# projects

application_id: 7286867
project_number: 5R21AG028307-02
project_title: The impact of aging on the inflammatory response
administering_ic: NIA
award_notice_date: 2007-08-15
opportunity_number: RFA-AG-05-011
application_type: 5
activity_code: R21
ic: AG
serial_number: 028307
program_official: FLORES, ROBERTO L
project_start_date: 2006-09-15
project_end_date: 2010-08-31
study_section: ZAG1-ZIJ-5(M1)
contact_pi_person_id: 1969952
contact_pi: STOUT, ROBERT D
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Elderly Individuals are more suceptible to bacterial infection and these infections are a major cause of morbidity and mortality in hospitalized elderly patients. Research on the adaptive immune response has identified several age-associated defects in  lymphocytes. Research on the innate response has been more sparse focusing for the most part on the functional responsiveness of isolated resting macrophages and neutrophils to in vitro stimuli. The inflammatory response in young mice is a highly orchestrated sequence of events that entail sequential extravasation of neutrophils monocytes and lymphocytes. The activities displayed by the macrophages and neutrophils are inflammatory microbicidal and cytotoxic. Upon successful debridement of the wound neutrophils apoptose and are phagocytized by macrophages and the macrophages fibroblasts and endothelial cells collaborate in wound resolution. If Th1 cells entering the site become activated they will help sustain the inflammatory and cytotoxic activities of the macrophages. We hypothesize that age-associated deficiencies in inflammation may be associated with a loss of orchestration of these events rather than a loss of responsiveness of the cells of the innate immune system. To explore the validity of this hypothesis we propose to examine the inflammatory response in young and aged mice using a model of intra-abdominal inflammation elicited by alum-precipitated egg albumin. To include T cells in the model mice will receive intravenously activated Th1-polarized OT-II ovalbumin-reactive T cells. The rate and degree of infiltration of neutrophils macrophages and T cells will be monitored. Neutrophils will be analyzed ex vivo for expression of secretory vesicles and specific granules expression of inflammatory cytokine and chemokine mRNA and apoptosis and analyzed in vitro for  phagocytosis H2O2 production and chemotaxis. Macrophages will be analyzed for expression of inflammatory and anti-inflammatory cytokine and chemokine mRNA for expression of cell surface co-stimulatory molecules and effective interaction with infiltrating T cells. This project will provide critical data on how advanced age impacts the inflammatory response and provide avenues of future study on means of therapeutic targeting of the deficiencies. Even transient improvement in inflammatory response will not only enhance microbial clearance and wound healing but likely will also enhance the efficacy of vaccination against infectious disease.

project_terms:
Acute;Address;Age;Aging;Albumins;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Bacterial Infections;Biological Assay;Blood Platelets;Brain;Cell Adhesion Molecules;Cell Aging;Cell Communication;Cell surface;Cells;Chemokine Receptor Gene;Chemotaxis;Chronic;Communicable Diseases;Consensus;Cytoplasmic Granules;Data;Debridement;Defect;Elderly;Endothelial Cells;Environment;Eugenia;Event;Extravasation;Fibroblasts;Future;Genes;Greater sac of peritoneum;Hormones;Human;Hydrogen Peroxide;IL2RA gene;Immune response;Immune system;In Vitro;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injections Intraperitoneal;Intervention;Intra-abdominal;Lung;Lymphocyte;Mice Inbred Strains;Modeling;Molecular;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neurosecretory Systems;Neutrophil Infiltration;Ovalbumin;Pathology;Pattern;Performance;Phagocytosis;Production;RNA Messenger;Rate;Research;Research Personnel;Resolution;Respiratory Burst;Rest;Secretory Vesicles;Site;Stimulus;Stress;T-Cell Activation;T-Lymphocyte;TNFSF5 gene;Th1 Cells;Tissues;Transgenic Organisms;Universities;Vaccination;Variant;Wound Healing;aged;aluminum sulfate;base;cell age;chemokine;cytokine;cytokine therapy;cytotoxic;egg;immune function;in vivo;insight;mRNA Expression;macrophage;microbial;microbicide;monocyte;mouse model;neutrophil;older patient;ovalbumin-alum;response;therapeutic target;wound


application_id: 7286191
project_number: 3R21DA021027-02S1
project_title: Neurocognitive consequences of adolescent drug use
administering_ic: NIDA
award_notice_date: 2006-09-11
opportunity_number: RFA-DA-05-007
application_type: 3
activity_code: R21
ic: DA
serial_number: 021027
suffix: S1
program_official: SIROCCO, KAREN
project_start_date: 2005-09-25
project_end_date: 2006-12-31
study_section: ZDA1
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):   The effects of adolescent drug use on cognitive functioning is a significant public health concern. Adolescence marks a time of considerable neural development particularly in brain regions that control attention and behavioral impulses. Drug use during these critical periods of brain development could impede or alter the normal course of neural maturation resulting in long-term cognitive deficits in these areas. There is also considerable interest in the possibility that stimulant medications such as methylphenidate used in the treatment of attention deficit hyperactivity disorder (ADHD) could sensitize adolescents to the rewarding and disinhibiting effects of other stimulants thus increasing their risk of abuse as this population enters young adulthood. Despite growing concern about the consequences of adolescent drug use little is known about the specific behavioral and cognitive deficits that might result from a history of adolescent drug use. The proposed R21 project is designed to identify specific inhibitory-based neurocognitive deficits associated with a history of adolescent drug use and to examine how this association is mediated by two established adolescent risk factors for substance abuse ADHD and conduct disorder (CD). Inhibitory deficits will be examined in two domains of functioning: control of behavioral impulses and the ability to select attention to relevant stimuli. Studies will use behavioral and psychophysiological techniques (EEG) to identify specific inhibitory deficits prior to and following a history of adolescent drug use. Drug challenge tests are also proposed to identify potential differences in the acute sensitivity to the neurocognitive and rewarding effects of abused drugs as a function of adolescent drug use history and adolescent history of ADHD and CD. The long-term objective of this research is to distinguish antecedent inhibitory deficits that contribute to risk of early-onset adolescent drug use from resultant inhibitory deficits that represent the underlying neurological insult following a protracted history of adolescent drug use.

project_terms:
adolescence (12-20);alcoholism /alcohol abuse;attention;attention deficit disorder;behavioral /social science research tag;behavioral habituation /sensitization;cardiovascular function;case history;clinical research;conduct disorder;disease /disorder onset;disease /disorder proneness /risk;drug abuse;drug habituation;electroencephalography;human subject;impulsive behavior;placebos;psychological tests;psychophysiology;questionnaires;short term memory;visual stimulus


application_id: 7286019
project_number: 5R03AG026530-02
project_title: Natural Killer Subset Senescence and Clonality in Aging
administering_ic: NIA
award_notice_date: 2007-08-15
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AG
serial_number: 026530
program_official: FLORES, ROBERTO L
project_start_date: 2006-09-15
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-III-F(01)Q]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Natural killer (NK) cells use KIR and CD94/NKG2A receptors to detect infected cells and cancer cells that have downregulated MHC class I molecules. Declining NK cell function is associated with infection and poor health in the elderly but little is know about NK receptor expression or population dynamics in the elderly. OUR LONG-RANGE GOAL is to manipulate NK cells to promote healthy aging. Our CURRENT OBJECTIVE is to study human NK population dynamics and turnover in aging especially as they relate to age related shifts in NK receptor expression. Supported by our novel preliminary data our CENTRAL HYPOTHESIS is that an age related change in NK receptor expression is caused by a change in NK development and this in turn alters NK function and turnover. A feature of this shifting balance is the accumulation of NK cells with restricted receptor repertoire. The RATIONALE of the proposed research is that a better understanding of NK population dynamics and shifting NK receptor expression may allow us manipulate innate immunity in healthy and unhealthy aging. Our SPECIFIC AIM is to investigate human NK population dynamics as they relate to KIR and CD94/NKG2 receptor expression and other defined NK subsets. We will 1. test the replication potential and expression of senescence markers in NK subsets with aging 2. measure turnover rates in KIR+ and NKG2A+ NK cells from young and elderly adult subjects 3. evaluate the incidence of NK subpopulations with restricted receptor repertoire in young and elderly subjects and will rigorously test whether the NK subpopulations are polyclonal or monoclonal. Our approach is INNOVATIVE. We have documented a reciprocal relationship between NK receptors in aging and we have demonstrated for the first time that NK subpopulations with restricted receptor repertoire are found in healthy elderly people. It is our EXPECTATION that the proposed study will rigorously test our hypotheses and lead to definitive future studies on NK subset development function proliferation and senescence.

