells;Cellular biology;Chemotactic Factors;Clinical;Clinical Research;Clinical Trials;Complex;Development;Diffuse;Discipline;Doctor of Medicine;E-Selectin;Echocardiography;Effectiveness;Engraftment;Experimental Animal Model;Foundations;Future;Gene Targeting;Gene Transfer;Genetic;Harvest;Heart;Hematopoietic stem cells;Homing;I-antigen;Immunohistochemistry;Immunologics;In Vitro;Infarction;Injection of therapeutic agent;Institution;Integrin alpha4beta1;Integrin alpha5beta1;Integrins;Intercellular adhesion molecule 1;Interleukin-10;Interleukin-4;Intervention;Invasive;Investigation;Laboratories;Lead;Left;Ligands;Mechanics;Mediating;Mice Knockout;Microscopy Confocal;Modeling;Molecular;Molecular Immunology;Molecular Profiling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial tissue;Myocardium;Natural regeneration;Nature;Numbers;P-Selectin;Pathologic;Pathology;Patients;Phenotype;Physiological;Physiological reperfusion;Physiology;Play;Process;Property;Protein Chemistry;Protocols documentation;Protocols Treatment;Reperfusion Therapy;Reporting;Research;Research Design;Role;Route;Simulate;Splenectomy;Stromal Cell-Derived Factor 1;Stromal Cells;Structure;Surface Antigens;Techniques;Testing;Therapeutic;Time;Tissues;Tolerance Graft;Transfection;Translating;Transplantation;Transplantation Homologous;Vascular Cell Adhesion Molecule-1;Ventricular;base;cell motility;chemokine;chemokine receptor;clinically relevant;concept;cytokine;cytokine therapy;gene therapy;hemodynamics;in vivo;insight;interdisciplinary approach;knockout gene;migration;model design;novel;novel therapeutics;peripheral blood;pre-clinical;preclinical study;prevent;reconstitution;repaired;research clinical testing;stem cell therapy;trafficking;transdifferentiation


application_id: 7209777
project_number: 5R01NS046566-04
project_title: Peroxynitrite-Induced Oxidative Damage in TBI
administering_ic: NINDS
award_notice_date: 2007-02-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 046566
program_official: HICKS, RAMONA R
project_start_date: 2004-02-01
project_end_date: 2009-01-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Extensive evidence now supports the concept that the reactive oxygen species (ROS)-mediated oxidative damage to lipids proteins and nucleic acids plays a major role in the acute pathophysiology of traumatic brain injury (TBI) and that antioxidant drugs which inhibit this damage will reduce secondary brain injury and improve neurological recovery. However the optimal design of antioxidant treatment for TBI requires a more complete understanding of the source and characteristics of ROS formation. Recent work indicates that mitochondria can become an important source of ROS when they become dysfunctional as a result of the massive TBI-induced rise in intracellular calcium (Ca++). Other work suggests that a key ROS formed by mitochondria is peroxynitrite (PON). PON-derived nitrogen dioxide (NO2) carbonate (CO3) and hydroxyl (OH) radicals can cause oxidative damage to mitochondrial lipids (lipid peroxidation) and proteins (carbonylation nitration) exacerbating intracellular Ca++ overload and triggering calpain-mediated cytoskeletal degradation and neurodegeneration. The specific aims of this proposal are to test the following hypotheses: 1) that post-traumatic oxidative damage in both diffuse and focal TBI is mediated by PON and that the time course of PON-mediated damage to lipids and proteins precedes calpain-mediated cytoskeletai damage and neurodegeneration 2) that mitochondrial dysfunction is a major source of PON and that mitochondria are an initial site of lipid and protein oxidative damage 3) that pharmacological scavengers of PON or PON-derived oxygen radicals can protect isolated brain mitochondria from oxidative damage and dysfunction and 4) that pharmacological scavenging of PON or PON-dedved oxygen radicals will effectively inhibit post-TBI oxidative damage and dysfunction in brain mitochondria and attenuate downsteam cytoskeletal degradation and neurodegeneration. Experiments will be carried out in models of moderate and severe diffuse and focal TBI. A systematic investigation of the role of PON in acute TBI and a careful examination of the neuroprotective efficacy of compounds which scavenge it after it is formed or that block PON-induced oxidative damage is expected to lead to a clinically effective and practical antioxidant neuroprotective strategy for acute TBI.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;Acute;Address;Adenine Nucleotides;Adult;Antioxidants;Attenuated;Behavioral;Blood Vessels;Brain;Brain Injuries;Buffers;Calcium;Calpain;Carbonates;Cerebrum;Characteristics;Classification;Contusions;Data;Diffuse;Elements;End Point;Esters;Exposure to;Extravasation;Functional disorder;Generations;Human Development;Hydroxyl Radical;Injury;Injury of central nervous system;Investigation;Lead;Link;Lipid Peroxidation;Lipids;Mediating;Mediator of activation protein;Membrane Potentials;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Mus;Nerve Degeneration;Neurologic;Neurons;Nitric Oxide Synthase;Nitrogen Dioxide;Nucleic Acids;Pathway interactions;Penicillamine;Peroxonitrite;Pharmaceutical Preparations;Pharmacologic Substance;Play;Production;Protein Processing Post-Translational;Proteins;Rain;Reactive Oxygen Species;Recovery;Relative (related person);Research;Rodent;Role;Site;Source;Staging;Testing;Therapeutic;Time;Traumatic Brain Injury;Tyrosine;U-83836E;Work;clinically relevant;comparative;concept;day;design;improved;inhibitor/antagonist;injured;innovation;lipid peroxidation inhibitor;male;mitochondrial dysfunction;mitochondrial membrane;nitration;novel;prevent;programs;research study;tool


application_id: 7209755
project_number: 5R01AI044254-07
project_title: Analysis of Borrelia burgdorferi Erp Proteins
administering_ic: NIAID
award_notice_date: 2007-03-09
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: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): Lyme disease is a significant threat to human health throughout many parts of the USA. The causative agent Borrelia burgdorferi is maintained in nature by infectious cycles involving ticks and many species of vertebrates with humans being incidental hosts. Understanding the mechanisms by which B. burgdorferi infects humans and is transmitted from vector ticks will be important in development of improved methodologies to prevent and treat this disease. During transmission from tick to mammal B. burgdorferi significantly increases expression levels of the Erp family of outer surface proteins. Expression of Erp proteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferi encode multiple Erp lipoproteins a ubiquity that is highly suggestive of important roles for these proteins in B. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulator factor H in vitro raising the possibility that these proteins may function in vivo to protect the bacteria from killing by the host's innate immune system. Based on results of our previous studies we hypothesize that Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processes and that these functions necessitate the bacteria regulate Erp expression. To test this hypothesis we will (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erp mutants 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 of transcription throughout mammalian and tick infection; and (3) characterize functions of the novel DNA binding proteins we discovered that specifically bind to erp operator DNA. Results of our studies will provide important 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;novel;prevent;tool;transmission process;vector


application_id: 7209748
project_number: 5R01GM042476-17
project_title: Function of snRNP particles in pre-mRNA splicing
administering_ic: NIGMS
award_notice_date: 2007-03-15
application_type: 5
activity_code: R01
ic: GM
serial_number: 042476
program_official: GREENBERG, JUDITH H
project_start_date: 1989-07-01
project_end_date: 2011-03-31
study_section: Cell Development and Function 1[CDF-1]
contact_pi_person_id: 1898350
contact_pi: RYMOND, BRIAN C.
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): The pre-mRNA transcripts of most mammalian genes contain multiple introns that must be precisely removed before the mRNA can be used in protein synthesis. For many genes this pre-mRNA splicing reaction is regulated by developmental or environmental signals. Errors in the splicing pathway can have devastating health consequences and account for approximately 15% of all known human genetic disorders. The diagnosis and treatment of splicing-related disorders will profit by a better understanding of the cellular rules governing intron removal. The pre-mRNA splicing enzyme or spliceosome is a large ribonucleoprotein complex composed of over 70 proteins and 5 small nuclear RNAs. A widely cited model of spliceosome assembly activation and disassembly (or the spliceosome cycle) has evolved from the results of in vitro experimentation conducted over the last 15 years. The modulation of splicing efficiency and alterative splice site selection often can be explained by changes in spliceosome assembly observed in the presence or absence of specific regulator proteins (or cis-acting elements). The recent isolation from yeast of a U2U5U6 ribonucleoprotein (RNP) complex reminiscent of a late stage or post-catalytic spliceosome supports this spliceosome cycle model. In contrast the identification of what appears to be a fully assembled but pre-mRNA-free "penta-snRNP" spliceosome from yeast raises the question of whether spliceosome disassembly actually occurs in vivo. We will address this apparent discrepancy by tests of two hypotheses. First that a spliceosome cycle occurs within cells and progresses through a series of splicing factor-dependent assembly and disassembly steps. Second that the Clf1p assembly factor facilitates integration of the prespliceosome with the U4/U6.U5 tri-snRNP particle through branchpoint reorganization that includes the recruitment of RNA export factors. This work will provide new experimental tools for the analysis of RNA processing and generate conceptual frameworks from which to view spliceosome assembly and the integration of the pre-mRNA splicing and RNA export pathways in living cells.

project_terms:
Accounting;Address;Biochemical;Catalysis;Cells;Complex;Condition;Deltastab;Development;Diagnosis;Disease;Dissociation;Environment;Enzymes;Event;Excision;Genes;Health;Hereditary Disease;Heterogeneous Nuclear RNA;Human;In Vitro;Introns;Investigation;Life;Modeling;Pathway interactions;Pentas;Protein Biosynthesis;Proteins;RNA;RNA Processing;RNA Splicing;RNA Messenger;Reaction;Recruitment Activity;Ribonucleoprotein U2 Small Nuclear;Ribonucleoprotein U5 Small Nuclear;Ribonucleoproteins;Ribonucleoproteins U6 Small Nuclear;Series;Signal Transduction;Site;Small Nuclear RNA;Small Nuclear Ribonucleoproteins;Spliceosome Assembly Pathway;Spliceosomes;Staging;Standards of Weights and Measures;Testing;Transcript;Work;Yeasts;base;cis acting element;in vitro Assay;in vivo;mRNA Precursor;tool


application_id: 7208080
project_number: 5R01HL078976-02
project_title: Saturated Fatty Acid and Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2007-02-27
application_type: 5
activity_code: R01
ic: HL
serial_number: 078976
program_official: ERSHOW, ABBY
project_start_date: 2006-03-15
project_end_date: 2011-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): The central hypothesis to be tested in this proposal is that binding of saturated fatty acid to SR-BI activates AMP kinase which results in the production of eNOS-dependent peroxynitrite and subsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heart disease for decades; however numerous studies have demonstrated that the type of fat may be more important than the total amount of fat in the diet. Unsaturated fats such as n-3 and n-6 fatty acids are thought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e. myristic acid and palmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenic in part by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearly influence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorial disease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause an increase in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal is to determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasma cholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acids that involve SR-BI caveolin AMP kinase and eNOS which subsequently results in the generation of the pro- atherogenic compound peroxynitrite. Three specific aims are proposed. Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolin and to determine the domain within caveolin that interacts with SR-BI. Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains within caveolin and AMP kinase that interact. Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fatty acid-induced peroxynitrite production and subsequently atherosclerosis.

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


application_id: 7208013
project_number: 5R37AG004542-21
project_title: HIPPOCAMPAL SYNAPTIC STRUCTURE--PHYSIOLOGY DURING AGING
administering_ic: NIA
award_notice_date: 2007-03-21
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1998-01-01
project_end_date: 2010-02-28
study_section: NSS
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
This is a proposal for a competitive continuation of a project on basic membrane and synaptic mechanisms of brain aging that has been ongoing for over 15 years. The past periods in this project have found two main electrophysiological alterations in rat hippocampal CAl neurons with aging: 1) impaired synaptic frequency potentiation (facilitation); and 2) an increase in voltage-gated Ca2+ influx. These results and others have contributed to the general Ca2+ hypothesis of brain aging and dementia. In the most recent period the single channel patch clamp configuration was adapted for brain aging studies and identified an increase in the membrane density of available L-type Ca2+ channels as a potential molecular basis for the changes with aging seen at the cellular level. Here the specific hypothesis that the increase in L-type Ca2+ channels is a key mechanism in both impaired function (synaptic potentiation or spike generation) and neuronal vulnerability to death of aged mammalian neurons will be tested. Studies will be conducted in rat hippocampal slices and long-term hippocampal cultures in which L-type Ca2+ channels are enriched. Effects of repetitive synaptic activation on the magnitude and topography of Ca2+ transients in hippocampal slice neurons of adult and aged rats will be studied using a rapid UV-compatible confocal laser scanning microscope for Ca2+ imaging simultaneously with intracellular electrophysiological recording. Multiple specific channel blockers and kinase modulators will be used to define critical Ca2+ entry pathways. These studies will determine whether postsynaptic Ca2+ transients particularly through L-channels can modulate neuronal short-term synaptic plasticity and contribute to changes in aged brain neurons. In parallel studies of cell cultures the role of time-dependent ion channel changes in cell death will be tested by investigating differences in vulnerability to excitotoxicity in cells with different complements of L-type channels. Single channel recording Ca2+ imaging pharmacologic blockade and kinase modulation will be used to define Ca2+ sources critical for necrosis and apoptosis.


application_id: 7197997
project_number: 5R03DC007315-02
project_title: Neural Substrates of Component Lexical Semantic Processes
administering_ic: NIDCD
award_notice_date: 2007-03-12
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: 2009-03-31
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:
DESCRIPTION (provided by applicant): Extracting meaning from words (lexical semantics) is critical to normal language functioning. Lexical semantic impairment can result from a variety of causes including developmental abnormalities stroke and degenerative diseases but may reflect damage to one or more component processes. Current language models have identified two qualitatively different components of the lexical semantic system: 1) An automatic component enables rapid access to semantics within milliseconds of lexical input; and 2) a controlled component evolves more slowly and guides strategic retrieval of semantic information not recovered automatically. In addition some processes associated with these components are thought to depend upon the modality of incoming stimuli. The objective of the project is to identify the neural correlates of these behaviorally separable automatic and controlled components of the lexical semantic system within and across visual and auditory modalities. In a preliminary study we identified dissociable neural correlates of visually cued automatic and controlled lexical semantic processing in healthy volunteers using event-related fMRI and a primed lexical decision task. A series of similar studies are proposed to characterize more precisely the roles of several frontal and temporal lobe brain regions in components of the lexical semantic system. The design is novel in that automatic and controlled semantic priming conditions will be compared directly using randomized designs identical to those used in behavioral research. There are three goals. The first goal is to characterize more precisely the role of a left frontal region in visually cued controlled retrieval of lexical semantic information. The second goal is to characterize more precisely the role of a left temporal region in visually cued automatic lexical semantic processing. The third goal is to identify neural regions involved in auditorily cued lexical semantics that overlap and are dissociable from those involved in visually cued lexical semantics. Identifying neural systems associated with component processes involved in extracting meaning from words is of central importance to understanding the structure and organization of the lexical semantic system and should aid diagnosis and rehabilitation of language disorders.

project_terms:
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: 7197351
project_number: 5R01HL074369-04
project_title: Monocarboxylate transporter in hypoxic preconditioning
administering_ic: NHLBI
award_notice_date: 2007-03-13
application_type: 5
activity_code: R01
ic: HL
serial_number: 074369
program_official: GOLDEN, AL
project_start_date: 2004-04-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZRG1-ALTX-4(02)M]
contact_pi_person_id: 1885973
contact_pi: WANG, YANG
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Tissue/organ hypoxia impacts on the progression and outcome of a variety of human disorders whereas environmental hypoxia threatens the life of healthy individuals such as high altitude sojourners. We have recently discovered a novel protective mechanism in unacclimatized mice that significantly prolongs survival of these animals when exposed to lethal hypoxia. The robust protection was induced by a simple procedure of whole-body hypoxic preconditioning (WHPC) became effective shortly after the induction and was accompanied by improved organ functions in the lung including reduced lung cytotoxicity vascular permeability and pulmonary edema and ameliorated gas-exchange function. Further we found that the lung consumed lactate under both normoxic and hypoxic conditions and that WHPC enhanced the uptake and metabolism of lactate in the lung. This enhancement appeared to depend on the upregulation of monocarboxylate transporter 2 (MCT2) a member of the transporter gene family responsible for lactate movement across the cellular and the mitochondrial membranes. We therefore hypothesize that WHPC protects the entire organism against hypoxia by improving organ functions in the lung and that the latter results from enhanced capacity of the lactate-metabolism machinery in this organ. To test this hypothesis we will (1) characterize the beneficial effect of WHPC on cellular integrity by measuring overall cytotoxicity markers and cell-specific markers for endothelial and epithelial cells. We will also examine whether the beneficial effect of WHPC on cellular integrity is correlated with tissue ATP content in the lung; (2) determine the role of lactate in energy metabolism in the lung by exploring lactate and glucose kinetics in the lung under normoxic and hypoxic conditions with or without WHPC. We will also examine whether disruption of lactate metabolic pathway attenuates the protective effects of WHPC; (3) delineate temporal expression patterns of MCT2 under normoxic and hypoxic conditions with or without WHPC pretreatment We will also delineate spatial expression patterns of MCT2 at the cellular and the subcellular levels; and (4) establish a cause-effect relationship between the upregulation of MCT2 and the protection afforded by WHPC by examining whether inhibition of MCT2 using pharmacological agents and siRNA-mediated gene silencing attenuates the protective effects of WHPC and whether overexpression of MCT2 in a transgenic mouse model mimics the protective effects of WHPC. Insights into the cellular and molecular basis of WHPC will underpin future efforts for exploiting this protective mechanism for therapeutic purposes.

project_terms:
Acclimatization;Acute;Altitude;Animals;Attenuated;Cells;Condition;Disease;Disruption;Energy Metabolism;Epithelial Cells;Exposure to;Future;Gases;Gene Family;Gene Silencing;Glucose;Human;Hypoxia;Individual;Interruption;Ischemic Preconditioning;Kinetics;Life;Lung;Lung Capacity;Markers Biochemical;Measures;Mediating;Metabolic Pathway;Metabolism;Molecular;Movement;Mus;Organ;Organism;Outcome;Oxygen;Pattern;Procedures;Protein Overexpression;Pulmonary Edema;Purpose;RNA Small Interfering;Rain;Role;Supplementation;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Up-Regulation (Physiology);Vascular Permeabilities;Week;base;cytotoxicity;day;improved;improved functioning;insight;member;mitochondrial membrane;mouse model;novel;preconditioning;protective effect;uptake


application_id: 7197289
project_number: 5R01HL036597-20
project_title: Pleural Liquid Exchange and Lung Mechanics
administering_ic: NHLBI
award_notice_date: 2007-03-08
application_type: 5
activity_code: R01
ic: HL
serial_number: 036597
program_official: GOLDEN, AL
project_start_date: 1995-07-01
project_end_date: 2009-03-31
study_section: Respiratory Physiology Study Section[RESP]
contact_pi_person_id: 1862938
contact_pi: LAI-FOOK, STEPHEN J
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
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this research is to study some factors that contribute to the formation of pleural liquid. The primary function of pleural liquid is lubrication of the pleural surfaces during breathing. Thus the mechanisms by which pleural liquid is formed in and cleared from the pleural space are important to understanding the pathogenesis of diseases such as pleural effusions and pleural adhesions. Our recent studies in the excised rat diaphragm showed transport properties similar to those of pleural and other interstitial membranes and suggested that part of the pleural liquid might be derived from the peritoneal cavity via the diaphragm. Studies by other investigators have suggested a role for active mesothelial transport of liquid and protein. This proposal focuses on two areas. One is the contribution to pleural liquid and protein from the peritoneal cavity via the diaphragm relative to the contribution from the microcirculation. The transport of radioactive tracer albumin from the circulation into the pleural space diaphragm and peritoneal cavity will be measured in conscious rats. Other experiments will study transport from the peritoneal cavity into the diaphragm circulation and pleural space. The effect of hypertension on transport will be studied using spontaneously hypertensive rats and its genetic normotensive control the Wistar-Kyoto rat. The second area of research deals with the contribution of active transport of liquid and protein across pleural membrane relative to passive transport by diffusion and bulk flow. The pericardial membrane and diaphragm will be studied because these tissues are free standing unlike the visceral and parietal pleurae that need to be stripped for in vitro studies. A specific objective is to develop a method to separate passive from active transport properties of pericardium and diaphragm tissues that have both mesothelium and interstitium.