project_terms:
Address;Adult;Age;Aging;Bacteria;Bone Marrow;Cell physiology;Cells;Clonality;Coupled;Data;Development;Elderly;Equilibrium;Future;Genes MHC Class I;Goals;Health;Histocompatibility Antigens Class I;Human;Immunity Natural;Incidence;Infection;KLRD1 gene;Knowledge;Lead;Lymphocyte;Measures;NK Cell Activation;Natural Killer Cells;Neoplasm Metastasis;Pathway interactions;Pilot Projects;Population Dynamics;Production;Proliferating;Publishing;Range;Rate;Receptor Signaling;Research;Rest;Sampling;Signal Transduction;Stromal Cells;Testing;Time;Virus;Work;age related;base;cancer cell;cytokine;expectation;healthy aging;in vivo;innovation;novel;originality;receptor;receptor expression;research study;response;senescence;tumor growth


application_id: 7285561
project_number: 5R44EB001579-03
project_title: A Shear Force Transfer Coupling for Soft Tissue Repair
administering_ic: NIBIB
award_notice_date: 2007-08-10
opportunity_number: PA-06-006
application_type: 5
activity_code: R44
ic: EB
serial_number: 001579
program_official: HENDERSON, LORI
project_start_date: 2003-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-SSMI-K(10)B]
contact_pi_person_id: 1886358
contact_pi: MELVIN, DAVID B
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 969951859
duns_number: 969951859
fips: US
organization_id: 4007401
organization_name: CARDIOENERGETICS, INC.
organization_city: Covington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2009-08-31
project_abstract:
DESCRIPTION (provided by applicant): Wound closures sometimes fail because tissues lack the organized connective tissue required by sutures and staples. In 2004 we assessed feasibility (Phase I) of FiberSecure; a coupling fundamentally different from conventional closures: holding is by shear not direct or normal force. We showed in that study and others (orthopedic and cardiac power uses) that this coupling of thousands of fine polyester fibers inserted as bundles are rapidly ingrown by solid tissue. Holding strength reaches theoretical limits i.e. tissue strength itself. It is the mechanism by which root fibrils of plants hold fiercely even in soft soil. These trials have shown to high probability (p<0.002 in this Phase I) stronger holding than control closures meticulously applied. There are 4 specific aims: (1) Validate healing stability in 12-month implantation begun at funding so any late changes are recognized and addressed (2) Select final design by randomized block study of 2 plausibly useful variations from histology histochemistry and strength (3) Adapt that design to regulatory (GMP) standards through a manufacturing process with a widely experienced commercial partner and (4) Study those GMP products for 180 days in a GLP (Good Laboratory Practices) certified facility. Testing uses an abdominal muscle model in Sinclair Miniature Swine. Achieving these 4 aims would result in devices for clinical use under a investigational protocol as the basis for an FDA submission. 510(k) regulations apply. Human and commercial benefit would be enormous. While conventional couplings work quite well for strong tissues many couplings are in tissues where they too often fail. Mortality and disability follow across many surgical disciplines from dehiscence (bursting apart or splitting open) of a sutured abdominal wound to peripartum uterine rupture after fibroid myotomy or prior cesarean to unsuccessful repairs of diverse tissues after blunt trauma to disrupted heart valve replacements in normal (unscarred) annuli. Each may be lethal. This is a device that can address that need. This work is pivotal to its realization.

project_terms:
Abdomen;Abdominal Muscles;Acute;Address;Adhesives;Animal Model;Animals;Area;Biological Assay;Biopsy Specimen;Bioreactors;Blunt Trauma;Bone structure of radius;Capital;Cardiac;Cells;Cicatrix;Clinical;Clip;Closure;Collaborations;Collagen;Collagen Fiber;Compatible;Connective Tissue;Contracts;Coupling;Criteria Selection;Data;Decompression Sickness;Depth;Devices;Discipline;Disruption;Elements;Ensure;Failure (biologic function);Fascia;Fatigue;Fatty acid glycerol esters;Fiber;Fibroblasts;Fibroid Tumor;Fibronectins;Filament;Friction;Funding;Goals;Guanosine Monophosphate;Healed;Heart Valves;Histocytochemistry;Histologic;Histology;Human;Hypertrophy;Individual;Industry;Inflammatory;Information Confidential;Institution;Interruption;Laboratories;Left;Life;Liver;Marketing;Mechanics;Medical Device;Modeling;Models Experimental;Mortality Vital Statistics;Muscle;Names;Numbers;Object Attachment;Operative Surgical Procedures;Orthopedics;Patients;Performance;Phase;Plant Roots;Plants;Polyesters;Pressure- physical agent;Principal Investigator;Probability;Process;Prosthesis;Proteins;Protocols documentation;Randomized;Range;Regulation;Relative (related person);Research;Resistance;Risk;Schedule;Skeletal system;Soil;Solid;Specialties Surgical;Specimen;Standards of Weights and Measures;Statistically Significant;Stress;Surface;Surgeon;Surgical incisions;Surgical sutures;Swine Miniature;Tendon structure;Terminology;Testing;Textiles;Thromboplastin;Time;Tissues;Trademark;United States Food and Drug Administration;Uterine Rupture;Variant;Vascular blood supply;Waxes;Week;Work;Wound Healing;base;commercialization;day;design;disability;expectation;experience;healing;implantation;interstitial;manufacturing process;member;programs;repaired;research study;response;size;soft tissue;tissue culture;tissue welding;wound


application_id: 7284210
project_number: 5R21DA021027-03
project_title: Neurocognitive consequences of adolescent drug use
administering_ic: NIDA
award_notice_date: 2007-08-29
opportunity_number: RFA-DA-05-007
application_type: 5
activity_code: R21
ic: DA
serial_number: 021027
program_official: SIROCCO, KAREN
project_start_date: 2005-09-25
project_end_date: 2009-08-31
study_section: ZDA1-MXS-M(22)
contact_pi_person_id: 6368360
contact_pi: FILMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The effects of adolescent drug use on cognitive functioning is a significant public health concern. Adolescence marks a time of considerable neural development particularly in brain regions that control attention and behavioral impulses. Drug use during these critical periods of brain development could impede or alter the normal course of neural maturation resulting in long-term cognitive deficits in these areas. There is also considerable interest in the possibility that stimulant medications such as methylphenidate used in the treatment of attention deficit hyperactivity disorder (ADHD) could sensitize adolescents to the rewarding and disinhibiting effects of other stimulants thus increasing their risk of abuse as this population enters young adulthood. Despite growing concern about the consequences of adolescent drug use little is known about the specific behavioral and cognitive deficits that might result from a history of adolescent drug use. The proposed R21 project is designed to identify specific inhibitory-based neurocognitive deficits associated with a history of adolescent drug use and to examine how this association is mediated by two established adolescent risk factors for substance abuse ADHD and conduct disorder (CD). Inhibitory deficits will be examined in two domains of functioning: control of behavioral impulses and the ability to select attention to relevant stimuli. Studies will use behavioral and psychophysiological techniques (EEG) to identify specific inhibitory deficits prior to and following a history of adolescent drug use. Drug challenge tests are also proposed to identify potential differences in the acute sensitivity to the neurocognitive and rewarding effects of abused drugs as a function of adolescent drug use history and adolescent history of ADHD and CD. The long-term objective of this research is to distinguish antecedent inhibitory deficits that contribute to risk of early-onset adolescent drug use from resultant inhibitory deficits that represent the underlying neurological insult following a protracted history of adolescent drug use.

project_terms:
Acute;Adolescence;Adolescent;Alcohols;Area;Attention;Attention deficit hyperactivity disorder;Behavior;Behavior Control;Behavioral;Brain;Brain region;Characteristics;Childhood;Chronic;Cognitive deficits;Conduct Disorder;Critical Period (Psychology);Data;Development;Dextroamphetamine;Disease;Disinhibition;Dose;Drug Exposure;Drug abuse;Drug usage;Electroencephalography;Foundations;Future;Impaired cognition;Impairment;Impulsivity;Individual;Lead;Link;Longitudinal Studies;Maintenance;Maps;Masks;Measures;Mediating;Methylphenidate;Modeling;Nature;Neurocognitive;Neurocognitive Deficit;Neurologic;Patient Self-Report;Personal Satisfaction;Pharmaceutical Preparations;Population;Problem behavior;Psychopathology;Psychophysiology;Recording of previous events;Regulation;Reliance;Research;Research Design;Research Personnel;Rewards;Risk;Risk Factors;Role;Staging;Stimulus;Substance abuse problem;Symptoms;System;Techniques;Testing;Time;adolescent drug use;adolescent substance abuse;adolescent substance use;alcohol effect;base;behavioral pharmacology;cognitive function;cognitive neuroscience;design;drug of abuse;early onset;early onset drug abuse;follow-up;frontal lobe;interest;neurodevelopment;neuropsychological;programs;psychostimulant;public health medicine (field);relating to nervous system;response;young adult


application_id: 7283960
project_number: 5R21AG024902-02
project_title: Intimate Partner Violence and Inflammatory Processes
administering_ic: NIA
award_notice_date: 2007-08-09
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AG
serial_number: 024902
program_official: NIELSEN, LISBETH
project_start_date: 2006-09-15
project_end_date: 2010-08-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1859875
contact_pi: NEWTON, TAMARA L.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This study will test associations between prior exposure to adult intimate partner violence (IPV) and inflammatory markers and processes that have been implicated in a variety of conditions associated with aging (e.g. cardiovascular diseases cognitive decline). It is proposed that IPV can have long-standing consequences for inflammatory processes particularly via the pathway of intrusive re-experiencing (e.g. recurrent unwanted memories of prior stressful events and physiological reactions to events reminders). Aim 1 is to establish the relationship between prior exposure to adult IPV and inflammatory markers and processes. Aim 2 is to examine how severity of IPV and severity of intrusive re-experiencing interactively contribute to inflammatory markers and processes. These aims will be examined in a cross-sectional study of two groups of healthy women who are newly postmenopausal; (1) women who are divorced/separated from violent marriages or heterosexual cohabiting relationships (n = 67) and (2) a comparison group of women divorced/separated from non-violent marriages/heterosexual cohabiting relationships (n = 33). The latter group will serve as a control for the stress of divorce/separation. Women will have blood drawn for assessment of basal concentrations of the acute-phase protein high-sensitivity C-reactive protein and the proinflammatory cytokine interleukin-6. lnterleukin-6 production by peripheral blood mononuclear cells in response to in vitro immunological challenge will also be assessed. All women will be interviewed to assess history of victimization including IPV and posttraumatic stress symptoms including intrusive re-experiencing. Recent research reveals that older adults' health status is associated with potentially traumatic events experienced decades earlier in adulthood. IPV is endorsed by 25% of adult women in the United States is a risk factor for posttraumatic stress disorder and has been associated with prevalence of chronic diseases in several cross-sectional studies. If the proposed hypotheses are supported they will suggest a plausible basis for linkages among IPV posttraumatic stress symptoms and inflammatory conditions associated with aging. One long-term implication would be that evidence-based behavioral interventions that effectively treat posttraumatic stress disorder may also reduce this disorder's contribution to women's risk for developing conditions associated with aging.

project_terms:
Acute-Phase Proteins;Adult;Age;Aging;Behavior Therapy;Biological;Blood;C-reactive protein;Cardiovascular Diseases;Chronic;Chronic Disease;Chronic stress;Cognitive;Condition;Cross-Sectional Studies;Disease;Divorce;Elderly;Elevation;Emotional;Event;Exposure to;Health Status;Heterosexuals;Image;Impaired cognition;In Vitro;Individual;Inflammatory;Injury;Interleukin-6;Interview;Life;Link;Marriage;Medical;Memory;Mental Depression;Numbers;Pathway interactions;Perception;Peripheral Blood Mononuclear Cell;Physiological;Postmenopause;Prevalence;Process;Production;Publishing;Reaction;Recording of previous events;Recruitment Activity;Recurrence;Research;Risk;Risk Factors;Severities;Stress;Stress Disorders Post-Traumatic;Stressful Event;Sympathetic Nervous System;Symptoms;Testing;Trauma;United States;Victimization;Violence;Woman;base;biological adaptation to stress;biopsychosocial;comparison group;cytokine;divorce/separation;experience;intimate partner violence;peripheral blood;response;stressor


application_id: 7283733
project_number: 5R01GM062866-06
project_title: STRUCTURAL BASIS OF RNA-CATALYZED AMINOACYLATION OF RNA
administering_ic: NIGMS
award_notice_date: 2007-08-22
application_type: 5
activity_code: R01
ic: GM
serial_number: 062866
program_official: PREUSCH, PETER
project_start_date: 2002-09-15
project_end_date: 2009-08-31
study_section: Biophysics and Biophysical Chemistry B Study Section[BBCB]
contact_pi_person_id: 1923548
contact_pi: ARNEZ, JOHN G
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
project_abstract:
DESCRIPTION (provided by applicant): Attachment of amino acids to adapter RNA molecules is a key reaction in protein biosynthesis. The aminoacylation reaction is catalyzed in the cell by aminoacyl-tRNA synthetases. Recently three classes of catalytic RNAs (ribozymes) that recapitulate this activity by transferring the aminoacyl moiety from a pre-formed adenylate to their own 3'-termini have been obtained through in vitro selection. The first class contains RNAs that accept any aminoacyl moiety whereas members of the second class are specific for phenylalanine and tyrosine. Ribozymes of the third class also catalyze the formation of dipeptides a reaction analogous to that catalyzed by a large ribozyme the ribosome. In this proposal the three-dimensional structures of self-aminoacylating RNAs of the three classes will be determined by x-ray crystallography. The ribozymes will be analyzed in complex with substrate and product analogs. The structural information obtained in this study will reveal the configuration of the active site of these ribozymes organization of the amino acid-specific binding pocket and the mechanism of catalysis. It will help clarify the issue of whether the aminoacyl transfer to a peptide or an RNA involves entropic catalysis (i.e. precise positioning of the substrates) or it requires special catalytic groups on the enzyme such as an acid or base; hence it will add to our understanding of the reactions catalyzed by the larger biological systems such as the aminoacyl-tRNA synthetases and the ribosome.

project_terms:
Acids;Amino Acids;Amino Acyl-tRNA Synthetases;Aminoacylation;Binding (Molecular Function);Biological;Catalysis;Catalytic RNA;Cells;Class;Complex;Crystallography;Dipeptides;Enzymes;In Vitro;Peptides;Phenylalanine;Positioning Attribute;Protein Biosynthesis;RNA;Reaction;Ribosomes;Sites Active;System;Tyrosine;adenylate;analog;base;member;three dimensional structure


application_id: 7283557
project_number: 5P01CA092372-05
project_title: Growth Regulation and Therapy of Leukemias and Lymphomas
administering_ic: NCI
award_notice_date: 2007-08-16
application_type: 5
activity_code: P01
ic: CA
serial_number: 092372
program_official: MCCARTHY, SUSAN A
project_start_date: 2003-09-30
project_end_date: 2009-08-31
study_section: Basic & Preclinical Study Section (C)[NCI-C]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
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: 2007-09-01
project_abstract:
The overall goal of this program project is to understand the molecular mechanisms underlying leukemia and lymphoma development and to devise novel therapeutic strategies to control lymphoid neoplasms. There are four highly interactive projects that progress from basic studies to clinically applicable therapeutic strategies with a delicate balance between in vitro and in vivo model systems. Project 1: Cell Cycle Progression of Normal and Malignant B Cells: Dr. Snow will study the role of cell cycle regulators in the ability of CD40 to synergise with BCR to induce cell cycle progression in normal B cells. They will determine the basis of the diverse response patterns of three subgroups of B cell lymphomas to CD40 signaling and the in vivo relevance of such CD40 signaling for B lymphoma growth using transgenic mice. Porject 2: Role of egr-1gene in the growth regulation of normal B cells and B cell lymphoma: Dr. Bondada will study the basis of B cell receptor induced down regulation of the immediate early gene egr-1 and its relation to lymphoma growth inhibition using BKS-2 a B cell lymphoma. The importance of egr-1 for B cell development and B lymphoma growth will be studied in transgenic mice that express a dominant negative form of the egr-1 protein. Project 3: Biological chaaracterization of human leukemic stem cells (LSC): Dr. Jordan will examine the novel concept that LSC are the basis of relapse of drug treated leukemias. The growth requirement of LSC will be characterized. Modulation of pro and anti-apoptotic genes will be explored to control leukemic cell growth. Project 4: Graft-versus-tumor (GVT) activity of syngeneic/allogeneic graft versus host disease(GVHD): Dr. Bryson will determine the cellular mechanisms involved in GVHD and in GVT reaction. They will test the hypothesis that cyclosporin A induced oxidative stress directly participates in the induction of SGVHD. Cellular basis of the lack of memory in GV7- responses will be studied. Support for three Cores a transgenic and genetically defined animal facility histopathology and administrative core is requested to support the rsearch in this PO1 application.

project_terms:
Allogenic;Apoptotic;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;Biological;Biological Models;Cell Cycle;Cell Cycle Progression;Cyclosporine;Development;Dominant-Negative Mutation;Down-Regulation;Equilibrium;Genes;Genes Immediate-Early;Goals;Graft-Versus-Tumor Induction;Graft-vs-Host Disease;Growth;Histopathology;Human;In Vitro;Jordan;Leukemic Cell;Lymphoma;Malignant - descriptor;Memory;Mice Transgenic;Molecular;Oxidative Stress;Pattern;Proteins;Reaction;Receptors Antigen B-Cell;Regulation;Role;Signal Transduction;Snow;Stem cells;Subgroup;TNFRSF5 gene;Testing;Therapeutic;Transgenic Organisms;animal facility;base;cell growth;concept;drug relapse;in vivo;in vivo Model;leukemia;leukemia/lymphoma;lymphoid neoplasm;novel;novel therapeutics;programs;response