project_terms:
Abdomen;Adhesions;Albumins;Area;Biological Transport Active;Blood Circulation;Breathing;Carrier Proteins;Conscious;Diaphragm (Anatomy);Diffusion;Disease;Genetic;Goals;Greater sac of peritoneum;Hydrostatic Pressure;Hypertension;In Vitro;Ion Transport;Liquid substance;Lubrication;Lung;Measures;Mechanics;Membrane;Mesothelial Cell;Mesothelium;Methods;Microcirculation;Nocodazole;Oryctolagus cuniculus;Parietal pleura;Pathogenesis;Pathway interactions;Pericardial body location;Pericardial sac structure;Peritoneal;Pleura;Pleural;Pleural effusion disorder;Pressure- physical agent;Property;Proteins;Radioactive Tracers;Rate;Rats Inbred SHR;Rats Inbred WKY;Rattus;Relative (related person);Research;Research Personnel;Role;Surface;Tissues;Transport Active Ion;Visceral;Water;inhibitor/antagonist;interstitial;macromolecule;normotensive;passive transport;research study;response;theories;transcytosis;transport inhibitor


application_id: 7197230
project_number: 2R01GM055343-25
project_title: Hepatic Drug Elimination in Pregnancy
administering_ic: NIGMS
award_notice_date: 2006-12-05
application_type: 2
activity_code: R01
ic: GM
serial_number: 055343
program_official: OKITA, RICHARD T
project_start_date: 1979-09-30
project_end_date: 2007-11-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-12-05
project_abstract:
DESCRIPTION (provided by applicant): This proposal focuses on the function and expression of MRP2 (ABCC2) the ABC transporter that mediates the biliary excretion of glucuronide and glutathione conjugates from the hepatocyte into bile. The proposal builds on our findings that 1) MRP2 transports tauroursodeoxycholate (TUDC) a bile acid used for the treatment of cholestatic liver disease including intrahepatic cholestasis of pregnancy (ICP) 2) estradiol-17B-D-glucuronide (E217G) causes increased permeability of the hepatocellular tight junction that coincides with endocytic retrieval of MRP2 and the bile salt export pump (BSEP) from the canalicular membrane and decreased bile flow and 3) identification of upstream open reading frames (uORF) in the 5' leader sequences of rat human and mouse MRP2. Aim 1 will characterize MRP2-mediated transport of hydrophilic bile acids including TUDC B-muricholic acid and tetrahydroxy bile acids and the importance of heterotropic and homotropic activation in their transport. We will also examine the ability of MRP2 variants to transport these bile acids. We will use an MRP2 baculovirus expression system in Sf9 cells to characterize transport. Aim 2 will determine the role of protein kinase C (PKC) and tight junction permeability in E217G-induced cholestasis. We will test the hypothesis that E217G disrupts hepatocyte tight junctions in a PKC-dependent manner that coincides with endocytic retrieval of key transporters MRP2 and BSEP from the canalicular membrane leading to cholestasis. We will use 4 model systems to test this hypothesis: in vivo studies in the rat the isolated perfused rat liver isolated rat hepatocyte couplets and HepG2 cells coupled with confocal fluorescence and electron microscopy to monitor the localization of transporters and tight junction proteins after treatment with E217G and in the presence and absence of PKC inhibitors. Aim 3 will characterize the importance of the uORF in rat human and mouse MRP2 mRNA on the translational regulation of MRP2 protein. We will characterize the differential tissue expression of MRP2 mRNA transcripts expressing the uORF and use site-directed mutagenesis to disrupt the uORF coupled with in vitro translation assays to investigate the importance of leaky scanning and the sequence of the peptide encoded by the uORF in regulating translation of Mrp2/MRP2. We will also determine whether the peptide encoded by the rat uORF is expressed in vivo. Significance: MRP2 is critical for elimination of polar metabolites from liver and kidney as well decreasing the intestinal absorption of dietary carcinogens and its expression in liver is decreased in pregnancy. Characterization of mechanisms of regulation of the activity localization and expression of MRP2 can lead to improved drug therapy for women in pregnancy and development of therapeutic measures to increase MRP2 function in cholestatic liver disease particularly in ICP.

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


application_id: 7196441
project_number: 5R01AI065545-03
project_title: CHLAMYDIAL INVASION OF NON-PHAGOCYTIC CELLS
administering_ic: NIAID
award_notice_date: 2007-04-03
application_type: 5
activity_code: R01
ic: AI
serial_number: 065545
program_official: HILTKE, THOMAS J
project_start_date: 2005-07-01
project_end_date: 2008-03-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1941640
contact_pi: CARABEO, REYNALDO 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
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that is the causative agent of a wide spectrum of human diseases including trachoma and the sexually transmitted disease chlamydia. Successful infection of cells by chlamydia involves attachment invasion establishment of a protective vacuole called an inclusion and inhibition of lysosomal fusion. With the advent of the C. trachomatis genome sequence and new cell biological and proteomic tools the mechanisms involved in these processes are just beginning to be revealed advancing our knowledge of chlamydia-host cell interactions. The long term goal is to define the molecular and biochemical mechanisms important for the successful establishment of infection by chlamydia. This proposal will specifically address the process of invasion. It is hypothesized that chlamydia uses multiple pathways of invading non-phagocytic cells. A recently identified molecule termed Tarp has been demonstrated to be translocated from the infecting elementary body across the host plasma membrane and into the cytosol where it is tyrosine phosphorylated by unknown host kinases and recruit actin. As a phosphoprotein Tarp may act as a signaling platform to recruit a number of adapter and effector molecules that mediate actin cytoskeletal remodeling. Specific Aim 1 will address the Rac GTPase dependent pathway and focus on the potential downstream mediators of actin recruitment. Specific Aim 2 will focus on the Tarp protein the tyrosine kinase(s) responsible for its phosphorylation the binding partners their roles in chlamydial invasion and the potential relationship of Tarp with the Rac GTPase. Specific Aim 3 will address the potential mechanism of actin recruitment by the Chlamydophila caviae Tarp homolog which does not contain the multiple repeat sequences present in C. trachomatis serovars L2 and D. These studies would not only reveal important insights into the biology of chlamydia but also the cellular process of signaling to the actin cytoskeleton that chlamydia subverts to facilitate its infection.

project_terms:
Actins;Address;Antibodies;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Biology;CD4 Antigens;Cell Communication;Cell membrane;Cell physiology;Cells;Chimera organism;Chimeric Proteins;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chlamydophila;Co-Immunoprecipitations;Complex;Cytoskeleton;Cytosol;Data;Decision Making;Dominant-Negative Mutation;Effectiveness;Goals;Grants Applications;Guanosine Triphosphate Phosphohydrolases;Hela Cells;Homologous Gene;Infection;Invaded;Knowledge;Life Style;Link;Localized;Lysosomes;Mammalian Cell;Mediating;Mediator of activation protein;Microscopy;Modeling;Models Experimental;Molecular;Mutation;Names;Numbers;Parasites;Pathogenesis;Pathway interactions;Phagocytes;Phosphoproteins;Phosphorylation;Phosphotransferases;Process;Protein Tyrosine Kinase;Proteins;Proteomics;Recruitment Activity;Reporting;Research;Research Personnel;Role;Sexually Transmitted Diseases;Signal Transduction;Site;Staging;System;Time;Trachoma;Transmembrane Domain;Tyrosine;Tyrosine Phosphorylation;Vacuole;crosslink;extracellular;genome sequencing;human disease;in vivo;insight;interest;intracellular parasitism;mutant;pathogen;programs;research study;tool


application_id: 7196438
project_number: 5R01AI048850-05
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2007-03-30
application_type: 5
activity_code: R01
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2003-04-01
project_end_date: 2008-05-31
study_section: Special Emphasis Panel[ZRG1-SSS-F(01)S]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
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: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of aP2 and keratinocyte fatty acid binding protein (mal-1). AP2 and mal-1 are FABPs which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs) which include metabolites of cyclooxygenase and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands thus impacting macrophage gene expression and function. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed and the activity of transcription factors known to be regulated by PPARs will be analyzed in wild-type and FABP-deficient macrophages. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model will be employed to provide a means to analyze FABP function in vivo in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes.

project_terms:
Accounting;Address;Adipocytes;Animals;Arachidonic Acids;Atherosclerosis;Autoimmune Process;Binding (Molecular Function);Brain;Cells;Cholesterol;Clinical;Data;Development;Diabetes Mellitus;Disease;Disease Progression;Down-Regulation;Encephalomyelitis;Enzymes;Experimental Autoimmune Encephalomyelitis;Family member;Fatty Acid-Binding Protein 1;Gene Expression;Gene Expression Regulation;Genes;Genetically Engineered Mouse;Infiltration;Inflammatory;Inflammatory Response;LOX gene;Laboratories;Ligands;Link;Lipoxygenase;Mediating;Metabolism;Modeling;Multiple Sclerosis;Mus;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Play;Production;Prostaglandin-Endoperoxide Synthase;Protein-Lysine 6-Oxidase;Proteins;Purpose;Regulation;Relative (related person);Role;Score;Severities;Signal Transduction;Spinal Cord;Stimulus;System;Testing;Therapeutic;Tissues;Transcription Factor AP-2 Alpha;base;chemokine;concept;cyclooxygenase 1;cyclooxygenase 2;cytokine;design;fatty acid binding protein;fatty acid-binding proteins;in vivo;keratinocyte;lipid transport;macrophage;protein function;receptor;receptor function;relating to nervous system;research study;response;transcription factor;uptake


application_id: 7196408
project_number: 5R01AI033481-14
project_title: Iron Transport and Regulation in Yersinia Pestis
administering_ic: NIAID
award_notice_date: 2007-04-03
application_type: 5
activity_code: R01
ic: AI
serial_number: 033481
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-07-01
project_end_date: 2008-05-31
study_section: Bacteriology and Mycology Subcommittee 1[BM-1]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
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: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant):  For over two thousand years Yersinia pestis the causative agent of bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Modern more contained epidemics are common in South America and Madagascar. In addition Y. pestis is a category A bioterrorism agent with natural zoonotic foci as readily available sources of the organism on nearly every continent. The ability of pathogens to acquire iron from their hosts is one critical parameter in the outcome of the infectious process. Y. pestis encodes nine potential inorganic iron transport systems and two heme/hemoprotein transport systems. Of these the siderophore-dependent yersiniabactin (Ybt) iron transport system and the Yfe ABC transporter are the most important systems for acquisition of inorganic iron. Ybt is essential in the early stages of bubonic plague and mutations in this system are avirulent in mice infected subcutaneously (SC). However Ybt- mutants are fully virulent via an intravenous (IV) route of infection. Yfe plays an important role during the later stages of the infection - a Ybt-Yfe- mutant is completely avirulent in mice by IV injection. By SC injection a Yfe- mutant is 75-fold less virulent than its Yfe+ parent suggesting that the Ybt system can partially compensate for a lack of the Yfe system but it is clearly not as effective in the later stages of disease. Expression of both systems is repressed by iron through the iron-responsive regulatory protein Fur. In addition the Ybt system is activated by an AraC-type regulator YbtA possibly acting in concert with the Ybt siderophore. The Yfe system is also repressed by excess manganese through the Fur protein. In vivo repression by manganese and Fur is a unique regulatory mechanism. The specific aims of this proposal are to continue characterizing genetic and biochemical aspects of 1) the Ybt and 2) the Yfe transport systems and 3) to analyze the expression of these two systems in vivo and determine their roles in systemic spread of the disease. We will identify any remaining elements necessary for the function of these systems examine the regulatory components controlling expression of these systems in vitro and in vivo and determine the role of these systems in the infectious disease process of plague. An understanding of the components and functions of these two-transport system may lead to their use as protective antigens or as targets for new drugs. Our studies will also provide insights into the role of Ybt and Yfe in the pathogenesis of plague and other disease-causing organisms and into the general importance of iron acquisition in bacterial disease processes.

project_terms:
ATP-Binding Cassette Transporters;Antigens;Bacterial Infections;Biochemical Genetics;Bioterrorism;Blood;Categories;Communicable Diseases;Disease;Elements;Epidemic;Goals;Heme;Heme Iron;Hemeproteins;Human;In Vitro;Infection;Injection of therapeutic agent;Intravenous;Iron;Laboratories;Lead;Life;Madagascar;Manganese;Modems;Mus;Mutation;Organ;Organism;Outcome;Parents;Pathogenesis;Pharmaceutical Preparations;Plague;Play;Pneumonic Plague;Process;Proteins;Recording of previous events;Recurrence;Regulation;Relative (related person);Repression;Role;Route;Siderophores;Source;South America;Staging;System;Virulence;Virulent;Yersinia pestis;antimicrobial;base;genetic regulatory protein;in vivo;insight;intravenous injection;mutant;pandemic disease;pathogen;yersiniabactin


application_id: 7196200
project_number: 1R01NS053905-01A1
project_title: PLP alternative splicing and oligodendrocyte differentiation
administering_ic: NINDS
award_notice_date: 2007-01-03
application_type: 1
activity_code: R01
ic: NS
serial_number: 053905
suffix: A1
program_official: UTZ, URSULA
project_start_date: 2007-01-03
project_end_date: 2011-12-31
study_section: Neurogenesis and Cell Fate Study Section[NCF]
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
5' Splice Site;Alternative Splicing;Binding (Molecular Function);Biochemical;Brain;Cells;Demyelinating Diseases;Disease;Disruption;Enhancers;Equilibrium;Exons;Folch-Pi apoprotein;Future;Generations;Genes;Genetic;Genetic Diseases Inborn;Human;Inherited;Maps;Mus;Mutation;Myelin;Myelin Proteolipid Protein;Nerve;Nervous system structure;Neuroglia;Numbers;Oligodendroglia;Protein Binding;Protein Isoforms;Proteins;RNA Interference;RNA Splicing;Regulation;Regulatory Element;Rest;Role;Site;Tissues;Transcript;cell injury;innovation;knock-down;nervous system disorder;novel;progenitor


application_id: 7196154
project_number: 2R01CA083237-06A2
project_title: Molecular Mechanisms of Metastasis Suppression by NM23
administering_ic: NCI
award_notice_date: 2006-09-25
application_type: 2
activity_code: R01
ic: CA
serial_number: 083237
suffix: A2
program_official: WOODHOUSE, ELIZABETH
project_start_date: 1999-08-01
project_end_date: 2011-07-31
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7875382
contact_pi: KAETZEL, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
DNA binding protein;DNA footprinting;cell line;gel mobility shift assay;genetic regulation;genetic regulatory element;genetic transcription;immunoglobulin genes;metastasis;neoplastic cell;platelet derived growth factor;southern blotting;transfection;tumor suppressor proteins


application_id: 7195695
project_number: 5R01HL062053-09
project_title: Host response to P. carinii in neonatal mice
administering_ic: NHLBI
award_notice_date: 2007-03-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 062053
program_official: PEAVY, HANNAH H
project_start_date: 1990-07-01
project_end_date: 2009-03-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Pneumocystis carinii (PC) pneumonia continues to be a significant problem among immunosuppressed individuals. Moreover neonatal animals have been shown to harbor subclinical PC infections and more recently it has been shown that a significant proportion of human infants also are either infected or colonized with PC. Very little is known about lung immune responses to PC or other fungal pathogens in neonates. We observed that neonatal mice challenged with an intranasal inoculation of PC fail to mount an inflammatory response before about 3 weeks of age whereas adult mice mount a response in a matter of a few days. Our goal in the previous funding period was to determine whether this delay in response was due to immaturity of neonatal lymphocytes or whether the neonatal lung environment is suppressive. We established that neonatal lymphocytes are functional when transferred into an adult lung environment and could stimulate clearance of PC infection. However transfer of adult cells to neonates did not alter the kinetics of inflammation nor clearance of the organisms suggesting that the neonatal lung environment could not support an immune response to PC. There was a significant deficit in the production of proinflammatory cytokines and chemokines in PC-infected neonatal lungs; whereas TGFI3 and IL-10 mRNA were constitutively expressed in neonatal lungs at levels similar to PC-infected adult lungs. These data suggested that the growth factors involved in postnatal lung development may also be immunosuppressive. For this proposal we have chosen to focus on this immunosuppressive lung environment with the goal of determining whether there is active suppression of inflammation in postnatally developing lungs. We hypothesize that the neonatal lung environment impacted on by growth factors and innate immune cells is immunosuppressive toward inflammatory responses against PC. This results in suppressed proinflammatory cytokine and chemokine production and delayed clearance of organisms. The following aims are designed to address this hypothesis: 1) to determine whether lung developmental growth factors are expressed at the protein level in response to PC in infant mice; 2) to determine whether immaturity of innate immune cells and mediators in the lungs suppress immune responses to PC; and 3) to determine whether interruption of negative regulators of immune function in neonatal lungs will promote inflammatory responses to PC. Very little is known regarding the development of immunity in the lungs and understanding this process is vital for protecting young children from potentially life-threatening infections.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Adopted;Adoptive Transfer;Adult;Age;Age-Years;Animals;Animals Newborn;Anti-Inflammatory Agents;Anti-inflammatory;B-Lymphocytes;Cell physiology;Cells;Child;Corticosterone;Data;Dendritic Cells;Development;Diagnosis;Doctor of Philosophy;Environment;Funding;Genes;Glucans;Goals;Growth Factor;Host Defense;Human;Immune;Immune response;Immunity;Immunohistochemistry;Immunologic Surveillance;Immunologic Immunofluorescence;Immunosuppressive Agents;Individual;Infant;Infection;Infectious Agent;Inflammation;Inflammatory;Inflammatory Response;Interleukin-10;Interruption;Kinetics;Knock-out;Life;Lung;Lymphocyte;Macrophages Alveolar;Mediator of activation protein;Mice Knockout;Microscopy Confocal;Mus;Neonatal;Numbers;Organism;Patients;Phagocytes;Pneumocystis;Pneumocystis Infections;Pneumocystis carinii;Pneumonia Pneumocystis carinii;Process;Production;Proteins;RNA Messenger;Signal Transduction;System;Terminology;Week;cell type;chemokine;cytokine;day;design;immune function;immunosuppressed;in vitro Assay;in vivo;lung development;mannose receptor;neonate;pathogen;postnatal;receptor;response


application_id: 7194534
project_number: 1R01EY017373-01A1
project_title: Progression of Uveitis and CD8 uveitogenic T cells
administering_ic: NEI
award_notice_date: 2007-01-26
application_type: 1
activity_code: R01
ic: EY
serial_number: 017373
suffix: A1
program_official: SHEN, GRACE L
project_start_date: 2007-02-01
project_end_date: 2008-02-29
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1959007
contact_pi: SUN, DEMING
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): immunotherapy for autoimmune diseases such as uveitis has been aimed at controlling CD4 autoreactive T cells. In this application we propose to test a new approach namely whether impeding the interaction between CD4 and CDS autoreactive T cells halts the progression of autoimmune uveitis. This hypothesis is supported by our findings that the adoptive transfer of in vitro activated interphotoreceptor retinoid-binding protein (IRBP)-specific T cells reproducibly induces chronic and/or recurrent uveitis in both rats and mice and that the pathogenic T cells that induce the disease contain a significant proportion of vigorously proliferating cells expressing CD8. We hypothesize that the progression of autoimmune uveitis is a consequence of the activation of increasing numbers of CDS autoreactive T cells which have a stronger tissue-damaging capability when they become highly activated due to their greater cytotoxic activity and also because of the expression of MHC I molecules required for T cell action in the autoimmune organ. In this hypothesis in the absence of CDS T cell activation CD4 IRBP-specific T cells would induce only mild or monophasic uveitis whereas when CDS T cells are activated severe recurrent uveitis would result. We will determine whether the reciprocal interaction between CD4 and CDS autoreactive T cells leads to severe tissue damage and disease progression and whether impeding this interaction blocks disease progression (Aim 1). We will also determine the factors that cause increased activation of CDS autoreactive T cells (Aim 2). Based on our preliminary results that T cells regulating autoimmune disease express high amounts of Foxp3 and that a subset of CDS IRBP-specific T cells expresses higher levels of FoxpS we will also determine whether pathogenic CDS autoreactive T cells can be distinguished from suppressive CDS T cells by the levels of FoxpS expressed (Aim 3). Chronic and recurrent uveitis pose the highest risk for ocular complications leading to blindness in humans. To provide a working model allowing the dissection of the pathogenesis of recurrent uveitis we have established a chronic non-recurrent model of uveitis in the mouse and a chronic recurrent model in the rat. Studies on the interrelationship between CD4 and CDS autoreactive T cells should provide much-needed insights into the pathogenic mechanism leading to disease progression and help in the development of supplemental therapies for this devastating disease.

project_terms:
Active Immunization;Acute;Adoptive Transfer;Antigens;Autoimmune Diseases;Autoimmune Process;Binding (Molecular Function);Blindness;CD4 Positive T Lymphocytes;CD8B1 gene;Cell Communication;Cells;Chronic;Development;Disease;Disease Progression;Dissection;Dose;Encephalomyelitis;Equilibrium;Human;Immune response;Immunotherapy;In Vitro;Joints;Lead;Ligands;Measures;Mice Knockout;Modeling;Mus;Numbers;Organ;Pathogenesis;Play;Population;Proliferating;Rattus;Recurrence;Recurrent disease;Reporting;Research Personnel;Risk;Role;Severity of illness;Signal Transduction;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;T-Lymphocytes Suppressor-Effector;Testing;Tissues;Uveitis;Work;autoimmune uveitis;autoreactive T cell;base;cytotoxic;in vivo;insight;interstitial retinol-binding protein;novel strategies;novel therapeutics;oligodendrocyte-myelin glycoprotein;programs;response


application_id: 7194143
project_number: 5R01NS046380-04
project_title: COX-2 Pathophysiology in Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2007-02-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 046380
program_official: KLEITMAN, NAOMI
project_start_date: 2004-02-01
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1-CNNT(01)Q]
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Traumatic spinal cord injury (SCI) results in a loss of voluntary motor and sensory function below the site of injury and affects some 300000 individuals in the United States with ~10000 new cases each year. Pathophysiological secondary responses following the initial insult promote additional and extensive damage occurring hours to weeks following injury and therefore are amenable to therapeutic interventions. Current therapies provide at best modest improvement of function and alternative strategies are warranted. The studies proposed in this application are designed to identify and better characterize the pathophysiological consequences of cyclooxygenase (COX) expression in traumatic spinal cord injury (SCI). Despite evidence of a pathological role for COX-2 induction in several models of central nervous system (CNS) injury the role of the two COX isoforms (COX-1 and COX-2) as a mediators of cell death following SCI is unclear. The overall objective of the proposed experiments is to provide evidence that COX functions as an intracellular activator of cytotoxic oxidative damage and a mediator of apoptotic cell death following SCI. Specific Aim 1 will use pharmacological strategies and a number of biochemical assays to examine the contribution of COX-1 and COX-2 to oxidative damage. Studies in Specific Aim 2 will document conclusively that COX expression occurs in cells that are undergoing apoptotic cell death following SCI (Aim 2a) and demonstrate that inhibiting the actions of either COX isoform reduces the appearance of apoptotic markers (Aim 2b). Studies proposed in Specific Aim 2 are a logical extension of Aim 1 as several studies have demonstrated that oxidative damage contributes to apoptotic cell death. Finally Specific Aim 3 will demonstrate the therapeutic potential of blocking the actions of COX-1 or COX-2 in SCI. This will include a battery of behavioral tests that are highly sensitive to changes in sensorimotor and coordinated locomotor function. In addition histological and morphological studies will be performed to document long term cell survival improved tissue sparing at the injury epicenter and enhanced myelination in fiber tracks distant to the site of injury. The outcome of these studies will document the pathophysiological involvement of COX expression in cell death following SCI which has clear clinical implications for developing therapies in the treatment of SCI in humans.

project_terms:
Address;Affect;Animals;Apoptosis;Apoptotic;Appearance;Behavior;Biochemical;Biological Assay;Cell Death;Cell Survival;Cells;Clinical;Coxibs;Demyelinations;Development;Distant;Enzymes;Event;Fiber;Functional disorder;Goals;Hour;Human;Individual;Injury;Injury of central nervous system;Limb structure;Locomotor Recovery;Measures;Mediator of activation protein;Modeling;Motor;Neuraxis;Numbers;Outcome;Placement;Prostaglandin-Endoperoxide Synthase;Protein Isoforms;Role;Sensory;Site;Spinal cord injury;Study Outcome;Testing;Therapeutic;Therapeutic Intervention;Tissues;United States;Week;behavior test;caspase-3;cell type;cyclooxygenase 1;cyclooxygenase 2;cytotoxic;design;functional improvement;improved;inhibitor/antagonist;kinematics;myelination;novel;research study;response


application_id: 7193305
project_number: 1T32DA022738-01
project_title: Therapeutic Strategies for Neurodegeneration Training Grant
administering_ic: NIDA
award_notice_date: 2006-09-25
opportunity_number: RFA-DA-06-008
application_type: 1
activity_code: T32
ic: DA
serial_number: 022738
program_official: BABECKI, BETH
project_start_date: 2006-09-26
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZDA1 KXN-G (08)]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application is in response to RFA-DA-06-008 entitled Training in Translational Research in Neurobiology of Disease (T32). The overall goal of the proposed Therapeutic Strategies for Neurodegeneration Training Program is to prepare promising predoctoral scholars (graduate students) postdoctoral scholars and clinical scholars for successful careers in translational neuroscience aimed at the discovery and development of disease-modifying pharmacological and genetic therapies for devastating neurodegenerative disorders or diseases such as spinal cord injury (SCI) traumatic brain injury (TBI) stroke and Parkinson's Disease (PD). We will provide broad-based training in modern research concepts regarding the pathophysiology of these and other neurodegenerative disorders and potential disease modifying molecular targets that can drive the discovery of pharmacological and gene therapeutic strategies by which the devastating effects of these disorders can be ameliorated. These strategies will include both "neuroprotective" and "neurorestorative" approaches. Funding is requested for 5 Predoctoral Scholars each year for 5 years. Beginning in year 2 funds are requested for 1 Postdoctoral Scholar and 1 Clinical Trainee. In the case of the latter the purpose is to provide a 1 year fellowship for a late stage neurology or neurosurgery resident a clinical fellow or a young Assistant Professor to spend a year cross-training in a basic research laboratory. Fourteen basic science and 5 clinical faculty from two basic science departments (Anatomy and Neurobiology and Physiology) two clinical departments (Neurology and Neurosurgery) and three centers (Spinal Cord & Brain Injury Research Center Morris K. Udall Parkinson's Disease Research Center and the Sanders-Brown Center on Aging) will participate in this Training Program. The training program for all of the trainees involves a strong emphasis on translationally-focused therapeutic discovery basic research. For the Predoctoral and Postdoctoral Scholars each will be expected to complete a multi faceted Clinical Tutorial specifically designed to be relevant to the disease focus of their research. All of the trainees will have the opportunity to participate in a rich offering of didactic course work seminars annual translationally-oriented research symposia and research externships and training courses. Recruitment of women and minorities will be emphasized.


application_id: 7192876
project_number: 1R15HL087185-01
project_title: Mechanical Stress and Myofibroblast Function: Implications for Pulmonary Fibrosis
administering_ic: NHLBI
award_notice_date: 2007-01-23
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: HL
serial_number: 087185
program_official: REYNOLDS, HERBERT Y
project_start_date: 2007-03-01
project_end_date: 2011-02-28
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 6773495
contact_pi: RICE, NANCY AYERS
other_pis: Not Applicable
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  We are interested in those mechanisms that mediate myofibroblast function under normal and pathological conditions. Myofibroblasts are necessary cells for tissue remodeling and repair. During wound healing myofibroblasts differentiate in response to various cellular signals which results in an increase in their muscle gene expression extracellular matrix secretion and contractility. The fact that under certain circumstances myofibroblasts persist and continue to secrete extracellular matrix has implicated them in interstitial fibrosis of the lung. In this proposal we are specifically interested in the role that mechanical stress i.e. contraction has in regulating endothelial nitric oxide synthase (eNOS) expression and activity in pulmonary myofibroblasts and subsequently how changes in eNOS correlate with myofibroblast apoptosis. Understanding those molecular mechanisms that lead to dissipation of myofibroblasts is essential in rational therapeutic design. Therefore we propose three specific aims to extend our knowledge regarding the role of contraction in mediating myofibroblast apoptosis via eNOS signaling: 1) we will evaluate how contraction of pulmonary myofibroblasts regulates eNOS expression at the gene RNA and protein levels using primary myofibroblast cell cultures; 2) we will determine how nitric oxide mediates pulmonary myofibroblast apoptosis using various pharmacological donors and selective inhibitors of NOS in primary myofibroblast cell cultures; and 3) we will assess the absence of sarcomeric myosin on bleomycin-induced pulmonary fibrosis in vivo histologically and biochemically using the myosin heavy chain IId null transgenic mouse model. The results from these studies will provide significant advancements in our understanding of the pathogenesis of pulmonary fibrosis and other pulmonary interstitial diseases. Furthermore over the 3 year funding period this project will engage numerous undergraduates to independent research enhancing their learning of scientific principles giving them an opportunity to make unique contributions to the study of this devastating family of diseases and stimulating their excitement for careers in biomedical research. Interstitial pulmonary fibrosis is a devastating lung disease that results from excess collagen in lungs as a result of a surplus of and/or overactive myofibroblast cells. Since relatively few drugs are available for the treatment of pulmonary fibrosis and their effectiveness is minimal at best a thorough understanding of the mechanisms regulating myofibroblast activity and death is important in designing new improved therapeutics. The nitric oxide pathway is an ideal place to begin in that this pathway is targeted by numerous pharmaceuticals that have already been evaluated for efficacy and toxicity and are approved for use by the U.S. Food and Drug Administration potentially eliminating years of clinical testing and saving millions of dollars.

project_terms:
Academic Research Enhancement Awards;Apoptosis;Biomedical Research;Bleomycin;Cells;Cessation of life;Collagen;Condition;Cultured Cells;Deposition;Disease;Effectiveness;Epithelial Cells;Extracellular Matrix;Family;Fibrosis;Funding;Gene Expression;Genes;Health Sciences;Histologic;Induction of Apoptosis;Institution;Knowledge;Lead;Learning;Lung;Lung diseases;MAP Kinase Gene;Mechanics;Mediating;Mice Knockout;Modeling;Molecular;Muscle;Myofibroblast;Myosin ATPase;Myosin Heavy Chains;NOS3 protein human;Nitric Oxide;Nitric Oxide Pathway;Pathogenesis;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Physiological;Production;Promotor (Genetics);Proteins;Pulmonary Fibrosis;Purpose;Research;Role;Signal Transduction;Smooth Muscle Actin Staining Method;Stress Mechanical;Students;Therapeutic;Tissues;Toxic effect;Transforming Growth Factors;Transgenic Organisms;United States Food and Drug Administration;Work;Wound Healing;career;design;experience;improved;in vivo;inhibitor/antagonist;interest;interstitial;mouse model;prevent;programs;repaired;research clinical testing;response


application_id: 7192482
project_number: 5R01HD042451-05
project_title: Development of Perceptual Organization in Infancy
administering_ic: NICHD
award_notice_date: 2007-02-09
application_type: 5
activity_code: R01
ic: HD
serial_number: 042451
program_official: FREUND, LISA S
project_start_date: 2003-04-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-6(03)M]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant): Pattern perception and organization provide the representations that form the basic processing units in the visual cognition system of adults. The overall aim of the proposed research is to investigate the origins and development of such perceptual organization abilities in infants. Specifically we are concerned with the very beginnings of perceptual unit formation and the operation of a variety of organizational principles during the first months of life. The research proposal describes a number of experiments that rely on visual preference procedures to study the organization of arrays of visual elements by young infants. The experiments seek to determine: (1) Which grouping principles lead to organized representations of visual pattern information? (2) Do some principles consistently take precedence over others thereby suggesting a hierarchy of rule use in the development of perceptual organization? (3) Can the principles work in an additive fashion thus suggesting a kind of threshold model for perceptual unit formation? (4) What is the time course of development for each of the various principles? Are the individual principles yoked or do they have independent developmental trajectories? And (5) What are the developmental factors (i.e. maturation experience) that affect the emergence of the different grouping principles? The significance of the proposed research is that it will provide knowledge about how perceptual units are formed their nature and their ontogenesis as well as how representations of visual pattern information by adults arise from the perceptual units of infants. In short this research will inform us about the formation of the coherent representations of visual patterns that form the basic functional units of human cognition. Knowledge about the development of this fundamental mental ability will also provide insights into understanding deviations from the normal course of perceptual-cognitive development.

project_terms:
Adult;Affect;Age;Binding (Molecular Function);Child;Class;Closure;Cognition;Cognitive;Data;Development;Development Infant;Elements;Environment;Event;Grouping;Hand;Human;Individual;Infant;Knowledge;Lead;Life;Modeling;Models Organizational;Modems;Nature;Numbers;Operative Surgical Procedures;Pattern;Procedures;Process;Psyche structure;Psychologist;Research;Research Proposals;Scientist;Shapes;Source;Structure;Surface;System;Texture;Time;Vision;Visual;Work;base;design;experience;infancy;insight;pattern perception;perceptual organization;preference;research study;size;theories;visual cognition


application_id: 7192384
project_number: 1R15GM079694-01
project_title: Identification and Characterization of Antiterminator RNAs
administering_ic: NIGMS
award_notice_date: 2007-01-12
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 079694
program_official: TOMPKINS, LAURIE
project_start_date: 2007-02-01
project_end_date: 2011-01-31
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 8534212
contact_pi: KING, RODNEY ALLEN
other_pis: Not Applicable
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The goal of this project is to understand a unique mechanism of transcription elongation control originally discovered in the bacteriophage HK022. Most members of the lambda phage family use phage-encoded proteins to promote early gene expression by suppressing transcription termination. HK022 does not encode an antitermination protein but relies instead on the direct interaction of sites in the nascent transcript with RNA polymerase. The specific hypothesis is that the activity of RNA-based antiterminators depends upon the recognition of sequence and structural information in the nascent transcript by RNA polymerase. This hypothesis is based upon previous studies that 1) have shown that mutations that disrupt base pairing in the RNA reduce antitermination and secondary mutations that re-establish base pairing restore terminator read through 2) interchanging segments of antiterminator RNAs drastically affects activity and 3) RNA-mediated antitermination is blocked by mutations in the beta prime subunit of E. coli RNA polymerase. The goal of this proposal is to identify the required sequence and structural elements of RNA based antiterminators. The specific aims are: 1) to identify additional examples of antiterminator RNAs in lambdoid phages; 2) to use in vivo in vitro and in silico approaches to determine the structurally and functionally important features of the newly identified antiterminator RNAs; and 3) to complete the annotation of two new phage genomes that possess RNA-based antiterminators. The antiterminator sequences discovered in HK022 provide unique examples of RNAs that control gene expression by directly modifying the transcription apparatus. Unusual modes of gene regulation are potential targets for drug design. Therefore a better understanding of antiterminator RNAs and their recognition by RNA polymerase may facilitate the discovery or development of therapeutic agents capable of altering the expression of virulence genes and thus attenuating disease processes. Western Kentucky University aspires to be the best comprehensive public institution in Kentucky and among the best in the nation. This project supports this mission and will enhance the research environment at Western by providing undergraduate students with numerous opportunities to learn the fundamentals of biomedical research while exploring a unique mechanism of gene expression control. The antiterminator sequences discovered in phage HK022 provide unique examples of RNAs that control gene expression by directly modifying the transcription apparatus. Unusual modes of gene regulation are potential targets for drug design. Therefore a better understanding of antiterminator RNAs and their recognition by RNA polymerase may facilitate the discovery or development of therapeutic agents capable of altering the expression of virulence genes and thus attenuating disease processes.

project_terms:
Affect;Attenuated;Bacteriophage HK022;Bacteriophage lambda;Bacteriophages;Base Pairing;Binding Sites;Biomedical Research;Comparative Genomic Analysis;Complex;Computer Simulation;DNA-Directed RNA Polymerase;Development;Disease;Drug Design;Elements;Environment;Escherichia coli;Evolution;Family;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genome;Goals;In Vitro;Institution;Kentucky;Learning;Mediating;Mission;Modeling;Mutation;Numbers;Process;Proteins;RNA;Reading;Research;Research Project Grants;Sequences RNA;Site;Structure;Students;Therapeutic Agents;Transcript;Transcription Elongation;Transcription Genetic;Universities;Virulence;antitermination;base;computer generated;design;in vivo;member;programs;research study;rho;transcription termination


application_id: 7191889
project_number: 1R25MH079332-01
project_title: Mechanisms of Neurologic Disease Course
administering_ic: NIMH
award_notice_date: 2006-09-26
opportunity_number: RFA-MH-06-006
application_type: 1
activity_code: R25
ic: MH
serial_number: 079332
program_official: DESMOND, NANCY L
project_start_date: 2006-09-25
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZMH1 ERB-Y (04)]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This R25 proposal is to support the development and implementation of a new graduate course Mechanisms of Neurologic Disease at the University of Kentucky (UK). UK has a strong program in neuroscience research. Our local chapter of the Society for Neuroscience includes 96 faculty 105 graduate students and 41 postdoctoral fellows. There are three Neuroscience T32 programs at UK focusing on the biology of aging sensory systems and oxidative stress. This proposal reflects our efforts to develop a new course on the neurobiology of disease that meets and exceed the expectations outlined in the RFA and the NIH Neuroscience Blueprint. Mechanisms of Neurologic Disease is organized into 8 major themes including disorders of cell migration and signaling channelopathies metabolic and mitochondrial disorders neuroimmune and transmissible disorders neurodegenerative disorders and protein aggregation triplet repeat disorders acute CNS insults and drug abuse and addiction. Mechanistic links among disorders will be emphasized. In addition one module will focus on state-of-the-art and emerging methods in neurobiology of disease research such as biosensors. The course will consist of didactic presentations by basic and clinical neuroscientists in addition to "journal club" format discussions of recent primary literature focusing on disease mechanisms or translational research. Outside experts will also be invited to lecture and meet with the students. In addition to the lectures and journal club discussions students must attend a consensus conference on the clinico-pathological diagnosis of Alzheimer's disease and related disorders offered monthly in the Sanders-Brown Center on Aging and attend a brain cutting session offered weekly by Pathology/Neuropathology. Additionally the students and faculty will organize a one day conference on translational research in one of the thematic areas. Program evaluation will include short and long term questionnaires. Dissemination of course materials will be through a course-specific web page and a multimedia CD. The course will be required for neuroscience trainees.