application_id: 7282721
project_number: 5R21RR022864-02
project_title: NOVEL UV OPTICAL WAVEGUIDES FOR SENSITIVE SPECTROSCOPY OF BIOMOLECULAR FILMS
administering_ic: NCRR
award_notice_date: 2007-08-06
opportunity_number: RFA-RR-05-001
application_type: 5
activity_code: R21
ic: RR
serial_number: 022864
program_official: FRIEDMAN, FRED K
project_start_date: 2006-09-01
project_end_date: 2009-08-31
study_section: ZRR1-BT-6(01)
contact_pi_person_id: 7844807
contact_pi: MENDES, SERGIO B
other_pis: Not Applicable
congressional_district: 03
department: PHYSICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
We propose here the development of an optical waveguide-based spectroscopic instrumentation in the ultra-violet (UV) region for research of unprecedented sensitivity in biomolecular thin-film assemblies. Single-mode integrated optical waveguides (IOW) have shown to provide the ultimate sensitivity to perform attenuated total reflection (ATR) absorption spectroscopy of molecular films and has been successfully demonstrated in protein films at the visible spectral region. However the lack of adequate optical waveguide materials has limited the extension of the technique into the UV region which represents a serious limitation as most important spectroscopic fingerprints of biomolecular species are located in the deep UV (300 -190 nm) region e.g. the aromatic groups of the protein amino acids tryptophan tyrosine and phenylalanine. The successful development of UV-compatible optical waveguides will allow us to implement a highly sensitive single-mode IOW ATR spectrometer at the UV spectral region (450 -190 nm). In this project we will focus on the critical and enabling developments of i) optical materials and process that can produce single-mode lOWs with low propagation loss in the UV spectral range and ii) a novel architecture for the single-mode IOW-ATR spectrometer that will greatly simplify its use for the investigation of molecular assemblies at the solid-liquid and solid-gas interfaces. To validate the capabilities of the novel technology we will apply it to several case studies including specific investigations of protein behavior at interfaces.  
  
Immobilization and adsorption of proteins and other biomolecules to solid surfaces is critical in the development of solid-phase-based bioanalytical techniques biocompatible materials and biosensors. Gaining a more detailed and accurate understanding of how proteins adsorb in what amount and conformation and establishing a systematic correlation between the physical/chemical environment and their bioactivity is an essential knowledge for designing novel biointerfacial processes and biomaterials for implants and for creating new biomedical diagnostics and drug delivery systems.

project_terms:
Adsorption;Amino Acids;Architecture;Arizona;Attenuated;Behavior;Biocompatible Materials;Biological;Biosensor;Case Study;Chemicals;Classification;Compatible;Condition;Coupling;Depth;Development;Diagnostic;Drug Delivery Systems;Environment;Film;Fingerprint;Formulations Drug;Gases;Gel;Glass;Housing;Immobilization;Implant;In Situ;Investigation;Knowledge;Laboratories;Light;Liquid substance;Molecular;Molecular Conformation;Monitor;Optics;Oxidation-Reduction;Phase;Phenylalanine;Process;Process of absorption;Proteins;Range;Research;Research Personnel;Science;Solid;Source;Spectrum Analysis;Surface;Techniques;Technology;Time;Today;Tryptophan;Tyrosine;Universities;Viola;base;biomolecular film;chemical property;college;density;design;detector;instrumentation;molecular assembly/self assembly;molecular film;monolayer;new technology;novel;programs;stoichiometry;tool;transmission process


application_id: 7282035
project_number: 5R03AG028162-02
project_title: Myocardial Stiffness in Aging Associated Diastolic Heart Failure
administering_ic: NIA
award_notice_date: 2007-08-01
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AG
serial_number: 028162
program_official: CARRINGTON-LAWRENCE, STACY
project_start_date: 2006-09-01
project_end_date: 2008-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diastolic dysfunction is the most common cause of congestive heart failure in elderly populations. One year mortality rates for afflicted individuals aged 70 years or older approximate 50%. Therapy options remain empirical. Although very little is known about the etiology of Diastolic Heart Failure (DHF) most studies agree that affected patients exhibit increased ventricular stiffness (reduced chamber compliance). The hypothesis underlying this work is that DHF in elderly populations reflects cross-bridge activity that persists inappropriately during the diastolic (or 'relaxed') phase of the cardiac cycle. These cross-bridges produce an 'active' component of myocardial stiffness that augments the heart's basal (passive) stiffness and impairs ventricular filling by increasing the resistance to inflowing blood. The proposed research will utilize Fischer 344 rats that exhibit aging-associated DHF at 25 months of age. Specific Aim 1 will establish the effects of aging on rat myocardial stiffness. Experiments will test the hypothesis that active stiffness due to inappropriately bound cross-bridges increases to a greater extent with aging than stiffness due to structural components. Intact trabeculae will be isolated from young (5 month) and old (25 month) rats and stretched in the presence and absence of BDM a cross-bridge inhibitor to establish the extent of age-dependent changes in active and passive stiffness. Specific Aim 2 will evaluate the effects of altered metabolite concentrations on active stiffness in young and old hearts. Experiments will utilize chemically permeabilized preparations isolated from 5 month and 25 month rat hearts and active stiffness will be assessed by measuring the tension responses to small stretches imposed under sarcomere length control. It is hypothesized that active stiffness due to persistent cross-bridge activity will be enhanced to a greater extent in the old hearts than in the young hearts when the concentrations of hydrogen ions phosphate ions and ADP are raised to levels mimicking ischemic myocardium. This research is relevant to public health because it investigates the novel hypothesis that aging-related DHF reflects inappropriate contractile activity during the relaxed phase of the cardiac cycle. The experimental results will provide new information about the underlying causes of DHF and should help scientists develop better treatments for diastolic dysfunction in elderly populations.

project_terms:
Affect;Age;Age-Months;Aging;Animals;Binding (Molecular Function);Blood;Cardiac;Collagen;Condition;Development;Diastolic heart failure;Elderly;Etiology;Exhibits;Fluorescence;Functional disorder;Heart;Heart Failure Congestive;Hydrogen-Ion Concentration;Individual;Ions;Ischemia;Length;Measurement;Measures;Mediating;Models Experimental;Mortality Vital Statistics;Muscle;Myocardial;Myocardial Ischemia;Myocardium;Myosin Heavy Chains;Patients;Phase;Population;Preparation;Protein Isoforms;Protons;Range;Rate;Rattus;Research;Resistance;Sarcomeres;Scientist;Solutions;Stimulus;Stretching;Testing;Therapeutic;Time;Triton X100;Ventricular;Work;age effect;age related;aged;connectin;erythritol anhydride;inhibitor/antagonist;inorganic phosphate;novel;public health medicine (field);research study;response


application_id: 7281850
project_number: 3P50DA005312-16S1
project_title: DRUG ABUSE PREVENTION - A LIFECOURSE PERSPECTIVE
project_terms: behavioral /social science research tag;drug abuse prevention;substance abuse related behavior
administering_ic: NIDA
award_notice_date: 2006-09-22
application_type: 3
activity_code: P50
ic: DA
serial_number: 005312
suffix: S1
program_official: GINEXI, ELIZABETH M
project_start_date: 1992-09-30
project_end_date: 2007-08-31
study_section: ZDA1
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_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 Center for Prevention Research at theUniversity of Kentucky is distinguished by thematic integration around theconstruct of novelty/sensation (N/S) seeking. Over the past 12 years we haveevaluated N/S seeking behavior at a number of complementary levels of analysisand have made considerable progress in our understanding of the onset anddevelopment of drug abuse and in applying this information to the developmentof more focused and effective prevention efforts. Our work has clearlybenefited from the strong interdisciplinary collaboration among distinct yetcomplementary laboratories both within the Center and with other ongoingprojects on the University of Kentucky campus. The three specific aims of theCenter Core are (1) Scientific: To generate and publish high quality preventionscience that is recognized as state-of-the-art research across relevantdisciplines; (2) Organizational: To provide an intellectually stimulatingcreative and productive environment in which research questions and issues areexamined from a multilevel interdisciplinary perspective; and (3) Leadership:To serve as a resource advocate and leader for drug abuse and preventionscience in part by training the next generation of drug abuse preventionresearchers.The substantive theme that consistently links scientists and research projectstogether in our Center is a broad and in-depth focus on N/S seeking behavior inthe onset and development of drug abuse and in applying this information forthe development of more focused and effective prevention efforts. The threeprojects proposed in the current application continue and extend the Center?son-going evaluations of the effects of N/S seeking on drug use and abuse. (1)Animal Laboratory: Individual Differences in Drug Response: An Animal Model(Mike Bardo PI). This project will use an animal model to study therelationship between N/S seeking and amphetamine reward; the guiding hypothesisis that novelty similar to stimulant drugs of abuse activates the mesolimbicdopamine reward system. (2) Human Laboratory: Drug Abuse Liability andSensation Seeking Status (Tom Kelly PI). This project will expand the researchteam?s prior work on N/S seeking as a moderator of the relationship betweendrug dose and the discriminative reinforcing and other behavioral effects andabuse liability of marijuana nicotine alcohol and methylphenidate. (3)Community Laboratory: Comprehensive Drug Prevention for Youth (Dick ClaytonPI). This project will continue a long-standing Center tradition of evaluationsof school-based curriculum-driven prevention programs with the evaluation of acomprehensive prevention program featuring both universal and selective highsensation value components.