project_terms:
Alzheimer&apos;s disease;Internet;computer assisted instruction;curriculum;education evaluation /planning;educational resource design /development;interactive multimedia;meeting /conference /symposium;nervous system disorder;neurobiology;neurology;neuropathology;neurosciences;postgraduate education;training;university


application_id: 7191564
project_number: 5R03HD051727-02
project_title: The function of Runx1 in the ovary
administering_ic: NICHD
award_notice_date: 2007-03-16
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: HD
serial_number: 051727
program_official: TAYMANS, SUSAN
project_start_date: 2006-03-01
project_end_date: 2009-02-28
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The goal of the present proposal is to elucidate the role of Runx1 a nuclear transcription factor in the ovary. We have recently identified that this transcription factor is dramatically and transiently induced in granulosa cells of periovulatory follicles after the LH [luteinizing hormone] surge. The periovulatory follicle undergoes rapid changes in the expression patterns of a myriad of genes to bring about ovulation and luteinization. Therefore transcriptional regulators induced by the LH surge are believed to play an essential role in the ovulatory process and luteinization. We have preliminary data showing that knockdown of the LH-induced Runx1 expression in periovulatory granulosa cells resulted in a decrease in progesterone production implicating the involvement of Runx1 in luteinization. We also found that Runx1 expression is regulated by the activation of the progesterone receptor and EGF [epidermal growth factor]-receptor two known key mediators for the ovulatory process. Based on these novel findings we hypothesize that Runx1 plays an important role(s) in ovulation and luteinization. The goal of this proposal is to: 1) demonstrate that the induction of Runx1 in periovulatory granulosa cells is essential for successful ovulation and luteinization and 2) determine the specific role(s) of Runx1 in periovulatory granulosa cells. To accomplish this goal we will generate mice lacking functional Runx1 specifically in granulosa cells and then examine the ovarian phenotype of these mutant mice (Specific Aim 1). Using the granulosa cell-specific Runx1 null mice we will identify the genes down-stream of Runx1 action in periovulatory granulosa cells (Specific Aim 2). Information derived from this proposal will provide new insight into the mechanism(s) involved in ovulation and corpus luteum formation. Such knowledge can be applied for promoting or inhibiting these critical facets of ovarian physiology thereby allowing us to better manage fertility infertility and ovarian-based disorders.

project_terms:
Alleles;Cells;Complex;Data;Defect;Development;Disease;Enzymes;Epidermal Growth Factor Receptor;Event;Exhibits;Fertility;Fertilization;Future;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Goals;Infertility;Knowledge;Luteinization;Luteinizing Hormone;Mediating;Mediator of activation protein;Meiosis;Mice Knockout;Mice Mutant Strains;Mice Transgenic;Molecular;Mullerian-inhibiting substance receptor;Mus;Nuclear;Oocytes;Ovarian;Ovary;Ovulation;Pathway interactions;Pattern;Phenotype;Physiology;Play;Process;Production;Progesterone;RNA Messenger;Role;Series;Stream;Structure of corpus luteum of ovary;Testing;animal breeding;base;granulosa cell;insight;mRNA Expression;novel;receptor;recombinase;response;transcription factor


application_id: 7189824
project_number: 5R01EY012998-07
project_title: Determinants of extraocular muscle function
administering_ic: NEI
award_notice_date: 2007-03-16
opportunity_number: RFA-EY-03-001
application_type: 5
activity_code: R01
ic: EY
serial_number: 012998
program_official: AGARWAL, NEERAJ
project_start_date: 2000-04-01
project_end_date: 2008-09-29
study_section: ZEY1-VSN(04)
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Congenital strabismus or eye misalignment affects about 4% of children.  However available therapies are not yet optimal with significance incidence of recurrence or unsatisfactory functional results.  The extraocular muscles the final effector arm of the oculomotor system are the target of surgical and pharmacological treatments for strabismus.  This is despite the fact that our understanding of extraocular muscle biology and function remains incomplete. Although the extraocular muscles are included in the skeletal muscle class there is emerging evidence that basic metabolic and functional characteristics of these small muscles are significantly different from those seen in typical skeletal muscles.  First mitochondria serve as novel fast calcium sinks in extraocular muscles and this mechanism is an important determinant of the functional characteristics of these muscles.  Second abnormal visual experience during a postnatal critical period significantly alters the extraocular muscles and renders them weaker slower and more fatigable.  Third the gene expression profile of the extraocular muscles is greatly different from that of other skeletal muscles. These data suggest that the divergent functional properties of the extraocular muscles must be met by alternative strategies for energy supply.  In consequence the objective of this project is to understand how metabolic pathways have adapted in the extraocular muscles to cope with their extreme functional requirements.  Using well-established functional molecular biological and biochemical assays this project will determine (1) the role of alternative energy supply pathways in rat extraocular muscles; (2) the extent to which rat extraocular muscle mitochondria are different; and (3) the role of normal visual experience in establishing these metabolic properties in rat extraocular muscles.  It is expected that these experiments will obtain significant new information the overall metabolic characteristics of the extraocular muscles and provide an integrative view of functional and metabolic properties of these muscles.  By understanding what sets the extraocular muscles apart from other skeletal muscles interventions that directly target these muscles can be envisioned.

project_terms:
Academy;Affect;American;Biochemical;Biogenesis;Biological;Biological Assay;Biology;Boxing;Buffers;Calcium;Characteristics;Child;Class;Condition;Creatine Kinase;Critical Period (Psychology);Cytoskeletal Modeling;Data;Development;Disease;Energy-Generating Resources;Enzymes;Eye;Fatigue;Functional disorder;Funding;Gene Expression Profile;Gene Expression Profiling;Glycogen;Hand;In Vitro;Incidence;Intervention;Knowledge;Lactate Dehydrogenase;Lactate Dehydrogenases;Life;Metabolic;Metabolic Pathway;Minor;Mitochondria;Modality;Molecular;Muscle;Muscle function;Muscle of orbit;Operative Surgical Procedures;Pathway interactions;Pediatrics;Pharmacological Treatment;Physiology;Pilot Projects;Play;Population;Property;Rattus;Recurrence;Research Design;Research Personnel;Resistance;Resolution;Role;Sensory;Skeletal muscle structure;Strabismus;Strikes Employee;Supply Energy;System;Testing;Upper arm;Visual;adenylate kinase;coping;experience;extracellular;glycogenolysis;improved;indexing;inhibitor/antagonist;member;novel;novel therapeutics;oculomotor;postnatal;programs;research study;response;therapy design;transcription factor


application_id: 7189804
project_number: 1R15GM074663-01A1
project_title: Reaction of Bulky Platinum Complexes with Proteins
administering_ic: NIGMS
award_notice_date: 2007-01-08
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 074663
suffix: A1
program_official: FABIAN, MILES
project_start_date: 2007-01-08
project_end_date: 2010-12-31
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 6525438
contact_pi: WILLIAMS, KEVIN M
other_pis: Not Applicable
congressional_district: 02
department: CHEMISTRY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to investigate how the size and shape of the amine ligands of platinum diamine complexes will affect both the type of protein adducts that form and the rate of formation of these adducts. An understanding of the factors influencing the binding of platinum to proteins has relevance to platinum complexes that are used as anticancer drugs. Preliminary studies have suggested that bulky diamine ligands prevent coordination of two methionine residues to a platinum atom and also greatly affect the rate of formation of the products. In contrast reaction with guanine is significantly less affected by bulk. Thus a primary advantage that may result from additional bulk may be a kinetic preference for platinum-DNA complexes over platinum-protein complexes; the former are responsible for the anticancer activity. The first aim is to use NMR spectroscopy and other techniques to characterize products formed by reaction of bulky platinum complexes with methionine and other amino acids. Adducts formed with peptides containing methionine residues will also be characterized to see if reaction occurs at sites other than methionine. The next aim will be to determine the effects of bulk on the rate of reaction with peptide and oligonucleotide complexes; it is hypothesized that bulk may favor reaction with the latter over reaction with the former. HPLC and/or NMR spectroscopy will be used to monitor the rates of reaction. Finally inductively coupled plasma-atomic emission spectroscopy (ICP-AES) will be utilized to study the factors that affect the binding of platinum to intact proteins or DNA sequences. The effects of bulk leaving ligand pH and other factors will be determined. This project will study how the size and shape of a platinum anticancer drug affects the reactions with key biological targets. Model systems will be used to study the reactions in order to determine whether larger platinum compounds may have advantages in terms of target selection.

project_terms:
Affect;Amides;Amines;Amino Acids;Antineoplastic Agents;Binding (Molecular Function);Biochemical;Biological;Biological Models;Chromatography High Pressure Liquid;Complex;Coupled;Cysteine;DNA;DNA Adduction;DNA Sequence;Data;Diamines;Guanine;Histidine;Kinetics;Lead;Left;Ligands;Methionine;Monitor;Nitrogen;Numbers;Oligonucleotides;Peptides;Plasma;Platinum;Platinum Compounds;Protein Binding;Proteins;Proteolysis;Rate;Reaction;Reaction Time;Relative (related person);Sampling;Shapes;Site;Spectroscopy NMR;Structure;Techniques;adduct;anticancer activity;emission spectroscopy;numb protein;preference;prevent;reaction rate;research study;size


application_id: 7189750
project_number: 1R15GM079608-01
project_title: Characterization of the P5 Subfamily of P-type Transport ATPases in Mice
administering_ic: NIGMS
award_notice_date: 2007-02-23
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 079608
program_official: CHIN, JEAN
project_start_date: 2007-03-01
project_end_date: 2010-02-28
study_section: Membrane Biology and Protein Processing Study Section[MBPP]
contact_pi_person_id: 6945317
contact_pi: SCHULTHEIS, PATRICK JOHN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): P-type ATPases which transport ions across cell membranes have been grouped into five subfamilies. The P1- P2- and P3-ATPases have been well characterized and include heavy metal ATPases NaK-ATPases HK-ATPases SERCAs and other Ca2+ATPases and bacterial Mg2+ATPases. The P4-ATPases are found only in eukaryotes and have been implicated in the transport of aminophospholipids. Although they are present in all eukaryotes little is known about the P5-ATPases other than the observations that loss of Cod1p one of the two yeast P5-ATPases leads to defects in glycoprotein processing endoplasmic reticulum associated protein degradation (ERAD) and constitutive activation of the unfolded protein response (UPR). Thus our objective is to obtain basic information regarding the distribution and ion specificity of the mammalian P5-ATPases. In preliminary studies we have identified 5 mammalian P5-ATPases termed Atp13a1-Atp13a5 determined their sequences and mRNA tissue distribution and begun development of isoform-specific antibodies and expression constructs. In Aim 1 we will develop isoform-specific antibodies and in situ hybridization probes and determine the membrane location and cell-type distribution of mouse Atp13a1-Atp13a5 using a combination of Western blot analysis of tissues and subcellular membrane fractions immunocytochemistry and in situ hybridization. In Aim 2 the ion specificity of the murine P5-ATPases will be determined. Membrane fractions from cell lines in which histidine-tagged versions of Atp13a1-Atp13a5 are over-expressed will be prepared and subjected to detergent solubilization. The His-tagged transporters will then be purified by nickel affinity chromatography and ion specificities will be determined by measuring cation-dependent ATP hydrolysis using sensitive assays of ATPase activity and phosphoenzyme formation. Ion uptake in whole cells or isolated membrane vesicles will also be analyzed using the appropriate radioisotope to confirm ion specificity. These studies will provide basic information that will be critical for more detailed mechanistic studies of the cell biological and physiological functions of this most poorly understood subfamily of mammalian P-type ATPases. The primary goal of the proposed study is to obtain basic information regarding the distribution and ion specificity of the mammalian P5-ATPases in order to better understand their cell biological and physiological functions. Given the presence of P5-ATPases in organisms as diverse as yeast and humans and that mutations in related transporters result in Darier's Hailey-Hailey and Wilson's disease among others it is likely that they will also be found to play a critical role in human health and disease.

project_terms:
ATP Hydrolysis;ATP phosphohydrolase;Address;Amino Acid Sequence;Anions;Antibodies;Biochemical;Biological;Biological Assay;Biological Transport Active;Blotting Northern;Blotting Western;Brain;Ca(2+) Mg(2+)-ATPase;Ca(2+)-Transporting ATPase;Cations;Cell Fractionation;Cell Line;Cell membrane;Cell physiology;Cells;Chromatography Affinity;Complement;DNA Complementary;Data;Defect;Dependence;Detergents;Development;Disease;Drug or chemical Tissue Distribution;Endoplasmic Reticulum;Eukaryota;Eukaryotic Cell;Exhibits;Fishes;Genes;Genome;Glycoproteins;Goals;Green Fluorescent Proteins;H(+)-K(+)-Exchanging ATPase;Health;Hela Cells;Hepatolenticular Degeneration;Histidine;Homeostasis;Human;Immunohistochemistry;In Situ Hybridization;Ion Transport;Ions;Label;Length;Localized;Location;Maintenance;Mammals;Measures;Membrane;Metals Heavy;Microsomes;Mus;Mutation;Na(+)-K(+)-Exchanging ATPase;Names;Nickel;Organism;Orthologous Gene;Peptides;Personal Satisfaction;Phenotype;Physiological;Play;Process;Protein Isoforms;Proteins;Publications;Pump;RNA Probes;RNA Messenger;Radioisotopes;Reporting;Research;Role;Signal Transduction;Specificity;Substrate Specificity;Testing;Time;Tissue Extracts;Tissues;Transcript;Vesicle;Yeasts;base;cell type;design;immunocytochemistry;member;protein degradation;research study;response;tool;uptake


application_id: 7189602
project_number: 7R01NS049209-02
project_title: Plasticity of Human Spinal Neural Networks After Injury
administering_ic: NINDS
award_notice_date: 2006-03-04
application_type: 7
activity_code: R01
ic: NS
serial_number: 049209
program_official: KLEITMAN, NAOMI
project_start_date: 2005-04-01
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1-MRS(01)Q]
contact_pi_person_id: 1884506
contact_pi: HARKEMA, SUSAN J
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): Clonus is one manifestation of spasticity and produces involuntary neuromuscular responses that can interfere with the ability to walk after spinal cord injury (SCI). Clonus results in oscillatory efferent output generated by repetitive afferent input and the activation of central neural oscillators. The frequency of clonus is similar when driven by different types of repetitive afferent stimuli such as during standing and stepping. Clonus can radiate across several spinal cord segments and the oscillatory efferent output is modulated by interneurons. Thus clonus can be used as a physiological probe to understand the functional organization of interneuronal circuits.  
We propose to study clonus during manual stretch of the plantarflexors standing and stepping to assess whether repetitive afferent input can alter the functional interneuronal organization of the human spinal cord.  
We will assess whether the specific afferent input related to loading modulates the central oscillators that generate clonus to modify efferent output after severe SCI. We hypothesize that manual stretch of the plantarflexors standing and stepping will result in different co-activation patterns of clonic EMG among ipsilateral and contralateral flexors and extensors. Also if a higher level of load to the legs is provided during standing and stepping the clonic EMG activity will be reduced with an increase in tonic activity of bilateral flexors and extensors. We have observed that when individuals after severe spinal cord injury undergo multiple stand or step training sessions clonus and spasticity are reduced. We propose that intensive training that provides specific sensory information related to loading can reconfigure spinal networks to modify and reduce clonus after severe SCI. We suggest that the repetitive afferent input related to loading induces significant and persistent functional reorganization of interneuronal circuits. We hypothesize that after intensive training the same afferent input will alter clonic EMG activity.  
The proposed studies will further our understanding of the mechanisms of clonus after severe SCI. Further we will learn whether the spinal neural networks responsible for clonus interact with those that generate standing and stepping. We will also understand whether the repetitive presentation of specific sensory information by training can reconfigure spinal neural networks to generate more functional motor output. Clonus is routinely treated with drugs or even invasive strategies with the intent to diminish clonus to enhance motor function. Unfortunately side effects rebound spasticity and limited recovery of function are often reported. We suggest that anti-spasticity medication may actually be interfering with the neural circuits needed for standing and walking. If this is the case then specific training that uses task appropriate sensory cues for standing and walking may alleviate clonus and spasticity reduce the need for medication and improve motor function in individuals with severe SCI.

project_terms:
clinical research;electromyography;gait;gastrocnemius muscle;human subject;interneurons;muscle function;myoclonus;nerve injury;neural information processing;neural plasticity;neuromuscular function;oscillatory blood flow;psychomotor function;spinal cord;spinal cord injury;stretch reflex


application_id: 7189031
project_number: 5R01HL076160-04
project_title: Direct Peritoneal Resuscitation from Hypovolemic Shock
administering_ic: NHLBI
award_notice_date: 2007-02-19
opportunity_number: RFA-HL-03-015
application_type: 5
activity_code: R01
ic: HL
serial_number: 076160
program_official: LIANG, ISABELLA Y
project_start_date: 2004-03-01
project_end_date: 2008-08-28
study_section: ZHL1-CSR-I(F1)
contact_pi_person_id: 7725997
contact_pi: GARRISON, RICHARD N
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):   The pathophysiology of Hemorrhagic shock consists of disruption of the cellular metabolic functions  endothelial barrier properties redistribution of body fluids and electrolytes a systemic inflammatory  response and a deleterious intestinal vasoconstriction and a disproportionate splanchnic hypoperfusion which persists even after adequate fluid replacement that restores and maintains hemodynamics. These pathophysiologic events cause local and remote tissue injury that culminates in multiple organ failure (MOF) by mechanisms which are poorly understood. It is hypothesize that initiation of direct intraperitoneal resuscitation (DPR) with a balanced physiologic salt solution supplemented with glucose (2.5%) at the time of conventional resuscitation (CR) from hemorrhagic shock can reverse the pathophysiology of this syndrome improving resuscitation outcome potentially preventing (MOF) and improving survival: a) by suppressing the hemorrhage-induced systemic inflammatory response b) by direct intestinal resuscitation to enhance visceral perfusion and cardiac output c) by improving endothelial cell responsiveness to vasodilators and d) by preventing the hemorrhage-induced water and electrolytes imbalance. To address this hypothesis we will utilize intravital microscopy and quantitative autoradiography (QAR) to perform in vivo studies in a rodent model of hemorrhagic shock which will be resuscitated with either CR or CR+DPR and determine the following: 1) Serum cytokines profile and level of prostanoid metabolites; 2) Endothelial cell function with dose-response curves to endothelial-dependent receptor-mediated and non-receptor mediated as well as endothelial-independent agonists; 3) The pattern of distribution of tissue water (intravascular thetaiv interstitial thetaif intracellular thetaic) in the gut and abdominal wall with QAR; 4) The role of neutrophils in the derangement of intestinal microvascular endothelium by measuring microvascular responses in the presence of anti-PMN serum and specific antibodies; and 5) The mechanisms involved in the ability of DPR to reverse the pathophysiology of the shock syndrome. Long-term objectives are to develop a pre-clinical protocol that utilizes DPR as a prelude to translation of the results to trauma patients and finally a clinical protocol that utilize DPR to prevent multiple organ failure in hemorrhage shock with resuscitation.