application_id: 7281642
project_number: 5R01HL078663-04
project_title: Lysolipid Signaling in Cardovascular Disease
administering_ic: NHLBI
award_notice_date: 2007-07-25
opportunity_number: RFA-HL-04-005
application_type: 5
activity_code: R01
ic: HL
serial_number: 078663
program_official: GOLDMAN, STEPHEN
project_start_date: 2004-09-24
project_end_date: 2009-08-31
study_section: ZHL1-CSR-I(S1)
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    Both thrombotic and inflammatory mediators contribute to the development of vascular disease. Blood platelets which are known to play an essential role in ischemic heart disease and stroke by contributing to acute thrombotic events also release potent inflammatory agents within the vasculature.  Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is produced by platelets and found in abundance in human atherosclerotic plaques.  LPA stimulates platelets leukocytes endothelial cells and smooth muscle cells by acting through specific cell surface G-protein coupled receptors (LPA1-3) to regulate cell growth differentiation survival motility and contractile activity. LPA may also be an agonist for the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma).  Thus LPA is poised to serve as a key mediator of both inflammatory and thrombotic responses and to be a pathophysiologic regulator of vascular cell function.  The objective of this application is to determine the physiologic contribution of LPA to events that are relevant to atherothrombotic vascular disease and to identify the LPA receptor(s) involved.  Our central hypothesis is that LPA generated in part by activated platelets stimulates phenotypic modulation of medial SMCs and that these responses regulate vascular tone and contribute to the development of intimal hyperplasia after arterial injury and in the setting of atherosclerosis.  We propose to test our hypothesis by integrating cellular pharmacologic and functional genomics approaches in the following three specific aims (1) establish a pathologic role for LPA in the vascular response to injury; (2) identify LPA receptors that mediate phentypic modulation of cultured vascular SMCs; (3) Identify the role of LPA receptors in the regulation of vascular tone.  To accomplish our goals we will use mice deficient in the three known G-protein coupled LPA receptors (LPA1-3) novel pharmacologic sub-type selective agonists and agonistists of LPA1-3 and mice with a PPARgamma mutation that abolishes ligand binding.  Our results will provide specific insights into the role of LPA signaling pathways in vascular physiology and pathology and may provide novels targets for the treatment and prevention of atherothrombotic disorders.

project_terms:
Acute;Address;Administrator;Agonist;Animal Model;Animals;Apple;Arterial Fatty Streak;Arterial Injury;Atherosclerosis;Attenuated;Bathing;Blood Platelets;Blood Vessels;Boxing;Businesses;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cell Culture System;Cell Separation;Cell physiology;Cell surface;Cells;Chronic;Complement;Computer software;Computers;Coupled;Cultured Cells;DNA Sequence;Development;Devices;Diagnosis;Disease;Disease Progression;Endothelial Cells;Environment;Equilibrium;Equipment;Event;Fees;Film;G-Protein-Coupled Receptors;GTP-Binding Proteins;Gamma counter;Gel;Genetic;Goals;Grant;Graph;Housing;Human;Hyperplasia;Incubators;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Jordan;Knowledge;Laboratories;Leukocytes;Ligand Binding;Liquid substance;Lysophospholipids;Medial;Mediating;Mediator of activation protein;Medical center;Methods;Microcomputers;Microscope;Microscopy Confocal;Modeling;Models Cardiovascular;Molecular;Molecular Biology;Mus;Muscle Cells;Muscle Contraction;Mutation;Myocardial Ischemia;Myocytes Smooth Muscle;Nuclear;Nuclear Receptors;Nucleic Acids;Oocytes;PPAR gamma;Pathologic;Pathology;Peptide Synthesis;Peroxisome Proliferators;Personal Satisfaction;Pharmacology;Phenotype;Physiological;Physiology;Play;Positioning Attribute;Prevention;Qualifying;Radioimmunoassay;Radioisotopes;Receptors Lysophosphatidic Acid;Regulation;Research;Research Personnel;Research Project Grants;Role;Running;Science of Chemistry;Signal Pathway;Signal Transduction;Speed (motion);System;Temperature;Testing;Thromboplastin;Thrombosis;Time;Universities;Vascular Diseases;Walking;Water;Work;base;cell growth;cell motility;defined contribution;functional genomics;improved;indium arsenide;innovation;insight;lipid mediator;lysophosphatidic acid;member;migration;monoclonal antibody production;novel;programs;receptor;receptor function;response;response to injury;stroke;tissue culture;tool;vector;vzg-1 Receptor


application_id: 7281374
project_number: 1R56DK074566-01
project_title: INTRACELLULAR ENERGY DELIVERY AND DIABETIC WOUNDS
administering_ic: NIDDK
award_notice_date: 2006-09-15
application_type: 1
activity_code: R56
ic: DK
serial_number: 074566
program_official: JONES, TERESA L Z
project_start_date: 2006-09-15
project_end_date: 2007-05-14
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-15
project_terms:
adenosine triphosphate;angiogenesis;bioenergetics;cytoprotection;diabetes mellitus;disease /disorder model;drug delivery systems;hairless mouse;intracellular;ischemia;liposomes;magnesium;medical complication;nonhuman therapy evaluation;therapy design /development;vascular endothelial growth factors;wound healing


application_id: 7279907
project_number: 5K01AA015344-03
project_title: Mechanisms of Sensitization to TNF hepatotoxicity in ALD
administering_ic: NIAAA
award_notice_date: 2007-08-13
opportunity_number: PAR-02-065
application_type: 5
activity_code: K01
ic: AA
serial_number: 015344
program_official: RADAEVA, SVETLANA
project_start_date: 2005-09-15
project_end_date: 2008-08-16
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 7929995
contact_pi: SONG, ZHENYUAN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcoholic liver disease (ALD) continues to be an important health problem in the United States. Abnormal hepatic methionine metabolism is an acquired metabolic abnormality in ALD and the effects of chronic alcohol intake on hepatic methionine metabolism are initially seemingly paradoxic. Whereas alcohol consumption causes hepatic deficiency of S-adenosylmethionie (SAMe) it elevates hepatic homocysteine levels a product of SAMe metabolism.   
  
Decreased SAMe levels and elevated homocysteine levels may contribute to alcohol induced liver injury. The effect of alcohol on S-adenosylhomocysteine (SAH) levels another metabolite in the methionine metabolism pathway has received little investigative attention. It is our working hypothesis that tumor necrosis factor (TNF) in conjunction with certain metabolic abnormalities observed in ALD such as altered intracellular methylation status due to abnormal methionine/SAMe/SAH metabolism play an etiologic role in the development of liver injury in ALD. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia generation of reactive oxygen intermediates activation of Kupffer cell NFkB with increased TNF production decreased hepatocyte MAT activity with subsequent SAMe deficiency increased S-adenosylhomocysteine (SAH) concentrations inhibition of transmethylation reactions decreased hepatic methylation status elevated expression/ activation/activity of proteins sensitive to intracellular methylation status such as caspase-8 mitochondrial dysfunction increased susceptibility to hepatic TNF cytotoxicity and subsequent liver injury. In this proposal we will evaluate inhibition of hepatic transmethylation reactions by chronic alcohol exposure as a mechanism for hepatic sensitization to TNF-induced cytotoxicity in a relevant model of ALD. The specific objectives of this project are as follows: 1. Evaluate the effects of inhibition of hepatic transmethylation reactions on "sensitization" to TNF hepatotoxicity; 2. Investigate possible mechanisms by which inhibition of transmethylation reactions sensitizes hepatocytes to TNF hepatotoxicity; and 3. Evaluate the effects of chronic alcohol consumption (+/- SAMe supplementation) on hepatic methylation status and sensitization to TNF-hepatotoxicity in rats intragastrically fed alcohol.   
  
This research will be performed with structured mentoring support and a detailed training program designed to maximize my opportunity to become an independent NIH-funded investigator.