project_terms:
Abdominal Muscles;Abdominal wall structure;Address;Adenosine Diphosphate;Adherence (attribute);Adhesions;Agonist;Alteplase;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antibiotic A23187;Antibodies;Anticoagulants;Arginine;Autoradiography;Autoradiography Quantitative;Bacterial Translocation;Bathing;Blood;Blood flow;Body Fluids;C-reactive protein;Calcium;Cardiac Output;Cause of Death;Cell membrane;Cell physiology;Cholinergic Agonists;Clinical;Clinical Protocols;Colloids;Condition;Deterioration;Disruption;Distal;Distal part of ileum;Dose;Drug or chemical Tissue Distribution;E-Selectin;Electrolytes;Endothelial Cells;Endothelium;Enzyme Immunoassay;Epoprostenol;Equilibrium;Event;Extracellular Matrix;Fluid Shifts;Fluid Therapy;Functional disorder;Generations;Glucose;Goals;Greater sac of peritoneum;Heart;Hemorrhage;Hour;Hydrostatic Pressure;Hypoxanthine;Hypoxanthines;Hypoxia;Impairment;Implant;Inflammatory;Inflammatory Response;Injury;Intensive Care Units;Intercellular adhesion molecule 1;Intestines;Intravenous;Ionophores;Ischemia;Label;Laboratories;Lead;Leukocytes;Liquid substance;Liver;Lung;Measurement;Measures;Mediating;Mediator of activation protein;Mefenamic Acid;Membrane;Membrane Potentials;Metabolic;Methods;Microscopy Video;Microvascular Permeability;Morbidity - disease rate;Mortality Vital Statistics;Multiple Organ Failure;Multiple Trauma;Muscle Tonus;Nitric Oxide Synthase;Nitroprusside Disodium Salt;Operative Surgical Procedures;Organ;Organ failure;Outcome;Oxygen;Pathway interactions;Patients;Pattern;Perfusion;Peritoneal;Peritoneal Dialysis;Peroxidase;Pharmaceutical Preparations;Phospholipase A2;Physiological;Physiological reperfusion;Plasminogen Activator Inhibitor 1;Play;Potassium;Pressure- physical agent;Procedures;Property;Prostaglandins;Protocols Treatment;Purines;Randomized;Range;Reaction;Reperfusion Therapy;Research;Resuscitation;Rodent Model;Role;Saline;Score;Serum;Shock;Shock Hemorrhagic;Shock Hypovolemic;Sodium;Sodium Chloride;Solutions;Staging;Superoxides;Surface;Swelling;Syndrome;Techniques;Testing;Therapeutic;Thinking function;Time;Tissues;Topical application;Transcriptional Activation;Translations;Trauma;Up-Regulation (Physiology);Vascular Cell Adhesion Molecule-1;Vascular constriction (function);Vasodilator Agents;Venous;Visceral;Water;Water-Electrolyte Imbalance;Xanthine Oxidase;Xanthines;base;capsule (pharmacologic);concept;cytokine;experience;extracellular;free radical oxygen;hemodynamics;improved;in vivo;inhibitor/antagonist;interstitial;intraperitoneal;intravital microscopy;leukocyte activation;lymph flow;migration;neutrophil;omega-N-Methylarginine;pre-clinical;prevent;programs;purine;receptor;research study;response;restoration;von Willebrand Factor;xanthine


application_id: 7188597
project_number: 5R01DC006698-03
project_title: NEURAL MODULATION OF CENTRAL TASTE PROCESSING
administering_ic: NIDCD
award_notice_date: 2006-05-12
opportunity_number: PA-03-115
application_type: 5
activity_code: R01
ic: DC
serial_number: 006698
program_official: SULLIVAN, SUSAN L
project_start_date: 2004-12-03
project_end_date: 2010-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT F
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
amygdala;corticotropin releasing factor;electrophysiology;experimental brain lesion;frontal lobe /cortex;hypothalamus;laboratory rat;limbic system;medulla oblongata;microdialysis;microelectrodes;neural information processing;neurochemistry;neurotensin;neurotransmitters;parabrachial nucleus;prosencephalon;radioimmunoassay;solitary tract nucleus;somatostatin;substance P;taste


application_id: 7188084
project_number: 5R01AI050656-05
project_title: Molecular Mechanisms Controlling KIR Genes in NK Cells
administering_ic: NIAID
award_notice_date: 2007-03-09
application_type: 5
activity_code: R01
ic: AI
serial_number: 050656
program_official: MILLER, LARA R
project_start_date: 2003-09-01
project_end_date: 2009-02-28
study_section: Experimental Immunology Study Section[EI]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): Natural killer (NK) cells use killer cell immunoglobulin-like receptors (KIR) to distinguish normal cells from infected and malignant cells. NK cells express an apparently random assortment of KIR genes. Our LONG RANGE GOAL is to use NK cells to treat cancer and infectious diseases. Our CURRENT OBJECTIVE is to identify how developing NK cells initiate and then maintain selective KIR gene expression. Supported by strong preliminary data our CENTRAL HYPOTHESIS is that promoter methylation controls locus-specific and allele-specific KIR gene expression. The RATIONALE for the proposed research is that understanding KIR gene regulation could lead to effective immunotherapy of cancer and infectious diseases. Furthermore our research will test the central paradigm of tissue-specific gene expression. The proposed research is a COLLABORATION between investigators at two universities. The principal investigator has an established record of research in NK ceils immune recognition of HLA class I molecules and molecular biology. The other investigators are leaders in gene expression control and in human NK cell development. The collaboration will produce a synergistic effect that is not easily matched by a single investigator. Our SPECIFIC AIMS are to 1. Test the molecular mechanisms of KIR gene expression control. 2. Define cis acting elements and trans-acting factors that control KIR gene expression. 3. Elucidate how developing NK cells initiate selective KIR gene expression. Our approach is INNOVATIVE. We have produced unique new data and we will combine several cutting-edge research techniques to rigorously test our hypotheses. It is our EXPECTATION that 1) we will develop a clear understanding of how NK cells maintain stable KIR expression; 2) we will define several important cis-acting elements and trans-acting factors that regulate KIR transcription; 3) we will identify what signals developing NK cells use to initiate KIR gene expression. Our results will be highly SIGNFICANT because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Of broader significance elucidation of KIR gene expression control will provide an important model for gene choice in development and offer insights into birth defects and cancer.

project_terms:
Alleles;Binding (Molecular Function);Cell Line;Cells;Class;Collaborations;Communicable Diseases;Complex;Congenital Abnormality;Control Locus;Cytomegalovirus;Data;Development;Elements;Enhancers;Family;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Goals;Hematopoiesis;Histone Deacetylase;Human;Immune;Immunity;Immunoglobulins;Individual;Insulator Elements;Interleukin-15;Interleukin-2;Interleukin-3;Interleukin-7;International;Killer Cells;Knowledge;Laboratories;Lead;Ligands;Lymphocyte;Malignant Neoplasms;Methylation;Modeling;Molecular;Molecular Biology;Natural Killer Cells;Normal Cell;Numbers;Principal Investigator;Promotor (Genetics);Proteins;Range;Reagent;Receptor Gene;Recruitment Activity;Regulation;Reporting;Research;Research Personnel;Research Technics;Signal Transduction;Site;Stem Cell Factor;Stromal Cells;T-Lymphocyte;Testing;Tissue-Specific Gene Expression;Trans-Activators;Transcription Genetic;Universities;Work;cancer cell;cancer immunotherapy;cancer therapy;cell killing;cis acting element;cytokine;expectation;improved;innovation;insight;leukemia/lymphoma;receptor;receptor expression


application_id: 7186713
project_number: 5F31NS052012-02
project_title: Substance P and the tectothalamic pathway
administering_ic: NINDS
award_notice_date: 2007-01-22
application_type: 5
activity_code: F31
ic: NS
serial_number: 052012
program_official: CHEN, DAOFEN
project_start_date: 2006-01-01
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-F02B(20)L]
contact_pi_person_id: 7390903
contact_pi: MASTERSON, SEAN P
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of the proposed experiments is to determine the causes of attention impairment during disease. However it is first necessary to understand the organization of circuits that may contribute to attention mechanisms in the normal brain. Many studies have implicated the pulvinar nucleus as an area that may regulate visual attention. The rodent lateral posterior (LP) nucleus is a region comparable to inferior regions of the primate pulvinar nucleus. The rodent LP nucleus is innervated by fibers which contain the neuropeptide substance P a neuromodulator known to facilitate neuronal firing properties. The LP nucleus receives visual input from projection cells within an area of the superior colliculus that is substance P- immunoreactive. A combination of tract tracing immunocytochemistry electron microscopy and in vitro electrophysiology will be used to examine the synaptic organization and functional properties of the tecto- thalamic pathway. Concomitant release of substance P with glutamate from tecto-thalamic terminals might enhance and potentiate glutamatergic input from the superior colliculus. Because the LP nucleus projects to the visual cortex the tecto-thalamic pathway could affect visual attention by modulating cortical circuitry.

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


application_id: 7183476
project_number: 5R01AI020941-23
project_title: Glycobiology of Leishmania
administering_ic: NIAID
award_notice_date: 2007-03-09
application_type: 5
activity_code: R01
ic: AI
serial_number: 020941
program_official: MCGUGAN, GLEN C
project_start_date: 1985-09-01
project_end_date: 2009-02-28
study_section: Tropical Medicine and Parasitology Study Section[TMP]
contact_pi_person_id: 7875234
contact_pi: TURCO, SALVATORE J
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by the applicant): Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis a major health problem worldwide. Leishmania have evolved a unique family of phosphoglycan (PG)- containing glycoconjugates including the GPI-anchored prototype lipophosphoglycan (LPG). The abundance location and uniqueness of the Leishmania glycoconjugates have implicated these molecules in critical roles for the parasite's survival in their harsh digenetic life cycle. Unfortunately the wide distribution of PG units and GPI domains across a considerable number of diverse glycoconjugates has hindered a comprehensive assessment of their individual functions and the enzymes responsible for their biosynthesis. In a separately funded grant we have surmounted this dilemma by isolating relevant genes via functional complementation of glycosylation mutants and cross-species manipulations. These studies have progressed sufficiently to enable us to focus this grant on the enzymology of the encoded proteins involved in glycoconjugate biosynthesis and expression which in turn represent indispensable opportunities toward scrutinizing the molecular pathways of glycoconjugate assembly in Leishmania. By fully characterizing key proteins encoded by selected genes we expect to meaningfully advance our understanding of how Leishmania assemble such an assortment of complex interrelated glycoconjugates and how they are biochemically involved in the parasite's life cycle.  The specific aims of this competing renewal application are:  1. to investigate the family of Golgi nucleotide-sugar transporters.  2. to characterize the multiple mannosylphosphoryltransferases (MPTs) involved in PG synthesis.  3. to determinate the relationship of a chaperone with galactosylation of PG repeat units.  4. to examine the proteins involved in controlling LPG length and side chain sugar modifications

project_terms:
Anabolism;Automobile Driving;Biochemical;Bioinformatics;Competence;Complex;Enzymatic Biochemistry;Enzymes;Family;Funding;Galactosyltransferases;Genes;Genetic;Glycobiology;Glycoconjugates;Glycosylphosphatidylinositols;Golgi Apparatus;Grant;Health;Individual;Investigation;Leishmania (genus);Leishmaniasis;Length;Life Cycle Stages;Location;Modification;Molecular;Molecular Chaperones;Numbers;Parasites;Pathway interactions;Polysaccharides;Proteins;Reaction;Role;Sand Flies;Side;Structure;Surface;Uridine Diphosphate Sugars;Virulence;base;genetic regulatory protein;glycosylation;glycosyltransferase;lipophosphonoglycan;metacyclogenesis;mutant;prototype;reconstitution;sugar;sugar nucleotide;transmission process


application_id: 7183459
project_number: 5R01AI049367-06
project_title: Blockade of host apoptosis by Toxoplasma gondii
administering_ic: NIAID
award_notice_date: 2007-03-12
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:
DESCRIPTION (provided by applicant): Toxoplasma gondii infected cells exhibit a profound blockade of apoptosis that manifests at multiple points in the apoptotic cascade. Our studies have shown an essential role for the hose transcription factor NFKB in the establishment of the parasite-directed anti-apoptotic state. Activation of NFxB by diverse cellular pathways occurs via the phosphorylation of specific Ser residues on its inhibitor kB. This phosphorylation event is  
catalyzed by a unique cellular kinase complex defining the kB kinase signalosome (IKK). In T. gondii infected cells Phospho-kB localizes at the parasitophorous vacuole membrane (PVM) the organelle defining the intracellular replication-permissive niche. The detection of P-kB at the PVM in cells devoid of all IKK activity suggested the presence of a parasite-encoded kinase (TglKK) is responsible. We find just such an 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 with defects in IKK. Initial studies examining the temporal nature of NFxB activation reveal a biphasic pattern of NFKB expression suggesting independent but temporally linked contributions of the host and parasite IKK activities. We propose to use host cell lines with specific lesions in pathways upstream of IKK as well as  
cell lines "locked" into a defined expression profile to better characterize the pertinent cellular pathways subverted by T. gondii infection. Finally we have developed a genetic screen to identify parasite genes involved in NFKB activation. Initial results bear out the evidence that the mechanism to subvert NFKB is multifactorial. Identification of these parasite genes and the elucidation of their roles in NFKB activation in the context of the studies on the cellular components will help define the signaling networks subverted by the parasite. Dissection of these pathways is particularly important given the targets of NFKB many of the cytokines implicated both in the pathogenesis of acute toxoplasmosis and the development of immunity to the 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: 7183457
project_number: 5R01AI065974-02
project_title: Molecular pathogenesis of Francisella Tularensis
administering_ic: NIAID
award_notice_date: 2007-03-09
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:
DESCRIPTION (provided by applicant): The causative agent of the fatal disease Tularemia Francisella tularensis (Ft) is a gram negative highly infectious intracellular bacterium that is classified as a Category A Select Bioterrorism Agent. Intracellular replication of Ft within macrophages is essential for disease manifestation. It is rather astonishing the relative paucity of knowledge about the molecular and cellular aspects of pathogenesis of this versatile and extremely virulent pathogen. Our preliminary data indicate that upon entry into macrophages Ft-containing phagosome (FCP) evades lysosomal fusion. The organism escapes from the phagosome into the cytoplasm by 2-12h post-infection. Our hypothesis is that specific modes of entry of Ft into macrophages allow the organism to modulate biogenesis of its phagosome by specific exported bacterial effectors into a niche that does not fuse to the lysosomes and allow subsequent escape of the organism into the cytoplasm where it replicates. 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-like stage. II. To identify mutants defective in arresting phagosome biogenesis and escape into the cytoplasm. III. To characterize the bacterial factors involved in arresting phagosome biogensis and escape into the cytoplasm. Significance: Pathogenesis of the Category A Select Bioterrorism Agent Ft is one of the least studied and understood among intracellular bacterial pathogens. Understanding how this organism exploits macrophages for proliferation and disease manifestation is fundamental to our knowledge of tularemia. The bacterial effectors involved in exploiting the macrophage are potential targets for treatment as well as potential 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: 7179677
project_number: 1R01HL086644-01
project_title: Computer Modeling of Perlecan as a Vascular Regulator
administering_ic: NHLBI
award_notice_date: 2007-01-19
application_type: 1
activity_code: R01
ic: HL
serial_number: 086644
program_official: GOLDMAN, STEPHEN
project_start_date: 2007-01-19
project_end_date: 2010-12-31
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 1879706
contact_pi: FANNON, MICHAEL W
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-19
project_abstract:
DESCRIPTION (provided by applicant): Blood circulation is a complex system. At every moment a multitude of molecules are transported simultaneously and continuously to specific targets in the vasculature. The ability to regulate whole panels of molecules by controlling the circulating concentration of a single moiety if discrete could provide a powerful tool to understand the causes prevention and treatment of cardiovascular disease and other disorders relating to blood vessels. Perlecan an important molecule in blood vessel and tumor growth could be such a molecule. Our hypothesis is that based on its high affinity for a number of growth factors that are crucial to normal and pathological vascular growth and development circulating perlecan has the potential to sequester these growth factors in blood preventing their interactions with vascular surfaces. Because of the complexity of this system however it is difficult to characterize at a macro level using in vitro or in vivo approaches alone. Computer modeling provides us with a powerful tool to test parameters and conditions such as multiple ligand interactions in solution and on vascular surfaces under flow which are crucial components in developing an accurate understanding. A simulated vessel model under flow will be used to test the predictive value of the model using a variety of testable conditions. Our specific aims are to: 1. Develop a model of endothelial cell binding based on the binding characteristics of three growth factors and the proteoglycan perlecan 2. Test the model using competitive binding assays with growth factors alone or in combination with other factors as a function of perlecan concentration 3. Refine the model to mimic the interactions of the growth factors and perlecan under flow and adjust the model to accommodate changes between what is observed in experimental assays and what is predicted based on flow conditions Our model will be the first step in attaining our long range goal of designing and testing Pharmaceuticals that exploit similar regulatory characteristics. By using a systems biology approach the interrelatedness of the blood vessels and the components being transported through them will be characterized at the level of the organism as a whole.

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


application_id: 7179641
project_number: 1R01CA124630-01
project_title: PTTG Role in Ovarian Tumorigenesis and Matastasis
administering_ic: NCI
award_notice_date: 2007-03-26
application_type: 1
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: 2007-03-26
project_abstract:
DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause of death from gynecologic malignancies in the United States. Molecular mechanisms that initiate and support ovarian tumorigenesis are not well defined. We cloned a novel oncogene "PTTG" also known as securin from human testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional protein and is highly expressed in many tumors including tumors of ovary. Introduction of PTTG into NIH3T3 and HEK293 cells induces cellular transformation and promotes tumor formation in nude mice suggesting its strong oncogenic function. Notably PTTG has been shown to inhibit separation of sister chromatids and to increase the synthesis and secretion of bFGF VEGF and IL-8 as well as activate the expression of the oncogene c-myc and PI3K/AKT signaling pathway suggesting that the oncogenic activity of PTTG may involve induction of aneuploidy and chromosomal instability increased angiogenesis and production of growth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitro and its deletion in animals (Knockout) results in reduction of tumor development suggesting its important role in maintenance of cancer phenotype. The long-term objectives of this application are to understand the role of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti- neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG in ovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine the effect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation progression and metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis; and iii) to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumor suppression and metastasis and determine mechanisms that lead to suppression of tumor growth and metastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovarian tumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTG function as anti-neoplastic agents. In addition transgenic animal model developed from our studies could enhance efforts aimed at developing new methods for detection prevention and treatment of ovarian cancer.