project_terms:
Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Attention;Chronic;Development;Endotoxemia;Funding;Generations;Goals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Homocysteine;Homocystine;Injury;Kupffer Cells;Liver;Mentors;Metabolic;Metabolism;Methionine;Methionine Metabolism Pathway;Methylation;Mitochondria;Modeling;Permeability;Play;Predisposition;Production;Proteins;Rattus;Reaction;Research;Research Personnel;Role;Structure;Supplementation;TNF protein human;Training Programs;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;United States;Work;alcohol effect;alcohol exposure;alcohol research;base;caspase-8;chronic alcohol ingestion;cytotoxicity;design;feeding;mitochondrial dysfunction;reactive oxygen intermediate;transmethylation


application_id: 7277954
project_number: 3R01RR020357-03S1
project_title: Zebrafish Mutant Mapping Facility
administering_ic: NCRR
award_notice_date: 2006-08-18
opportunity_number: PAR-02-142
application_type: 3
activity_code: R01
ic: RR
serial_number: 020357
suffix: S1
program_official: O'NEILL, RAYMOND R
project_start_date: 2004-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to accelerate the identification of zebrafish genes discovered during mutagenesis screens. This proposal is in response to PAR-02-142 to develop "Tools for Genetic Studies in Zebrafish." A major focus of this PA is to use novel screens to identify mutants of interest. However an essential part of this effort is to identify the genes responsible for the novel phenotypes generated. While thousands of mutants already have been described only 167 genes are listed in the zebrafish database (ZFIN) for which mutations are known (although there are probably some not listed). The major reason for this is the time consuming nature of the positional cloning strategy that must be used. The major bottleneck in gene discovery by positional cloning is the need to do whole genome linkage mapping. This takes considerable resources and time as well as technical expertise. This goal of this proposal is to eliminate this bottleneck by setting up a high throughput mapping facility. The usual laborious task of screening sometimes hundreds of markers to find one that is linked to the mutation of interest will be accomplished in 2 days. This will be done using fluorescence sequencers to automate genotyping of SSLPs (short sequence length polymorphisms) that span the genome. The mapping will be done in two main stages. First an approximate location will be determined using bulk segregant analyses. Second once closely flanking markers are identified 500-1000 individual mutant embryos will be genotyped to identify the region containing the mutant gene. Third for a small number of mutants the genes will be identified. The core will map a minimum of 100 mutants per year and identify the gene in 5-10 although both these numbers are likely to increase dramatically once the genome sequence is completed. The service will be modular so that investigators can have the initial mapping phases done by the facility and then complete the mutant gene isolation in there own laboratories. This project will have considerable impact because it will greatly accelerate the discovery of genes that already have been shown to be models of human diseases. The facility is committed to full and open access and all data pertaining to mapping will be made available at publication. Given the importance of zebrafish as a model organism this facility will have an immediate impact on the rate at which mutant genes are discovered which will provide new insights into the genetic underpinnings of important biochemical pathways involved in disease.


application_id: 7277498
project_number: 3R01CA073599-08S1
project_title: Redox Regulation of Tumor Suppression by MnSOD
administering_ic: NCI
award_notice_date: 2006-08-23
application_type: 3
activity_code: R01
ic: CA
serial_number: 073599
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 1998-09-01
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The overall goal of this research is to elucidate the mechanisms by which oxidative stress mediates tumor promotion. The studies we conducted in the previous funding period indicate that overexpression of the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) suppresses the incidence and multiplicity of Papilloma in the DMBAJTPA multi-stage skin carcinogenesis model. Unexpectedly reduction of MnSOD by heterozygous knockout of the MnSOD gene did not result in increased tumor incidence or multiplicity. The lack of increased susceptibility to DMBA/TPA-induced tumors in the MnSOD knockout mice is due to an increase in both apoptosis and proliferation after TPA treatment. The increased apoptosis in MnSOD-deficient mice is associated with increased p53 accumulation in the mitochondria.Based upon these novel findings we propose to test the following four interrelated hypotheses and to determine how modulation of apoptosis and antioxidant levels based upon the mechanistic insights learned from this study may alter the outcome of tumor formation in a well-established skin carcinogenesis model. Specific aim 1: Apoptosis precedes proliferation in an oxidant-induced tumorigenesis model. Specific aim 2: Oxidative stress accumulating in mitochondria serves as a death signal which induces p53 translocation to mitochondria. Specific aim 3: P53 translocation to mitochondria is an important event leading to amplification of the transcription-dependent apoptosis of p53. Specific aim 4: Increased p53 stability contributes significantly to increased p53 protein levels after TPA application. Specific aim 5: Determine if tumorigenesis is altered by redox-based intervention of apoptosis and proliferative pathways. MnSOD-transgenic and MnSOD-deficient mice as well as wild-type mice in the same inbred background will be used as in vivo models. The epidermal-derived JB6 variants will be used as in vitro models. The results of the proposed studies will provide information on the sequence of molecular events during an early stage of tumorigenesis the mechanisms by which a previously unrecognized role of p53 may participate in the promotion stage of skin carcinogenesis and a proof-of-principle for redox-mediated intervention of tumorigenesis.

project_terms:
antioxidants;apoptosis;carcinogenesis;cell proliferation;disease /disorder model;electron microscopy;flow cytometry;genetic transduction;genetically modified animals;immunoprecipitation;laboratory mouse;manganese;mitochondria;neoplasm /cancer genetics;oxidative stress;p53 gene /protein;phorbols;protein transport;skin neoplasms;superoxide dismutase;transcription factor;tumor suppressor proteins;western blottings


application_id: 7277278
project_number: 5F31AI064120-03
project_title: Minority predoctoral fellowship program
administering_ic: NIAID
award_notice_date: 2007-08-10
application_type: 5
activity_code: F31
ic: AI
serial_number: 064120
program_official: HERNANDEZ, MILTON J
project_start_date: 2005-08-01
project_end_date: 2008-01-25
study_section: Special Emphasis Panel[ZRG1-IDM-P(29)L]
contact_pi_person_id: 8002596
contact_pi: MANIRARORA, JEAN N
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-01
project_abstract:
DESCRIPTION (provided by applicant):  CD4+CD25+ regulatory T cells play a major role in the control of immunity as the lack of this T cell population results in the activation of autoreactive T cells and the development of autoimmune diseases. It has been reported that the level of CD4+CD25+ regulatory T cells is lower in autoimmune-prone mice such as NZBxNZWFI (BWF1) and NOD mice. The central hypothesis of this proposal is that autoimmune-prone mice may have a defect in CD4+CD25+ regulatory T cell function which may play a role in the pathogenesis of autoimmune diseases. Our preliminary studies suggest that NOD antigen presenting cells (APC) play a crucial role in the defect of CD4+CD25+ regulatory T cell function but that activation of NOD APC restores normal regulation in vivo. The objective of this proposal is therefore to develop novel strategies using TLRs to restore optimal regulation in NOD mice and to characterize the mechanisms of this regulation. Moreover we will investigate whether APC from diabetic patients have also a defect in activating regulatory T cells and whether enhancement of their APC function can ameliorate regulation as well as whether regulatory T cells from diabetic patients can be activated directly via TLRs.

project_terms:
Address;Adoptive Transfer;Antigen-Presenting Cells;Autoimmune Diseases;Autoimmune Process;Bacteria;Biological Assay;Cell physiology;Cells;Defect;Development;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Exhibits;Fellowship Program;Freund's Adjuvant;Harvest;Immunity;In Vitro;Infectious Agent;Ligands;Mice Inbred NOD;Minority;Monoclonal Antibody HuM291;Mus;Nature;Pathogenesis;Patients;Play;Polymerase Chain Reaction;Population;Probiotics;Regulation;Reporting;Role;Stimulus;T-Cell Development;T-Cell Proliferation;T-Lymphocyte;TLR3 protein human;Testing;Time;Toll-like receptors;autoreactive T cell;cell type;cytokine;design;diabetic;in vitro Assay;in vivo;novel strategies;pre-doctoral;prevent;research study;type I diabetic


application_id: 7276677
project_number: 5P01ES011860-05
project_title: Cardiovascular Toxicity of Environmental Aldehydes
administering_ic: NIEHS
award_notice_date: 2007-08-29
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
program_official: NADADUR, SRIKANTH
project_start_date: 2003-09-15
project_end_date: 2010-06-30
study_section: ZES1-SET-A(P7)
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: 2007-09-01
project_abstract:
This Program-Project Grant is to identify and define the cardiovascular effects of environmental aldehydes and pollutants that generate aldehydes. The project will integrate molecular and cellular aspects of aldehyde toxicity delineate the contribution of individual pathways involved in the detoxification of the aldehydes and elucidate how aldehydes affect atherosclerosis platelet and endothelial activation and myocardial function. Acrotein and trans-2-hexanal will be studiedas model aldehydes most prevalent in the environment. The Program consists of 4 Projects and 3 Cores. Project 1: Aldehyde Metabolism and Cardiovascular Disease focuses on the metabolism of these toxicants in mice. These studies are designed to identify the major metabolic products and the biochemical pathways that metabolize aldehydes and how glutathione S-transferases regulate this metabolism and cardiovascular toxicity. Project 2: Atherogenic Effects of Environmental Aldehydes will test the hypothesis that exposure to unsaturated aldehydes exacerbates atherogenesis. Spontaneously atherosclerotic apoE-null mice will be exposed to these pollutants and changes in lesion progression and markers of vascular inflammation will be measured and resultant alterations in plasma lipoproteins will be determined. The central hypothesis of Project 3: Role of Platelet Activation and Vascular Pathology in Aldehyde Toxicity is that environmental aldehydes activate blood cells and induce proinflammatory responses in the vascular endothelium. To test this hypothesis we will examine platelet activation by aldehyde investigate the role of platelet microparticle formation in aldehyde-induced vascular changes and assess the ability of these aldehydes to stimulate platelet-lesion interactions. In Project 4: Acute and Chronic Cardiotoxicity of Aldehydes will examine how aldehydes acutely depress contractibility exacerbate ischemic injury and chronically induce inflammatory states contributing to remodeling characteristic of heart failure. For this we will delineate the mechanisms by which aldehyde inflict contractile dysfunction abolish ischemic preconditioning and induce pathological myocardial remodeling. The Administrative Core (A) will serve as the organizational focus and will provide infrastructure support including statistical analysis datamanagement coordinated sample handling and storage and sentinel monitoring for systemic toxicity. The Bioanalysis Core (B) will provide and integrated centralized facility for biochemical determinations and mass spectrometry. The Inhalation Facility Core (C) will provide uniform acrolein exposures to mice via inhalation. Successful completion of this project will lead to a better understanding of the cardiovascular consequences of aldehyde exposure and will provide direction to future assessments of human risk and susceptibility.