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: 7179209
project_number: 7R01GM050388-12
project_title: Lysophosphatidic Acid: Synthesis Actions & Inactivation
administering_ic: NIGMS
award_notice_date: 2006-03-01
application_type: 7
activity_code: R01
ic: GM
serial_number: 050388
program_official: IKEDA, RICHARD A
project_start_date: 1994-08-01
project_end_date: 2008-06-30
study_section: Physiological Chemistry Study Section[PC]
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
budget_start_date: 2005-11-01
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (sn-1 acyl 2-hydroxy glycerol 3-phosphate LPA) is a biologically active extracellular lipid mediator that promotes growth differentiation survival and motility in many different cells. Some of these effects are mediated by specific G-protein coupled receptors. LPA has critical roles in a broad range of physiological and pathophysiological processes that include early development inflammation thrombosis atherosclerosis wound healing reproduction and cancer. In the first funding period of this award we identified genes encoding phospholipase D (PLD) and Lipid Phosphate Phosphatase (LPP) enzymes. In the second funding period of the award we investigated the structure regulation and functions of these enzymes identifying key roles in the synthesis and inactivation of LPA. We also characterized a new class of LPP-related (LPR) integral membrane proteins that regulate cellular morphology and cytoskeletal organization. This proposal describes studies to test hypotheses about how these three classes of proteins function to regulate LPA signaling. Lipid binding and mutational studies suggest that a representative LPR protein LPR1 could a "receptor-like" mediator of the well-characterized effects of LPA on cell morphology. We will determine the mechanism by which LPR1 regulates the formation of filopodia and related actin-rich structures in fibroblasts and epithelial cancer cells. Secondly we will define the processing regulation and role in constitutive and agonist promoted LPA production of a lysophosphatidiylcholine (lysoPC)-selective lysophospholipase D that is a potent regulator of cancer cell growth and motility. Finally we will use genetic approaches and novel selective chemical inhibitors to determine the role of lipid phosphate phosphatases (LPPs) in regulation of LPA signaling in mouse vascular smooth muscle cells which are highly responsive to LPA and play a central role in atherosclerosis and vascular responses to injury. The broad long term goal of our research is identify the physiological and pathophysiological functions of LPA signaling. Resolution of the interrelated issues outlined above is central to this goal because it will ultimately lead to the design of pharmacological and genetic strategies to manipulate LPA signaling in vivo.

project_terms:
HeLa cells;RNA interference;animal tissue;biological signal transduction;cell growth regulation;cell line;cell morphology;cell motility;cell proliferation;enzyme activity;enzyme mechanism;fibroblasts;gene expression;gene mutation;glycoproteins;lipid biosynthesis;lysolecithins;lysophospholipase;lysophospholipids;muscle cells;phosphatidate phosphatase;protein binding;protein localization;protein structure function;vascular smooth muscle


application_id: 7177463
project_number: 5R01EY014701-04
project_title: GABAc Receptors & Mouse Retinal Ganglion Cell Responses
administering_ic: NEI
award_notice_date: 2007-03-15
application_type: 5
activity_code: R01
ic: EY
serial_number: 014701
program_official: MARIANI, ANDREW P
project_start_date: 2004-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
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: 2007-02-01
project_abstract:
DESCRIPTION (provided by applicant): Vision requires the integration of many aspects of the visual field into a cohesive whole that is used by the organism to navigate its environment. The mammalian retina is a laminar structure and each layer is populated by several cell types that combine to define the response properties of the retinal ganglion cells (RGCs) which transmit the signal to the brain. The many aspects of the visual scene are encoded by two parallel pathways within the retina that either detect increases or decreases in light intensity. There are many types of RGCs and their responses are defined by the inputs they receive. One key element in shaping their response properties is inhibition which like other regions of the brain is mediated by glycine and gamma amino butyric acid (GABA). GABA inhibition is mediated by three receptors GABAA GABAB and GABAC all of which are present in the retina. One challenge then is to determine how each of these inhibitory and excitatory inputs shapes the responses of the RGCs. A new tool towards attaining this goal is the ability to manipulate the mouse genome and selectively remove specific inputs the effect of which then can be assessed on the RGCs. However unlike the extensive literature for cat rabbit and primate relatively little is known about the fundamental properties of murine RGCs. The goal of this proposal is to characterize the response properties of mouse RGCs both in vivo and in vitro and in particular determine the role that GABACR-mediated input plays in shaping the responses. The specific aims are (1) to determine the effect of eliminating genetically GABACR-mediated inhibition on a subset of RGC response properties recorded in vivo and (2) correlate structure and function of a diverse set of RGCs and determine the impact of eliminating GABACR-mediated input on the response properties of each of these cell types. These data will enhance our understanding of the role of inhibition in shaping the response of the output cells of the retina and therefore important aspects of integration of information in the visual field.

project_terms:
Agonist;Biological Models;Brain;Brain region;Butyric Acid;Butyric Acids;Cells;Cellular Morphology;Class;Complement;Data;Depth;Environment;Evaluation;Eye;Feedback;Felis catus;Glycine;Goals;Goldfish;In Vitro;Indium;Individual;Knowledge;Light;Literature;Mediating;Mice Knockout;Morphology;Mus;Nerve Fibers;Optic Nerve;Organism;Oryctolagus cuniculus;Output;Pathway interactions;Physiological;Play;Preparation;Primates;Property;Relative (related person);Reporting;Retina;Retinal;Retinal Ganglion Cells;Role;Salamander;Sampling;Shapes;Signal Transduction;Specificity;Structure;Systems Analysis;Thinking function;Vision;Visual;Visual Fields;cell type;defined contribution;genome mouse;in vivo;interest;light intensity;receptor;response;retinal adaptation;theories;tool;visual receptive field


application_id: 7177394
project_number: 7K01CA106599-02
project_title: Regulation of apoptosis by Bcl-XL Bak and Bax
administering_ic: NCI
award_notice_date: 2006-03-28
opportunity_number: PAR-03-104
application_type: 7
activity_code: K01
ic: CA
serial_number: 106599
program_official: ECKSTEIN, DAVID J
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
BCL2 gene /protein;Bax gene /protein;RNA interference;apoptosis;calcium flux;cell line;electrophysiology;endoplasmic reticulum;gene expression;gene expression profiling;genetic regulation;membrane permeability;microarray technology;neoplasm /cancer genetics;oligonucleotides;protein localization;recombinant proteins


application_id: 7176868
project_number: 5R01DC007194-02
project_title: Genomics of Olfactory Regeneration
administering_ic: NIDCD
award_notice_date: 2007-02-28
application_type: 5
activity_code: R01
ic: DC
serial_number: 007194
program_official: DAVIS, BARRY
project_start_date: 2006-03-01
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-K(03)M]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): The sensory neurons of the mammalian olfactory epithelium can be regenerated even if they are completely eliminated. This capacity which lasts throughout the life of the animal is of significant interest for both basic and applied neuroscience research. Its mechanisms are presumed to be relevant to the search for regeneration-promoting therapies for neurodegenerative disorders and trauma of the nervous system. To extend our understanding of olfactory regeneration we have identified 1260 transcripts whose abundance within the olfactory epithelium changes after removal of the olfactory bulbs a manipulation that causes the selective death and subsequent regeneration of the olfactory sensory neurons. Of these transcripts 303 increase contemporaneously with the proliferation of sensory neuron progenitors. The functions of the proteins encoded by these 303 transcripts predict several underlying processes including transcriptional activation of cell proliferation and differentiation up-regulation of the cell cycle axon outgrowth and cell signaling. Only a handful of these proteins have previously been linked to olfactory regeneration. In this application we propose to focus on a subset of gene products that are likely to be critical for proliferation and differentiation of the olfactory sensory neurons. The first specific aim is to define the capacity for each transcript to be involved in olfactory regeneration by determining which cell types express them including spatial and temporal overlap with markers of known progenitor cell types. The second and third aims focus further on a small subset of genes for which targeted deletions are available. These aims test whether the absence of the gene alters the development or regeneration of the olfactory epithelium leading to changes at the behavioral cellular or molecular level. The proposed experiments will definitively test whether several proteins are dispensable for olfactory regeneration and will define the potential roles of a couple dozen additional proteins.

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


application_id: 7176361
project_number: 3F31AI064120-01A1S1
project_title: Minority predoctoral fellowship program
administering_ic: NIAID
award_notice_date: 2006-02-10
application_type: 3
activity_code: F31
ic: AI
serial_number: 064120
suffix: A1S1
program_official: HERNANDEZ, MILTON J
project_start_date: 2005-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1]
contact_pi_person_id: 8002596
contact_pi: MANIRARORA, JEAN N
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  CD4+CD25+ regulatory T cells play a major role in the control of immunity as the lack of this T cell population results in the activation of autoreactive T cells and the development of autoimmune diseases.  It has been reported that the level of CD4+CD25+ regulatory T cells is lower in autoimmune-prone mice such as NZBxNZWFI (BWF1) and NOD mice. The central hypothesis of this proposal is that autoimmune-prone mice may have a defect in CD4+CD25+ regulatory T cell function which may play a role in the pathogenesis of autoimmune diseases.  Our preliminary studies suggest that NOD antigen presenting cells (APC) play a crucial role in the defect of CD4+CD25+ regulatory T cell function but that activation of NOD APC restores normal regulation in vivo. The objective of this proposal is therefore to develop novel strategies using TLRs to restore optimal regulation in NOD mice and to characterize the mechanisms of this regulation. Moreover we will investigate whether APC from diabetic patients have also a defect in activating regulatory T cells and whether enhancement of thejr APC function can ameliorate regulation as well as whether regulatory T cells from diabetic patients can be activated directly via TLRs.


application_id: 7174079
project_number: 7R01CA096496-05
project_title: Lysophospholipid Mediators in Ovarian Cancer
administering_ic: NCI
award_notice_date: 2006-05-23
application_type: 7
activity_code: R01
ic: CA
serial_number: 096496
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2002-02-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-ET-1(01)M]
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
budget_start_date: 2006-05-23
project_abstract:
DESCRIPTION (provided by applicant): Cancer cell proliferation is driven by         overexpression or mutational activation of normal cellular pathways that            control cell growth and differentiation. Recent work suggests that autocrine        actions of the receptor-directed lipid growth factor lysophosphatidic adid          (LPA) play a central role in the etiology of ovarian cancer. Growth                invasiveness and resistance to chemotherapeutics of ovarian cancer cells are        all dependent on LPA. Ovarian cancer cells synthesize LPA and release this          mediator into ascites fluid which accumulates in the peritoneum and bathes          abdominal tumors. Current therapies for late stage ovarian cancer that include      surgery radiation and chemotherapy have not improved cure rates for the            disease. Targeting the synthesis and actions of LPA may therefore provide a         novel treatment strategy for pharmacological intervention in ovarian cancer.        Although the receptors and signaling pathways involved in responses to LPA are      well understood surprisingly little is known about the enzymes and cellular         processes involved in LPA synthesis release and inactivation. We have              identified phospholipases and lipid phosphatases that play critical roles in        the synthesis and metabolism of LPA and related bioactive lipid mediators. The      goal of the research described in this proposal is to define the enzymes and        pathways involved in the synthesis and inactivation of LPA by ovarian cancer        cells. Molecular genetic and pharmacological manipulation of these pathways         will allow us to evaluate the potential for therapies that target LPA               metabolism in treatment of ovarian cancer. Successful completion of the             research will provide the framework and impetus to develop novel effective          therapeutics for ovarian cancer.

project_terms:
acid anhydride hydrolase;autocrine;carboxylic ester hydrolases;clinical research;enzyme activity;epithelium;female;human subject;lipid metabolism;lysophospholipids;ovary;ovary neoplasms;phosphomonoesterases;women&apos;s health


application_id: 7173844
project_number: 5P01AG013494-10
project_title: Aging of Central Dopaminergic Systems in Primates
administering_ic: NIA
award_notice_date: 2007-03-05
application_type: 5
activity_code: P01
ic: AG
serial_number: 013494
program_official: CHEN, WEN G
project_start_date: 1997-02-18
project_end_date: 2010-01-31
study_section: ZAG1-ZIJ-3(O1)
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
arra_indicator: N
budget_start_date: 2007-03-15
project_abstract:
DESCRIPTION (provided by applicant): Behavioral slowing is one of the cardinal features of human aging contributing to the debilitating deterioration of motor functions in senescence. Our principal hypothesis for the past five years of research on this Program Project has been that changes in central dopaminergic pathways constitute a fundamental component of age-associated motoric declines. Converging evidence from our studies and others are providing strong support for this hypothesis. Our experimental plan for the next five years is designed to further our understanding of CNS processes underlying behavioral slowing and analyze therapeutic approaches for intervention. Specifically our studies focus on the dopamine (DA) neurons in the substantia nigra (SN) and their projections to the caudate nucleus putamen and globus pallidus of the basal ganglia. The proposed studies will analyze key junctions in the neural circuitry regulating motor functions in the basal ganglia using behaviorally characterized female rhesus monkeys ranging in age from young adulthood to old age (5-25years+) as a model of human aging. Collectively the three Projects and three supporting Cores in this Program will critically test the following hypotheses:  Hypothesis 1 - That while changes in dopaminergic functions occur throughout the basal ganglia alterations in neural processing in the SN is a principal component of age-associated motor declines.  Hypothesis 2 - That functional changes in the basal ganglia dopaminergic system including in tyrosine hydroxylase (TH) dopamine transporters (DAT) and DA receptors are closely associated with age-associated motoric declines.  Hypothesis 3 - That anatomical changes in normal aging in the basal ganglia are less predictive than functional changes of age-associated declines in motoric performance.  Hypothesis 4 - That local administration of the potent dopaminergic trophic factor GDNF (glial cell line-derived neurotrophic factor) into the SN significantly repairs and restores age-associated declines in SN dopaminergic functions.


application_id: 7173726
project_number: 5R01AI051592-05
project_title: Cis-acting RNA elements in hepatitis C virus replication
administering_ic: NIAID
award_notice_date: 2006-12-20
application_type: 5
activity_code: R01
ic: AI
serial_number: 051592
program_official: KOSHY, RAJEN
project_start_date: 2003-01-01
project_end_date: 2008-12-31
study_section: Experimental Virology Study Section[EVR]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
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: 2007-01-01
project_abstract:
Hepatitis C virus (HCV) is the major etiologic agent of non-A non-B (NANB) viral hepatitis infectingapproximately 4 million people in the U.S. HCV has a positive-stranded RNA genome consisting of a singleopen reading frame (ORF) flanked by the untranslated regions (UTR) at the 5' and 3' ends. The ORFencodes a large polypeptide that is processed to structural and nonstructural viral proteins. The roles of viralproteins and conserved RNA sequences/structures in HCV replication are poorly understood. The overallgoal of this research proposal is to determine the sequence and structural requirements of cis-acting RNAelements in the 5' and 3' UTRs in viral RNA replication. Both the 5' and 3' UTR sequences are highlyconserved among various HCV isolates. Genetic studies have demonstrated that both 5' and 3' UTRs areessential for HCV RNA replication. We hypothesize that the conserved 5' and 3' UTRs contain cis-actingRNA elements important for control of HCV RNA replication. The highly conserved 5'UTR harbors twodistinct RNA elements a short 5'-proximal RNA element with a stern-loop structure and a longer element ofinternal ribosomal entry site (IRES). To determine cis-acting RNA elements in the 5'UTR and to define theirroles in HCV RNA replication we will perform systematic mutagenesis analyses of the conservedsequences/structures by nucleotide deletions substitutions and replacement with non-HCV IRES. The3'UTR consists of three distinct regions a highly conserved 98 nucleotides that form three stern-loopstructures a poly(U/C) tract of variable length and a variable region at immediate downstream of the ORF.Cis-acting RNA elements in the 3'UTR for HCV RNA replication will be defined by nucleotide deletions andsubstitutions. The effects of mutations in the 5' and 3' UTRs on HCV RNA replication will be determined byusing reverse genetics systems. We have developed a DNA-based HCV replicon replication system. Wehave also demonstrated that a DNA-based HCV 'minigenome' RNA was replicated when active replicasecomplex was provided in trans. These reverse genetics systems for HCV RNA replication will be used todetermine cis-acting RNA elements in the 5' and 3' UTRs and their roles in HCV RNA replication.Information gained from these studies will immediately contribute to our understanding of the molecularmechanism of HCV RNA replication and provide meaningful insights to the design of effective strategies forcontrolling HCV infection.

project_terms:
3' Untranslated Regions;5' Untranslated Regions;Animal Model;Biochemical;Biological Assay;Bos taurus;Cattle;Classification;Complex;Conserved Sequence;Coupled;Cultured Cells;Development;Diarrhea;Elements;Facility Construction Funding Category;Genetic;Genome;Goals;Hepatitis B;Hepatitis C;Hepatitis C virus;Human;Human poliovirus;Immunoglobulin Variable Region;Indium;Infectious hepatitides;Internal Ribosome Entry Site;Length;Molecular;Mutagenesis;Mutation;Nucleotides;Open Reading Frames;Personal Satisfaction;Polioviruses;Poly A;Poly U;Process;Proteins;RNA;RNA replication;RNA Messenger;RNA Viral;Replicon;Research Proposals;Role;Sequences RNA;Site;Structure;System;Transcription Genetic;Untranslated Regions;Viral;Viral Nonstructural Proteins;Viral Pathogenesis;Viral Proteins;Virion;Virus Replication;base;design;insight;molecular chaperone GRP78;mutant;poly(U-C);polypeptide;positional cloning;replicase


application_id: 7172688
project_number: 5K23DE015298-02
project_title: Central Pain Processing in Chronic Face Pain:fMRI Study
administering_ic: NIDCR
award_notice_date: 2007-01-25
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015298
program_official: HARDWICK, KEVIN S
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7351795
contact_pi: DE LEEUW, RINSKJE
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal for a K23 "Mentored Patient-Oriented Research Career Development Award" will provide the candidate with five years of continuous funding to gain a broad knowledge in the design and conduct of complex clinical oral health trials. This training will enhance the research environment of the Orofacial Pain Center and mentoring capacity of the University of Kentucky College of Dentistry. The candidate earned a PhD in General Medicine from the University of Groningen and received three years of postgraduate graduate training in Orofacial Pain at the University of Kentucky. This award would allow the candidate to evolve to an independent investigator and would prepare the candidate to successfully mentor MS and PhD candidates in orofacial pain research. The training program consists of two phases: a didactic component emphasizing courses in research design biostatistics data analysis and epidemiology and a research phase involving a neuroimaging investigation of central pain processing in patients with chronic face pain.  
  
Three specific aims are proposed in this training application: Specific Aim 1. To assess the presence of pain augmentation in patients with chronic masticatory myofascial pain; Specific Aim 2. To investigate differences in location and extent of activation of brain regions involved in trigeminal pain processing between patients with chronic masticatory muscle pain and pain-free volunteers; and Specific Aim 3. To investigate the influence of estrogen level on cerebral activation in response to an acute experimental pain stimulus in patients with chronic masticatory muscle pain and pain-free volunteers. Dr. Charles Carlson PhD Professor Departments of Psychology and Oral Health Science and research director of the Orofacial Pain Center and Dr. Don Gash PhD Alumni Professor and Chair Department of Anatomy and Neurobiology and director of the Magnetic Resonance Imaging and Spectroscopy Center will mentor the candidate. There is limited information on cerebral activation in response to stimulation of trigeminal structures in healthy pain-free volunteers as well as in chronic face pain patients. The available data support that there are important differences in the cerebral processing of pain in chronic pain patients compared to pain-free subjects. Moreover the existing data suggest that in chronic pain conditions the medial pain system the structures associated with the processing of the emotional-affective component of pain exhibits altered activity. Additionally there is a lack of information about the influence of estrogen on the central processing of pain. The available data suggest that estrogen may have an inhibitory / anxiolytic effect on the perception of pain possibly by modulating the endogenous opioid system. Because neuroimaging data on this topic are scarce and chronic pain conditions are predominant in women of reproductive age the role of estrogen on pain should be further explored.