application_id: 7274451
project_number: 7R01AR047577-06
project_title: Muscle and Bone Maintenance in Hindlimb Suspended Rats
administering_ic: NIAMS
award_notice_date: 2006-08-11
opportunity_number: PA-00-088
application_type: 7
activity_code: R01
ic: AR
serial_number: 047577
program_official: NUCKOLLS, GLEN H
project_start_date: 2002-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-SMB(01)S]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE 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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this proposal is to perform a                          comprehensive analysis of a novel form of resistance exercise training as a         countermeasure to offset the loss in musculoskeletal structure and function         after exposure to microgravity. Rats continuously maintained in a hindlimb         suspended state will be subjected to resistance training using flywheel            technology. We hypothesize that this form of resistance training that is           gravity-independent will prevent muscle atrophy and loss of bone mineral           density normally associated with hindlimb suspension. Force generated during        training will be quantitated using a load cell and correlated with skeletal         muscle mass fiber cross-sectional area and performance in Aim I. To identify      specific mechanisms responsible for the changes in muscle properties in             response to flywheel training the dynamics of muscle protein homeostasis will      be systematically quantitated. Aim 2 will explore the effects of flywheel           training on bone mass density and strength. Quantitation of the strain             required for maintenance of bone properties using a strain gage will be             correlated to muscle force to allow the development of a training regimen that      is beneficial to the entire musculoskeletal system. The relative contribution       of apoptotic muscle fiber nuclear loss and osteocyte apoptosis to loss of           musculoskeletal function during hindlimb suspension and the effect of flywheel      training will be determined in Aim 3. Finally in Aim 4 muscle and bone marrow     stem cells will be isolated and proliferation and differentiation analyzed to       determine if changes in these cellular processes potentially contribute to the      response to hindlimb suspension and flywheel resistance training. This approach     will provide a basic understanding of mechanisms contributing to maintenance of     the musculoskeletal system via resistance exercise during microgravity. Our         experiments are directly relevant to studies being carried out in humans to         determine efficacy of flywheel training protocols. Together results may            provide insight into the use of resistance exercise as a countermeasure to the      loss of muscle and bone that occurs during space flight.

project_terms:
apoptosis;atrophy;bone density;bone disuse atrophy;cell differentiation;cell proliferation;densitometry;exercise;gravity;homeostasis;immobilization of body part;laboratory rat;limbs;microarray technology;muscle cells;muscle function;muscle proteins;musculoskeletal disorder therapy;protein biosynthesis


application_id: 7274274
project_number: 5P01AG010836-13
project_title: LONG-TERM INTERVENTION CORE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 9001
contact_pi_person_id: 7875396
contact_pi: PORTER, NADA MICOVIC
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: 2006-09-01
budget_end_date: 2007-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
This core is designed to establish a facility and procedures for definitively testing whether an intervention treatment alters the rate of brain aging in rodent models. Although the NIA supports a Consortium that runs intervention clinical trials for select agents there is growing recognition of a need for additional testing programs at the preclinical level.  However critical putative mechanisms and hypotheses of brain aging and AD are emerging from this PPG and elsewhere that warrant systematic testing. Long-term interventions are essentially the only way to test whether an experimental intervention alters the rate of gradual processes of aging and age-related pathology. Thus there is a need for an intervention program that focuses on animal models of brain aging and AD. The program project has two parallel longitudinal components (at Universities of Kentucky and Alabama) and will assess the effectiveness of "intervention treatments" in slowing the progression or alleviating aspects of brain aging and cognitive decline in a rat model of aging (F344 rats) and in a mouse model of AD (APP/PS1 mice). In F344 rats the long-term interventions will be initiated at middle age prior to the onset of cognitive decline. The same approach will be used in APP/PS1 mice. However because of the accelerated pathology of this model treatment will begin at 3 months prior to cognitive decline and the appearance of pathological markers. The treatments chosen are compatible with long-term exposure and have few side effects. The four initial agents (minocycline memantine vitamin D lipoic acid) test key hypotheses in various Projects of the PPG. All have compelling evidence for their potential efficacy against processes involved in aging and are currently approved for other indications in humans. A search of the clinical trials web site or the NIH CRISP database of sponsored grants reveals that none of these interventions are currently in clinicai/preciinical trial as aging interventions. Our use of these existing therapies as potential aging interventions therefore represents a novel use of these treatments. Thus these candidate interventions appear to be highly feasible and there is substantial evidence indicating potentially favorable outcomes. Importantly the selection of these agents for long-term tests is hypothesisdriven and will directly advance the aims of multiple Projects within the program project.

project_terms:
Alzheimer&apos;s disease;aging;amantadine;antibacterial agents;antiparkinson drugs;biomarker;biomedical facility;brain;brain disorder chemotherapy;cognition disorders;drug screening /evaluation;genetically modified animals;laboratory mouse;laboratory rat;neuropathology;neuropsychological tests;nonhuman therapy evaluation;short chain fatty acid;tetracyclines;vitamin D


application_id: 7274273
project_number: 5P01AG010836-13
project_title: AD: OXIDATIVE STRESSCALCIUM AND MITROCHONDRIAL DISORDER
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0011
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
budget_end_date: 2007-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Aging and age-related disorders such as Alzheimer's disease (AD) are associated withprogressive decreases in cognitive function. Markers of inflammation are also well-documented in both aging and AD brains but it is not known how inflammatory pathways are initiated nor are the cell types involved in the inflammatory cascade identified. In addition to inflammation calciumoverload oxidative stress and proteasome inhibition are all thought to participate in age-relateddeclines. New data from our laboratory suggests that these seemingly disparate phenomena may be linked; whereby changes in proteasome expression and activity in response to increased intracellular calcium and oxidative stress initiate inflammation in neurons. The focus of this proposal therefore is to test the hypothesis that oxidative stress- and calcium-induced alterations to the proteasome lead to inflammation in aging and AD brains. Studies will determine the effects of increasing doses of age- and AD-related stimuli on proteasome subunit expression proteasome activity and immune signaling in cultured neurons. The relationships between proteasome alterations calcium homeostasis inflammatory signaling and cell death will be determined. Studies will also be carried out in cultured astrocytes microglial cells and oligodendrocytes to determine cell-type specific components of proteasome-dependent inflammation and cytotoxicity. Additionally the role of preserved proteasome homeostasis and prevention of proteasome-dependent inflammation in the therapeutic effects of minocycline and estrogen will be tested in vitro and in vivo.Concurrently this project will serve as a Core for the PPG generating primary cultures of ratneurons and glial cells and providing quantitative assessments of inflammatory and proteasomehomeostasis in long-term intervention studies. Completion of these studies will greatly increase our understanding of the role of the proteasome in the aging brain and could aid in the development of novel therapies for brain aging by targeting inflammation.

project_terms:
Alzheimer&apos;s disease;aging;antibacterial agents;antiinflammatory agents;calcium flux;cell component structure /function;cell death;cytoprotection;disease /disorder etiology;estrogens;gene expression;genetic regulation;homeostasis;inflammation;laboratory rat;mitochondrial disease /disorder;neurogenetics;neuroimmunomodulation;neuropathology;neuroregulation;nonhuman therapy evaluation;oxidative stress;proteasome;tetracyclines;tissue /cell culture;tissue /cell preparation


application_id: 7274272
project_number: 5P01AG010836-13
project_title: MITOCHONDRIA ROS CA2+ AND CAPLAIN IN THE AGING CNS
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0010
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
budget_end_date: 2007-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The underlying  hypothesis is that an age-related accumulation of oxidative damage tomitochondria causes increasing mitochondrial dysfunction resulting in impaired Ca 2+ regulation greater production of reactive oxygen species (Aim 1) and greater release of death-related proteins in response to insult (Aim 2). Calpains Ca2+-activated cysteine proteases are impacted by both Ca 2+ dysregulation and oxidative stress. Preliminary results suggest that m-calpain is associated with mitochondria where its substrates may include many cell-death related proteins (Aim 3). Mitochondrial calpain would be ideally situated for regulation by mitochondrial Ca 2+ release and redox mechanisms similar to the recently described mitochondrial nitric oxide synthase. The age-related alterations in mitochondrial function and cell death proteins are hypothesized to be exacerbated in vulnerable brain regions in AIzheimer's disease (AD) as compared to resistant brain regions and mitochondrial function in elderly individuals with less severe cognitive decline and neuropathology (Aim 4). However increased oxidative stress in aging and AD may limit the activity of calpain and other cysteine proteases possibly protecting against the consequences of Ca 2+ dysregulation but also limiting the proteolysis of substrate proteins (Aim 4). To examine the basic premise that an age-related accumulation of oxidative damage to mitochondria results in their dysfunction iwe will examine the efficacy of long-term anti-oxidant (lipoic acid) and NMDA receptor antagonism (memantine) intervention in attenuating the age-related alterations in mitochondrial function (Aim 5). The above studies of mitochondrial function will be performed on synaptic and non-synaptic mitochondrial fractions isolated from the cortex and cerebellum of rats of ages 1-24 months and from human brain autopsy tissues obtained from individuals with various levels of cognitive function and AD-related  europathology.The maximum postmortem interval is 5h. While many aspects of mitochondrial dysfunction have been examined in aging and AD few studies have examined isolated mitochondria and even fewer have evaluated synaptic vs. non-synaptic mitochondria. Together the studies outlined in this project will provide a comprehensive evaluation of mitochondrial function and dysfunction in aging and AD and the relationship of mitochondrial dysfunction to the age-related Ca2+ deregulation and oxidative stress.