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


application_id: 7172206
project_number: 1P30AG028383-01
project_title: CLINICAL CORE - SATELLITE
administering_ic: NIA
application_type: 1
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (M1)]
subproject_number: 9005
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-15
budget_end_date: 2007-06-30
project_terms:
African American;Alzheimer&apos;s disease;aging;biomedical facility;brain disorder diagnosis;clinical research;comprehensive care;data collection;early diagnosis;health care;health care quality;home health care;human subject;longitudinal human study;medical outreach /case finding;mental health education;neuropsychological tests;patient care management;postmortem


application_id: 7171153
project_number: 5P20RR017702-04
project_title: COBRE: UL: ADMIN: ALTERATION & RENOVATION
project_terms: congenital disorders;developmental genetics
administering_ic: NCRR
award_notice_date: 2005-07-04
opportunity_number: RFA-RR-02-003
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2005-07-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-A(02)
subproject_number: 0009
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this application for a Center of Biomedical Research Excellence (COBRE) is to foster health-related research and increase the competitiveness of junior unfunded investigators at the Birth Defects Center at the UL School of Dentistry for independent funding. If funded this COBRE will augment and strengthen the biomedical research capacity at the Birth Defects Center through provision of flexible support to expand and develop biomedical faculty research capability. The program is led by an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal. The application seeks support for junior investigators from several complementary disciplines each of whom will be mentored by an established well-funded senior biomedical research faculty member recognized for his/her scientific expertise in the area of the junior investigator's research proposal. This approach is a critical assurance of success of this initiative. This application represents an integrated series of studies focusing on two common themes - molecular mechanisms of birth defects and cellular signal transduction - that encompass a number of diverse scientific disciplines. Faculty from three different departments in the Schools of Dentistry and Medicine representing a multiplicity of scientific disciplines present a multifunctional approach to questions of the molecular basis of developmental anomalies. This application if funded will substantially enhance the development of five young investigators with outstanding potential to develop into competitive independent and collaborative investigators. A detailed plan for their research career development has been formulated expectations and goals for achieving extramural support is outlined the extent of departmental and university support provided to these junior faculty is substantial clear and tangible evidence of institutional commitment has been documented and sufficient and adequate space and equipment resources for the conduct of the proposed studies exists.


application_id: 7170366
project_number: 2P20RR015592-06
project_title: KY COBRE: PILOT PROJECTS
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2005-09-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-8(02)
subproject_number: 0006
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
HIV infections;clinical research;estradiol;estrogen receptors;female;hormone regulation /control mechanism;hormone related neoplasm /cancer;human immunodeficiency virus;human subject;membrane proteins;menstrual cycle;neuroendocrine system;neuroprotectants;progesterone receptors;receptor expression;temporomandibular joint syndrome;women&apos;s health


application_id: 7170365
project_number: 2P20RR015592-06
project_title: ACTIONS OF ESTRADIOL & SERMS ON COGNITION MOOD & EFFECT
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2005-09-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-8(02)
subproject_number: 0005
contact_pi_person_id: 1858700
contact_pi: KELLY, THOMAS J.
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
GABA receptor;amphetamines;behavioral /social science research tag;clinical research;cognition;emotions;estradiol;female;gender difference;hormone regulation /control mechanism;human subject;menstrual cycle;progesterone;psychopharmacology;selective estrogen receptor modulators;triazolam;women&apos;s health


application_id: 7170364
project_number: 2P20RR015592-06
project_title: PROTECTIVE ACTIONS OF ESTRADIOL/SERMS ON BRAIN/HIV
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2005-09-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-8(02)
subproject_number: 0004
contact_pi_person_id: 8534501
contact_pi: BERGER, JOSEPH R
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AIDS dementia complex;HIV infections;clinical research;disease /disorder proneness /risk;estradiol;estrogen receptors;female;hormone regulation /control mechanism;human immunodeficiency virus;inflammation;leukocyte oxidative burst;microglia;neuroprotectants;selective estrogen receptor modulators;virus protein;women&apos;s health


application_id: 7170363
project_number: 2P20RR015592-06
project_title: EFFECTS OF ESTRADIOL & SERMS ON THE HYPOTHALAMUS
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2005-09-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-8(02)
subproject_number: 0003
contact_pi_person_id: 1891759
contact_pi: JENNES, LOTHAR H
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
brain derived neurotrophic factor;choline acetyltransferase;clinical research;estradiol;estrogen receptors;female;glutamate transporter;hormone regulation /control mechanism;hypothalamus;immunocytochemistry;in situ hybridization;neuroendocrine system;receptor expression;selective estrogen receptor modulators;tamoxifen;women&apos;s health


application_id: 7170362
project_number: 2P20RR015592-06
project_title: EFFECTS OF ESTRADIOL & SERMS ON THE OVARY
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2005-09-01
project_end_date: 2006-04-30
study_section: ZRR1-RI-8(02)
subproject_number: 0002
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
clinical research;collagenase;estradiol;estrogen receptors;female;gene expression;genetically modified animals;graafian follicles;hormone regulation /control mechanism;laboratory mouse;mammary gland;microarray technology;oogenesis;ovary;peroxisome proliferator activated receptor;receptor expression;selective estrogen receptor modulators;women&apos;s health


application_id: 7170298
project_number: 2P20RR015576-06
project_title: REMEYLINATION AND SPINAL CORD INJURY REPAIR
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 0006
contact_pi_person_id: 8141627
contact_pi: CAO, QILIN
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_terms:
cell transplantation;combination therapy;electrophysiology;laboratory rat;myelination;nervous system disorder chemotherapy;nervous system regeneration;neurotrophic factors;nonhuman therapy evaluation;oligodendroglia;spinal cord injury;therapy design /development


application_id: 7170297
project_number: 2P20RR015576-06
project_title: SIGNALING PATHWAYS IN NEURONAL APOPTOSIS
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 0005
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
project_terms:
DNA damage;NMDA receptors;apoptosis;biological signal transduction;mitogen activated protein kinase;nervous system regeneration;neural degeneration;neuropharmacology;neuroprotectants;serine threonine protein kinase;spinal cord injury


application_id: 7170296
project_number: 2P20RR015576-06
project_title: COBRE: UL: HUMAN OLFACTORY EPITHELIUM SOURCE STEM CELLS
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 0003
contact_pi_person_id: 6492007
contact_pi: ROISEN, FRED JERROLD
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_terms:
central nervous system;laboratory rat;nervous system disorder therapy;nervous system regeneration;respiratory epithelium;spinal cord injury;stem cell transplantation


application_id: 7170295
project_number: 2P20RR015576-06
project_title: COBRE: UL:RECONSTRUCTING LOCOMOTOR CIRCUITRY-SPINAL CORD
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 0002
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
disease /disorder model;gray matter;motor neurons;nervous system disorder therapy;nervous system transplantation;spinal cord injury;stem cell transplantation;white matter


application_id: 7170294
project_number: 2P20RR015576-06
project_title: COBRE: UL: METHYLPREDNISOLONE AND SCI: A NEW APPROACH
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 0001
contact_pi_person_id: 7936903
contact_pi: SHIELDS, CHRISTOPHER B
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_terms:
drug administration routes;drug screening /evaluation;laboratory rat;methylprednisolone;nervous system disorder chemotherapy;nonhuman therapy evaluation;pharmacokinetics;spinal cord injury;therapy design /development


application_id: 7170293
project_number: 2P20RR015576-06
project_title: COBRE: UL: CENTRAL NERVOUS SYSTEM INJURY: MICROSCOPY
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 9005
contact_pi_person_id: 6492007
contact_pi: ROISEN, FRED JERROLD
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_terms:
bioimaging /biomedical imaging;biomedical facility;central nervous system disorders;microscopy;nervous system regeneration;spinal cord imaging /visualization;spinal cord injury


application_id: 7170292
project_number: 2P20RR015576-06
project_title: COBRE: UL: CENTRAL NERVOUS SYS INJURY & REPAIR:CORE D
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 9004
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
behavior test;biomedical facility;central nervous system disorders;electrophysiology;nervous system regeneration;psychomotor function;spinal cord injury


application_id: 7170291
project_number: 2P20RR015576-06
project_title: COBRE: UL: CENTRAL NERVOUS SYSTEM INJURY & REPAIR:CORE C
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 9003
contact_pi_person_id: 6406198
contact_pi: ONIFER, STEPHEN M
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_terms:
animal care;biomedical resource;laboratory rat;nervous system regeneration;spinal cord injury;spinal cord surgery;veterinary medicine


application_id: 7170290
project_number: 2P20RR015576-06
project_title: COBRE: MSU: CONSORTIUM WITH MSU: INHIBITORY MOLECULES
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 9002
contact_pi_person_id: 1948710
contact_pi: CANNING, DAVID R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
astrocytes;axon;biomedical resource;cell differentiation;cell growth regulation;dendrites;gene expression;growth factor;microarray technology;nervous system regeneration;nervous system transplantation;neurogenetics;polymerase chain reaction;spinal cord injury;tissue /cell culture;western blottings


application_id: 7170289
project_number: 2P20RR015576-06
project_title: COBRE: UL: NERVOUS SYSTEM INJURY & REPAIR: CORE B: CELL CULTURE & MOLECULAR CORE
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2005-08-01
project_end_date: 2006-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 9001
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT
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_terms:
biomedical resource;molecular biology;nervous system regeneration;spinal cord injury;stem cells;tissue /cell culture


application_id: 7169778
project_number: 7K25HL068704-05
project_title: Calcium Waves in Atrial Cells
administering_ic: NHLBI
award_notice_date: 2006-02-27
opportunity_number: PA-99-087
application_type: 7
activity_code: K25
ic: HL
serial_number: 068704
program_official: SCOTT, JANE
project_start_date: 2002-01-22
project_end_date: 2006-11-30
study_section: ZHL1-CSR-M(O2)
contact_pi_person_id: 1863012
contact_pi: IZU, LEIGHTON T.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):This training grant is designed to provide the principal investigator (Pl)with the necessary didactic training and laboratory experience to become anindependent biomedical researcher. The PI?s immediate career goals are toacquire the knowledge in using supercomputers and the experimental skills ofelectrophysiology and microscopy necessary to develop a quantitativeunderstanding of atrial excitation-contraction (E-C) coupling. The Pl?s long-termcareer goal is to lead a multidisciplinary team of physiologistsmathematicians physicians and computer programmers in developing aquantitative understanding of both normal and pathological E-C coupling inatrial cells. Mammalian ventricular cells have an extensive transverse(t)-tubularsystem that rapidly conducts the action potential from the cellsurface to the interior triggering a near synchronous calcium (Ca) releasefrom the sarcoplasmic reticulum (SR) and activation of myofibrils throughoutthe cell. Atrial cells lack an extensive t-tubular system. How Carelease from the SR far from the cell surface is triggered is unclear. Theoverall hypothesis is that in atrial cells Ca entry during an actionpotential triggers regenerative Ca release from the SR at the cell surface andthis regenerative Ca release ("Ca wave") propagates as a wave radially to thecenter of the cell. The Specific Aims are: (1) Test this hypothesis bycorrelating atrial single-cell contraction rate and magnitude with the Cawave?s velocity and amplitude using video rate 2-dimensional confocalmicroscopy and fluorescent Ca indicators. (2) Develop a mathematical model ofthe atrial cell Ca control system and solve the model numerically usingsupercomputers. (3) Evaluate the model by comparing the model?s predictionswith experimental measurements of Ca waves in voltage-clamped atrial cellsusing confocal microscopy. A quantitative model of the atrial Ca controlsystem is necessary for understanding both normal E-C coupling and the originsof pathological spontaneous Ca waves which recent data suggest can triggeratrial arrhythmias.

project_terms:
atrium;calcium flux;calcium indicator;cardiac myocytes;confocal scanning microscopy;electrophysiology;heart electrical activity;human tissue;laboratory rat;mathematical model;neuromuscular transmission;sarcoplasmic reticulum;supercomputer;tissue /cell culture;video microscopy;voltage /patch clamp


application_id: 7169648
project_number: 5R01AI058842-03
project_title: Nanoparticle HIV Protein Vaccines for Cellular Responses
administering_ic: NIAID
award_notice_date: 2007-01-17
application_type: 5
activity_code: R01
ic: AI
serial_number: 058842
program_official: AHLERS, JEFFREY D
project_start_date: 2005-04-15
project_end_date: 2007-06-30
study_section: HIV/AIDS Vaccines Study Section[VACC]
contact_pi_person_id: 7876835
contact_pi: MUMPER, RUSSELL J
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: 2007-01-01
project_abstract:
DESCRIPTION (provided by applicant): Currently there is no effective vaccine for HIV infection. HIV vaccines can potentially be used for prevention of infection or therapeutically to control the level of HIV replication post-exposure. The overall goal of this 5-year research proposal is to develop nanoparticle-based HIV-1 vaccines to elicit enhanced Th1 cytotoxic T lymphocyte (CTL) and humoral immune responses to recombinant Tat (1-72) and Gag p24 proteins. The immunogenicity of the developed nanoparticle-based HIV-1 Tat (1-72) and Gag p24 vaccine will further be enhanced by 1) the attachment of a dendritic cell targeting ligand mannopentaose to the nanoparticles and 2) coating the nanoparticles with CpG to target the toll-like receptor-9 (TLR-9). Optimized nanoparticles vaccines will be compared to a heterologous prime boost strategy based on vaccinia expressing antigen and adjuvanted protein. Recombinant HIV Tat (1-72) and Gag p24 proteins and his-tagged proteins will be synthesized and purified to homogeneity by Dr. Nath's laboratory at Johns Hopkins and tested for bioactivity. In Dr. Mumper's laboratory at the University of Kentucky the proteins will be either coated on anionic nanoparticles (Type 1) or attached to nanoparticles made with a small amount of accessible nickel at the surface (Type 2). Both types of solid nanoparticles (<100 nm) will be made from novel oil-in-water microemulsion precursors. Dr. Mumper's lab will characterize the nanoparticles perform in-vitro uptake and activation studies in mouse and human dendritic cells and perform animal experiments to determine the humoral immune responses of the nanoparticle-based formulations and perform immunohistochemical analyses. Dr. Woodward's laboratory at the University of Kentucky will be responsible for ELISPOT CTL multi-probe ribonuclease tetramer cell proliferation assays as well as confocal microscopy and flow cytometry experiments.  Dr. Nath's laboratory will perform studies demonstrating that sera from immunized mice can suppress Tat-induced LTR-transactivation and will assess the effect of Tat and Gag p24 antisera on HIV replication. In addition Dr. Nath's lab will produce vaccinia expressing antigen.

project_terms:
Acquired Immunodeficiency Syndrome;Adjuvant;Adjuvanticity;Affinity;Antibodies;Antibodies Enhancing;Antibody Formation;Antigens;Binding (Molecular Function);Biological Assay;CD8B1 gene;Caliber;Capsid Proteins;Cell Proliferation;Cells;Charge;CpG dinucleotide;Cytoplasm;Data;Dendritic Cells;Dendritic cell activation;Development;Disease;Dose;Elements;End Point;Engineering;Epitopes;Exons;Experiments Animal;Flow Cytometry;Formulations Drug;Gagging;Gene Products env;Gene Products gag;Genes MHC Class I;Genes env;Goals;HIV;HIV Infections;HIV Nonprogressors;HIV vaccine;HIV-1;HIV-1 vaccine;Histidine;Human;IgE;Immune Sera;Immune response;Immune system;Immunization;In Vitro;Infection Control;Infection prevention;Intramuscular;Kentucky;Laboratories;Lead;Life Cycle Stages;Ligands;Longitudinal Studies;MPP1 protein human;Mannans;Microscopy Confocal;Mus;Nature;Nickel;Numbers;Oils;Oligonucleotides;Onset of illness;Particle Size;Pathway interactions;Patients;Personal Satisfaction;Preparation;Principal Investigator;Process;Production;Proteins;Protocols documentation;Recombinant Proteins;Recombinants;Recruitment Activity;Relative (related person);Research;Research Personnel;Research Proposals;Ribonucleases;Serum;Signal Transduction;Solid;Splenocyte;Subtypings Lymphocyte;Surface;System;T-Lymphocyte;T-Lymphocytes Cytotoxic;Testing;Toll-like receptor 9;Toll-like receptors;Trans-Activation (Genetics);Universities;Vaccines;Vaccinia;Viral Load result;Virus;Water;aluminum sulfate;base;concept;cytokine;cytotoxic;desire;enzyme linked immunospot assay;gp-120 Antigen;immunogenic;immunogenicity;in vivo;innovation;interest;mannopentaose;mannose receptor;nanoparticle;neutralizing antibody;novel;pol genes;prevent;programs;receptor;research study;response;subcutaneous;tat Protein;uptake;vaccine delivery


application_id: 7169246
project_number: 5R01DE017138-02
project_title: Oral Immunity and Adjuvant Receptors
administering_ic: NIDCR
award_notice_date: 2007-01-23
application_type: 5
activity_code: R01
ic: DE
serial_number: 017138
program_official: LUNSFORD, DWAYNE
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-02-01
project_abstract:
DESCRIPTION (provided by applicant): The need to develop new vaccines against mucosal pathogens has compelled a search for adjuvants that can effectively stimulate mucosal immunity to vaccine proteins most of which are poor immunogens. Toll- like receptors (TLRs) and gangliosides are considered "adjuvant receptors" because their interaction with certain classes of noxious microbial molecules generates potent immunomodulatory signals in antigen-presenting cells (APCs) that mobilize adaptive immunity. An ideal adjuvant should thus stimulate adjuvant receptors without however inducing toxic effects. This application will investigate the adjuvant activities of a novel ganglioside-binding TLR2 agonist recently identified by our group. The molecule under investigation is the pentameric B subunit of a unique E. coli enterotoxin designated Type Mb (LT-llb) and quite different from Type I enterotoxins such as cholera toxin. In contrast to the intact toxin the B subunit (designated LT- llb-B) induces TLR2-dependent activation of transcription factor NF-KB which plays a central role in the induction of immunoregulatory cytokines and costimulatory molecules on APCs such as dendritic cells. The overall hypothesis is that LT-llb-B exhibits immunomodulatory activity which requires the cooperation of GD1a ganglioside and TLR2 promotes antigen-presenting cell function and induces mucosal immunity. We thus Aim to elucidate the immunomodulatory mechanisms of LT-llb-B and demonstrate its mucosal adjuvanticity. Specifically using immunological biophysical and cell imaging techniques we will determine cooperative interactions between gangliosides and TLR2 in response to LT-llb-B and the importance of these interactions in up-regulating dendritic cell-mediated functional costimulation to CD4+T cells. Moreover it will be determined if these adjuvant mechanisms of LT-llb-B correlate with induction of mucosal adjuvant activity in vivo. The proposed studies are supported by a plethora of preliminary findings and are facilitated by the availability of (a) engineered wild-type and single point substitution mutants of LT-II molecules (b) model cell systems where expression of receptors of interest is manipulated and (c) a well-established mouse mucosal immunization model. Using these models and state-of-the-art interdisciplinary techniques the generated data will form the basis for our ultimate objective which is to establish LT-llb-B as a safe and effective adjuvant in vaccine formulations against oral or other mucosal pathogens.

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


application_id: 7166828
project_number: 5R01DK073586-02
project_title: Prolonged Diabetic Damage to Cardiac Mitochondria
administering_ic: NIDDK
award_notice_date: 2006-12-15
opportunity_number: RFA-DK-05-001
application_type: 5
activity_code: R01
ic: DK
serial_number: 073586
program_official: JONES, TERESA L Z
project_start_date: 2006-01-15
project_end_date: 2009-12-31
study_section: ZDK1-GRB-N(O1)S
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N.
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   In diabetic patients complications such as cardiomyopathy develop over many years of hyperglycemia. We are proposing that the prolonged time course stems from the gradual accumulation of damage to mitochondrial DNA caused by increased mitochondrial generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). For several reasons mitochondrial DNA is especially vulnerable to damage and some types of damage are poorly repaired. We hypothesize that mitochondrial DNA damage is causal for cellular and organ dysfunction in the diabetic state. Our laboratory developed the OVE26 mouse model of Type I diabetes optimal for following chronic development of complications. Cardiac mitochondria from long-term diabetic OVE26 mice exhibit morphological degeneration decreased glutathione content and increased DNA damage. Transgenic mice with increased activity of the mitochondrial antioxidant MnSOD targeted to the heart when crossed onto the OVE26 background show less contractile dysfunction improved mitochondrial morphology and a significant improvement in mitochondrial respiration. We propose that MnSOD overexpression suppresses damage to the mitochondrial genome and that this accounts for improved cardiomyocyte function. To test the hypothesis that progressive mitochondrial DNA damage by ROS or RNS contributes to the development of diabetic cardiomyopathy we will carry out the following Specific Aims: Aim 1: Evaluate mutations and deletions in mitochondrial DNA and correlate these changes with mitochondrial respiratory function electron  ROS generation and cardiomyocyte contractility. Aim 2: Determine if there is a cause and effect relationship between mitochondrial DNA damage and diabetic cardiomyopathy. On the OVE26 diabetic background mitochondrial DNA will be protected by cardiac overexpression of MnSOD and mitochondrial targeted OGG1. We will also determine whether both DNA damage and diabetic cardiomyopathy are exacerbated by crossing existing OGG1 knockout animals to our diabetic mice. Aim 3: Assess whether systemic therapy with agents that bind free transition metals can prevent superoxide from forming more reactive species that damage mitochondrial DNA. Results of these investigations may be directly applicable to the development of new therapies which minimize or absolutely prevent certain diabetic complications.

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


application_id: 7166075
project_number: 5R01AI025098-19
project_title: Characterization of the Hms phenotype of Yersinia pestis
administering_ic: NIAID
award_notice_date: 2007-01-12
opportunity_number: PA-03-080
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-09-30
project_end_date: 2009-01-31
study_section: Bacteriology and Mycology Subcommittee 2[BM-2]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
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:
Yersinia pestis primarily causes a zoonotic disease - plague. Although humans are an accidental dead-end hostbubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2000human plague cases occur yearly and small epidemics in South America and Southeast Asia are common. In additionY. pestis has great potential for use as a bioterrorism agent. In nature the bacterium has an obligate flea-mammal(primarily rodent) life cycle. Survival of plague in nature is dependent upon its ability to propagate in fleas and upon its transmission from fleasto mammals. In this proposal we will focus on determinants of the hemin-storage (Hms) phenotype of Y. pestis that areinvolved in the flea portion of the bacterial life cycle. The Hms + phenotype is required for Y. pestis to cause blockageof the proventricular valve of fleas. Blockage of this valve between the esophagus and stomach of the flea is requiredfor transmission of the disease from fleas to mammals. In vitro the Hms +phenotype is characterized by binding ofenormous quantities of exogenous hemin or Congo red (CR) dye to the outer membrane fraction of cells grown at 26-34C but not at higher temperatures. Thus Hms + cells of Y. pestis incubated at 26C on CR agar form red colonies. Wenow hypothesize that the Hms phenotype of Y. pestis is the result of an extracellular matrix or biofilm produced by theHms system. The mechanisms of proventricular blockage roles of Hms proteins in biofilm formation andmechanisms of temperature regulation of the phenotype remain to be elucidated. We propose to continue studies onidentifying essential hms genes analyzing the regulation of expression of the Hms + phenotype as well as characterizingthe biochemical properties and physiological role(s) of the Hms system. The specific aims of this proposal are - 1) genetic analysis of essential hms genes; 2) analysis of the regulation ofHms expression; 3) biochemical analysis of the Hms system; and 4) analysis of the physiological role(s) of the Hmssystem. These studies will enhance our understanding of bacterial features that are required for Y. pestis to block theflea which is essential for the transmission of plague from fleas to mammals. This will facilitate measures to control oreliminate natural reservoirs of plague and control disease transmission. In addition elucidation of the enzymaticactivities of Hms proteins and regulatory mechanisms controlling the synthesis of the extracellular matrix likelyproduced by the Hms system may have relevance for biofilm formation by other pathogenic bacteria.

project_terms:
Agar;Asia Southeastern;Bacteria;Binding (Molecular Function);Biochemical;Biological Assay;Bioterrorism;Catalytic Domain;Cell Fraction;Cells;Congo Red;Disease;Dyes;Epidemic;Escherichia coli;Esophagus;Extracellular Matrix;Fleas;Gene Expression Regulation;Genes;Genomics;Hemin;High temperature of physical object;Human;Immunoprecipitation;In Vitro;Incubated;Individual;Life;Life Cycle Stages;Mammals;Measures;Membrane;Microbial Biofilms;Microscopy;Mutagenesis;Mutagenesis Site-Directed;Mutation;Nature;Phenotype;Physiological;Plague;Play;Pneumonic Plague;Principal Investigator;Production;Property;Proteins;Proventriculus;Recurrence;Regulation;Rodent;Role;South America;Stomach;System;Temperature;Testing;Transcriptional Regulation;Yersinia;Yersinia enterocolitica;Yersinia pestis;base;bis(3'5')-cyclic diguanylic acid;crosslink;disease transmission;genetic analysis;genetic regulatory protein;mutant;pandemic disease;pathogenic bacteria;programs;research study;transmission process


application_id: 7166069
project_number: 5R01AI064421-02
project_title: Analyzing and modulating immunoregulatory defects in autoimmune disease
administering_ic: NIAID
award_notice_date: 2006-12-20
application_type: 5
activity_code: R01
ic: AI
serial_number: 064421
program_official: ESCH, THOMAS R
project_start_date: 2006-01-01
project_end_date: 2010-12-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
DESCRIPTION (provided by applicant): Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimmunity. Although the thymus appears to be a major site of CD4+CD25+ T cell development it is still unclear whether there are also peripheral sites of development. We have found recently that CD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in the periphery. Conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells may be a very important mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenance and a defect in this process could contribute to autoimmune disease development. We have found that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in the thymus but a significantly lower percentage in the periphery. Furthermore NOD CD4+CD25- T cells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function strongly suggesting that NOD mice may have a defect in this conversion process and may therefore be unable to maintain this regulatory population. The central hypothesis of this proposal is that enhanced conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice can prevent diabetes. We will test this hypothesis by studying the mechanisms and defects in conversion in NOD mice determine whether this process can be restored and whether restoration is associated with amelioration of disease. By understanding the defects in conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice it may be possible to devise strategies to overcome these defects and thereby develop therapies to prevent or treat autoimmune disease.

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


application_id: 7166055
project_number: 5R01HL055477-11
project_title: Toxicity and Detoxification of 4Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2006-12-14
application_type: 5
activity_code: R01
ic: HL
serial_number: 055477
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2010-12-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
DESCRIPTION (provided by applicant): Although several studies suggest that myocardial injury during ischemia/reperfusion is in part due to reactive oxygen species the mechanisms by which these oxidants injure the heart and those by which the heart protects itself from their effects are not known. We propose that the myocardial effects of oxidative stress are mediated in part by 4-hydroxyalkenals such as 4-hydroxy-trans-2-nonenal (HNE) which are derived from oxidation of lipoproteins and membrane lipids. Our previous work has led to the identification of the major biochemical pathways of HNE detoxification in cardiovascular tissues. These results suggest that aldose reductase (AR)-catalyzed reduction of HNE and its glutathione conjugate is a particularly critical step in this metabolism because inhibition of AR increases HNE accumulation in the ischemic heart and abolishes the cardioprotective effects associated with the late phase of ischemic preconditioning (PC). Based on these observations and our preliminary data we now plan to test how the ischemic heart metabolizes HNE and whether this is facilitated by the activation of AR due to nitric oxide (NO) generated during ischemia. Using both ex vivo and in situ murine models of myocardial ischemia-reperfusion injury we will identify ischemic changes in AR and HNE metabolism and identify the chemical nature of AR modification and the oxidants and triggers that induce it (Aim 1). In addition we will determine the role of endothelial and inducible NO synthases (NOS) in activating AR and increasing HNE detoxification in the ischemic heart using mice deficient in individual NOS isoforms or overexpressing inducible NO synthase in the heart (Aim 2). To understand the mechanisms of AR-mediated cardioprotection we will examine changes in the mitochondria and myocardial survival signaling (Aim 3) and elucidate how pharmacologic inhibition of AR or cardiospecific overexpression of AR (or its murine homolog FR-1) affects ischemia-reperfusion-induced mitochondrial permeability transition and NF-kappaB activation (Aim 3). Successful completion of this project will lead to a better understanding of mechanisms of cardioprotection due to ischemic PC and NO and could form the basis of new clinical approaches to limit myocardial infarction. Delineation of the contribution of specific enzymes to HNE metabolism in the ischemic heart will be useful in identifying population subgroups that may be highly susceptible to oxidative stress caused by cardiovascular disease.

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


application_id: 7164576
project_number: 1R41CA115093-01A2
project_title: Novel estrogen receptor ligands from plant genomics
project_terms: estrogen receptors;human;ligands;plants
administering_ic: NCI
award_notice_date: 2006-08-17
opportunity_number: PA-06-007
application_type: 1
activity_code: R41
ic: CA
serial_number: 115093
suffix: A2
program_official: SONG, MIN-KYUNG H
project_start_date: 2006-08-17
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1 EMNR-E (10)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M
other_pis: Not Applicable
congressional_district: 03
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
project_abstract:
DESCRIPTION (provided by applicant): Plants produce many types of molecules such as chalcones flavones and flavonones that interact with human estrogen receptors (ERs). Some of these may have therapeutic value in different types of hormone-sensitive cancer but the full capacity of the plant genome to generate such ligands has not been explored. This project uses a functional genomics approach in which activation of the human ER is functionally linked to expression of a green fluorescent protein (GFP) reporter construct in a transgenic plant line. When a population of these plants is subjected to random "gain of function" mutations those individual mutants that overproduce ER agonists should be readily identifiable by their green fluorescence. This phase 1 STTR aims to transfer this "in situ screening" technology from the whole plant to the level of single plant cells with a consequent massive increase in screening throughput. In addition small modifications to the technology should enable identification of ligands that are ER antagonists. The resulting screening strategy will then be applied to a large mutant population of N tabacum protoplasts and "positive" subpopulations of microcultures isolated for further study in phase 2. The aim is to make the underlying biotechnology of greater value as a drug discovery platform particularly when applied to nuclear receptor ligands of potential value in cancer pharmacotherapy. Project Narrative: New drugs are needed to treat cancers such as breast cancers. Plants produce molecules that could be used in cancer treatment if identified and properly developed. The project uses promising new biotechnology methods to find molecules in plants that work even better than existing drugs so that these molecules can be further studied and possibly developed into the next generation of anti-cancer drugs.


application_id: 7162804
project_number: 1P30AG028383-01
project_title: EDUCATION AND INFORMATION CORE
administering_ic: NIA
application_type: 1
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (M1)]
subproject_number: 9004
contact_pi_person_id: 8536107
contact_pi: WEKSTEIN, DAVID R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-15
budget_end_date: 2007-06-30
project_terms:
African American;Alzheimer&apos;s disease;aging;biomedical facility;caregivers;clinical research;continuing education;health care personnel education;human subject;longitudinal human study;medical outreach /case finding;meeting /conference /symposium;mental health education;training


application_id: 7162803
project_number: 1P30AG028383-01
project_title: NEUROPATHOLOGY CORE
administering_ic: NIA
application_type: 1
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (M1)]
subproject_number: 9003
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-15
budget_end_date: 2007-06-30
project_terms:
Alzheimer&apos;s disease;aging;amyloid proteins;biomedical facility;cerebrospinal fluid;cognition disorders;enzyme linked immunosorbent assay;histopathology;longitudinal human study;meeting /conference /symposium;neuritic plaques;neurofibrillary tangles;neuropathology;postmortem;protein quantitation /detection;synaptosomes;tissue /cell preparation;tissue resource /registry


application_id: 7162802
project_number: 1P30AG028383-01
project_title: BIOSTATISTICS AND DATA MANAGEMENT CORE
administering_ic: NIA
application_type: 1
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (M1)]
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-15
budget_end_date: 2007-06-30
project_terms:
Alzheimer&apos;s disease;aging;archives;biomedical facility;data management;data quality /integrity;experimental designs;human data;longitudinal human study;medical outreach /case finding;mental health information system;statistical service /center;statistics /biometry


application_id: 7162801
project_number: 1P30AG028383-01
project_title: CLINICAL CORE
administering_ic: NIA
application_type: 1
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (M1)]
subproject_number: 9001
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
budget_end_date: 2007-06-30
project_terms:
African American;Alzheimer&apos;s disease;Parkinson&apos;s disease;aging;biomedical facility;clinical research;cognition disorders;human subject;longitudinal human study;medically underserved population;nervous system disorder diagnosis;neuroimaging;neuropsychological tests;postmortem;sample collection


application_id: 7162656
project_number: 1R13CA124224-01
project_title: Louisville Breast Cancer Update
administering_ic: NCI
award_notice_date: 2006-08-22
opportunity_number: PA-06-041
application_type: 1
activity_code: R13
ic: CA
serial_number: 124224
program_official: XIE, HENG
project_start_date: 2006-09-01
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZCA1 GRB-T (M1)]
contact_pi_person_id: 7874100
contact_pi: CHAGPAR, ANEES B
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_terms:
breast neoplasms;meeting /conference /symposium;neoplasm /cancer therapy;patient care management;travel


application_id: 7162530
project_number: 5R01NS036660-08
project_title: Detection of presymptomatic Alzheimer's disease by fMRI
administering_ic: NINDS
award_notice_date: 2007-01-18
application_type: 5
activity_code: R01
ic: NS
serial_number: 036660
program_official: REFOLO, LORENZO
project_start_date: 1997-09-30
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)S]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
project_abstract:
Alzhimer's disease (AD) is preceded by a period when detectable changes in brain function occurwithout warning symptoms. This period may be twenty years or longer. Activation measured byfunctional magnetic resonance imaging is reduced during confi_ntation naming in normal women whohave increased risk of late-onset Alzbeimer's disease at an average age of only 53 years. These sameindividuals have reduced activation in the posterior cingulat cortex during a memorization task amongother disparities. Our hypothesis is that the altered functional MRI responses in naming workingmemory and memorization will quantifiably worsen with age due to progressive underlyingAlzheimcr's disease pathology. Disease-modifying treatments applied in this early pre-symptomaticstage of AD could have profound impact by preventing the onset of cognitive symptoms. Millions arecurrently being spent on large-scale prevention trials with AD symptoms as end-points. By providinga biomarker ofpre-symptomatic AD progression fMRI could potentially reduce the duration and costsof such trials. This continuation proposal is designed to detect changes in brain function in high-AD riskindividuals over time. We will study normal education-matched groups of high- and low-AD risksubjects in the age ranges 40-65 and 65-90 years using fMRI stimulus tasks which have previouslydemonstrated regional disparities in high-AD risk individuals. In addition we will repeat the naming andfluency fMRI studies performed previously in high- and low-AD risk individuals after an interval offive years in order to detect longitudinal changes in activation. The convergence of evidence from thesecross-sectional and longitudinal studies could provide powerful evidence for a model of Alzheimer'sdisease as a relentless slowly progressive brain pathology that begins early in adult life but remainscompensated until it produces clinical symptoms in its late stages.

project_terms:
Adult;Age;Age Group Unspecified;Alzheimer's Disease;Alzheimer's disease model;Analysis of Variance;Appearance;Appendix;Area;Back;Biological Markers;Biological Neural Networks;Blood Vessels;Brain;Brain Pathology;Categories;Clinical;Cognition;Cognitive;Data;Detection;Disease;Disease Progression;Educational aspects;End Point;High Risk Woman;Image Analysis;Imagery;Individual;Inferior;Knowledge;Left;Letters;Life;Longitudinal Studies;Magnetic Resonance Imaging Functional;Maps;Matched Group;Measures;Memory;Memory Short-Term;Methods;Names;Nerve Degeneration;Neuro-Oncological Ventral Antigen 2;Neurobehavioral Manifestations;Parietal;Participant;Pathology;Performance;Prevention;Principal Investigator;Process;Publishing;Purpose;Range;Rate;Recruitment Activity;Regressions Linear;Research;Risk;Risk Factors;Scanning;Score;Staging;Stimulus;Symptoms;Temporal Lobe;Testing;Time;Visual;Woman;Workload;aged;base;cohort;cost;design;disorder risk;interest;middle age;older women;prevent;programs;research study;response


application_id: 7162089
project_number: 5R01GM072756-02
project_title: Dissection and Reconstitution of Human Mismatch Repair
administering_ic: NIGMS
award_notice_date: 2006-12-13
application_type: 5
activity_code: R01
ic: GM
serial_number: 072756
program_official: PORTNOY, MATTHEW
project_start_date: 2006-01-01
project_end_date: 2009-12-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-01-01
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 genomic instability and eventually to cancer predisposition. Despite the fact that the excision-step of the human MMR reaction has been recently reconstituted using purified proteins including MutS alpha MutL alpha EXO1 and RPA many fundamental questions in MMR still remain unanswered. For example how mismatch-provoked excision initiates and terminates and what role MutL alpha plays in MMR are unknown. Through the reconstitution of the 5' nick-directed human MMR reaction we found that MutL alpha negatively regulates mismatch-provoked EXO1-catalyzed excision and terminates it immediately upon mismatch removal. Given the dependency of the EXO1-catalyzed mismatch excision on MutS alpha and physical interactions among EXO1 MutS alpha and MutL alpha we hypothesize that mismatch-provoked excision is precisely regulated through interactions among these proteins. Specifically in the presence of a mismatch MutS alpha preferentially interacts with EXO1 to promote excision; but the removal of the mismatch by EXO1 allows EXO1 to preferentially interact with MutL alpha which then terminates the excision. To test this hypothesis a series of EXO1 MutS alpha MutL alpha mutant proteins that disrupt the interaction of EXO1 with one Mut protein but not the other will be constructed expressed and purified. These mutant proteins will be tested in an in vitro reconstitution system for their ability to perform mismatch-provoked excision at the initiation and at the termination. Analysis of the excision intermediates in each reaction will reveal how the interactions among MutS alpha and MutL alpha and EXO1 regulate a particular step of the excision reaction. Finally to understand how efficiently the MMR system terminates mismatch-provoked excision the excision termination sites for heteroduplexes with different sequence contents and distances separating the mismatch and the strand break will be precisely determined. In addition to revealing the molecular mechanism of mismatch-provoked excision this study will provide important clues to understand many puzzling phenomena in mlh1 null mutants regarding 5' directed MMR meiotic cell apoptosis and anti-recombination.

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


application_id: 7161362
project_number: 5K08DE014845-05
project_title: Nuclear Co-Activators in Developing Craniofacial Tissue
administering_ic: NIDCR
award_notice_date: 2006-12-20
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: DE
serial_number: 014845
program_official: HARDWICK, KEVIN S
project_start_date: 2003-01-01
project_end_date: 2008-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7031215
contact_pi: PHILIPOSE, JOHN T
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The purpose of this application is to seek training support for a well-defined period of specialized studythat will enable the applicant to develop into an outstanding clinician and research scientist. Theapplicant's commitment to a career in laboratory research is substantial and in the judgement of thecandidate's mentors his potential to develop into an independent investigator is excellent. Acomprehensive six year plan for the applicant's training program is presented in the current application.The training program includes didactic coursework and supervised basic science research experiencesthat will culminate in attainment of the Ph.D. degree in Pharmacology &Toxicology as well as completionof specialized postgraduate residency training in Orthodontics. A senior well-funded and experiencedbasic science research mentor and a clinical mentor with substantial research experience have beenidentified to provide cohesion and integration of the scientific growth and development of the applicant. Adetailed research thesis proposal is presented in the current application that integrates the applicant'sresearch training area (molecular mechanisms of craniofacial growth) with his orthodontic clinical trainingand future interests in academic dentistry. One hundred percent of the applicant's full-time professionaleffort as outlined in the training program proposed in the current application will be devoted to the goalsof this K-08 award.

project_terms:
Area;Award;Basic Science;Cell Proliferation;Clinical;Cyclic AMP;Dentistry;Doctor of Philosophy;EGF gene;EP300 gene;Embryonic Development;Epithelial;Funding;Future;Goals;Growth;Growth and Development function;Judgment;Link;Maxilla;Medial;Mediating;Mentors;Mesenchymal;Molecular;Mus;Nuclear;Orthodontic;Orthodontics;Palate;Pharmacology and Toxicology;Play;Proteins;Purpose;Research;Research Personnel;Research Training;Research Laboratory;Residencies;Role;Scientist;Signal Transduction;Time;Tissues;Training;Training Programs;Training Support;career;cohesion;craniofacial;experience;interest


application_id: 7160758
project_number: 1P01HL080100-01A1
project_title: CORE
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8817787
contact_pi: RATERI, DEBRA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
angiotensin II;animal care;animal colony;aorta aneurysm;blood pressure;bone marrow transplantation;cardiovascular imaging /visualization;disease /disorder model;genetic registry /resource /referral center;genetically modified animals;genotype;laboratory mouse;model design /development;pathologic process;ultrasound


application_id: 7160757
project_number: 1P01HL080100-01A1
project_title: CORE--Human Studies
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 7332137
contact_pi: MUKHERJEE, DEBABRATA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
abdomen;angiotensin II;aorta;aorta aneurysm;biomedical facility;blood banks;blood tests;cardiovascular disorder risk;cardiovascular imaging /visualization;genetic registry /resource /referral center;genotype;hormone metabolism;human genetic material tag;human tissue;immunocytochemistry;statistics /biometry;tissue resource /registry


application_id: 7160754
project_number: 1P01HL080100-01A1
project_title: Specific Secretory Phospholipase A2 Isozymes Promote Aneurysm Formation
administering_ic: NHLBI
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
abdomen;angiotensin II;aorta aneurysm;cardiovascular disorder risk;cell migration;disease /disorder model;enzyme activity;gene expression;genetic susceptibility;genetically modified animals;inflammation;isozymes;laboratory mouse;macrophage;pathologic process;phospholipase A2;prostaglandin endoperoxide synthase;protein localization