project_terms:
Alzheimer&apos;s disease;aging;amantadine;antioxidants;antiparkinson drugs;brain disorder chemotherapy;calcium flux;calpain;cell death;central nervous system;clinical research;disease /disorder etiology;free radical oxygen;genetically modified animals;human tissue;intermolecular interaction;laboratory rat;mitochondrial disease /disorder;nerve /myelin protein;neural degeneration;neuropathology;neuroregulation;nonhuman therapy evaluation;postmortem;protein structure function;tissue /cell culture


application_id: 7274271
project_number: 5P01AG010836-13
project_title: CA2+ REGULATION AND MITOCHONDRIA IN BRAIN AGING/ AD
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0008
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
budget_end_date: 2007-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Amyloid beta-peptide (Abeta) is central to the pathogenesis of Alzheimer's disease (AD) and the AD brain is under extensive oxidative stress. Previous research from our laboratory combined these two observations into a model for neurodegeneration in AD a model based on Abeta-associated free radical oxidative stress. In neurons Abeta-associated free radical oxidative stress and toxicity depend critically on methionine residue 35 of Abeta(1-42) and both are prevented or modulated by exogenous antioxidants. We have used the emerging techniques of proteomics coupled with immunoblottmg methods to identify specifically oxidatively modified proteins in AD brain. We now propose to extend these observations to sporadic and inherited AD and rodent models thereof to gain insight into the mechanisms of Abeta (1-42) in the oxidative stress and neurotoxic properties of this peptide. In Specific Aim # 1 we will use proteomics to test the hypothesis that there will be a common set of oxidized proteins in inherited and sporadic AD that differ from those of normal aging and that these oxidized proteins in common are important in the pathogenesis of AD. Similar studies in mice models of inherited AD are hypothesized to lead to the identity of the same common proteins. In Specific Aim #2 we will test the hypothesis that mitochondrial dysfunction and Ca 2+ accumulation in brain from genetic mutations relevant to AD will be found in adult brain mitochondria from the model chosen in Specific Aim #1 compared to adult brain from wild-type mice. Those proteins identified by proteomics in the systems studied will be expressed in SY5Y cells and challenged with Abeta(1-42) to determine if there is increased vulnerability to oxidative stress mitochondrial dysfunction Ca 2+ accumulation and cytotoxicity. In Specific Aim #3 we will use proteomics to test the hypothesis that Abeta(1-42)-induced oxidative stress in embryonic neuronal cultures obtained from the rodent model of familial AD chosen in Specific Aim # 1 leads to the same oxidatively modified proteins as exists in adult brain from this animal and in human familial AD brain. In Specific Aim #4 we will investigate whether oxidative stress induces mitochondrialalterations in neuronal cultures obtained from the rodent model of inherited AD chosen in Specific Aim #1 or whether mitochondrial alterations induced in these cultures leads to oxidative stress. In Specific Aim # 5 we will test the hypothesis that endogenous or exogenous antioxidants protect brain in-vivo against oxidative stress in the rodent model chosen in Specific Aim # 1. This is a comprehensive set of proposed studies employing novel approaches in systems ranging from sporadic and inherited AD brain to genetic animal models of AD to neuronal cultures designed to gain insight into Abeta-associated free radical oxidative stress and neurotoxicity and their modulation by endogenous and exogenous antioxidants. The increased understanding that will result from these studies will provide insight into potential therapeutic interventions in this important dementing disorder that affects millions of Americans.

project_terms:
Alzheimer&apos;s disease;aging;amyloid proteins;antioxidants;calcium flux;disease /disorder etiology;embryo /fetus cell /tissue;gene mutation;genetically modified animals;hippocampus;intermolecular interaction;laboratory mouse;mitochondria;mitochondrial disease /disorder;nerve /myelin protein;neural degeneration;neurogenetics;neurons;neuropathology;neuroregulation;neurotoxins;nonhuman therapy evaluation;oxidation;oxidative stress;protein structure function;proteomics;tissue /cell culture


application_id: 7274270
project_number: 5P01AG010836-13
project_title: GENE EXPRESSION AND CA2+ IN BRAIN AGING/ ALZHEIMER'S
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0006
contact_pi_person_id: 6176244
contact_pi: CHEN, KUEY-CHU
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: 2006-09-01
budget_end_date: 2007-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The overall goal of this project is to identify genes/proteins that play a causal role in brain aging/risk for AD. We will test the hypothesis that interactions of steroids with Ca2+ signaling pathways are underlying causal factors that act in early mid-life using gene microarrays combined with sophisticated biostatistical analyses and real-time PCR protein assays and in situ hybridization. In the first three specific aims we will extend our previous work by determining which changes in gene expression take place earliest in normal aging rats and also in an animal model of AD the APP/PS1 mouse. Comparison of these two models will reveal how normal aging transitions into pathological aging and will identify risk factors for AD. In addition we will carry out microarray analyses of single neurons and gila to that test the hypothesis that aging is a process of neuronal involution and gUallmicroglial activation. We will coordinate this project closely with Project 3 in order to determine the temporal relationship between altered gene expression and Ca 2+ dysregulation assessed by physiological techniques. In the last twospecific aims we will test the hypothesis that steroid hormones and their coordinating transcription factors and Ca2+-regulated signaling molecules play a role in inducing changes in gene expression that mimic those in aging. These studies will be carried out using viral-mediatedoverexpression/knockdown of steroid hormone receptors or Ca2+-regulated signaling proteins in mixed cultures of hippocampal cells. Subsequent experiments will be carried out in cell-type specific cultures (neurons gila microglia) in order to identify where the changes in gene expression originate. Gene expression changes elicited by these treatments will be determined first using microarrays and subsequently real-time PCR of selected panels of aging biomarkers. Taken together these studies will elucidate the role of both factors previously implicated in brain aging (steroid hormones Ca 2+- regulating molecules) and will identify novel factors and pathways as well. Further this Project in collaboration with Project 3 and Cores A B and C will define more clearly the relationship of gene expression cascades to Ca 2+ dysregulation in aging/AD.

project_terms:
Alzheimer&apos;s disease;aging;animal genetic material tag;calcium flux;disease /disorder etiology;disease /disorder proneness /risk;gene expression;genetic regulation;genetically modified animals;glia;hippocampus;hormone regulation /control mechanism;laboratory mouse;laboratory rat;microarray technology;molecular pathology;neural degeneration;neurogenetics;neurons;neuropathology;neuroregulation;protein structure function;steroid hormone;steroid hormone receptor;tissue /cell culture


application_id: 7273895
project_number: 5R21AG028816-02
project_title: A screen for small molecule inhibitors of soluble Abeta oligomer assembly
administering_ic: NIA
award_notice_date: 2007-07-30
opportunity_number: PAR-05-056
application_type: 5
activity_code: R21
ic: AG
serial_number: 028816
program_official: SUNEJA, SANOJ
project_start_date: 2006-09-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-BST-L(50)R]
contact_pi_person_id: 2421413
contact_pi: LEVINE, HARRY
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Soluble oligomeric forms of the Alzheimer's beta-peptide (Abeta(1-42)) are receiving increasing attention as potential mediators of the neurotoxic activity of Abeta and as a possible causative agent for Alzheimer's disease. The search for potentially therapeutic anti-oligomer compounds has been hampered by the lack of a high-throughput screening assay and artifactual interactions of compounds with antibodies. This exploratory proposal applies a novel inexpensive assay format to screen for compounds that inhibit the formation of soluble Abeta oligomers or destabilize their structure facilitating biological clearance. A small library of pharmaceutical agents will be screened to establish performance parameters followed by evaluation of a more extensive pharmacophore library to identify structures of potential interest. Specific Aim 1. To develop a high-throughput assay system to identify compounds to inhibit Abeta oligomer formation. Preventing Abeta(1-42) oligomer assembly at an early stage will prevent stable toxic species from being formed. Oligomeric species of synthetic N-terminally biotinylated Abeta(1-42) will be quantified with a novel biotin-avidin single site binding assay. This method is preferable for primary screening over even oligomer-specific antibodies because it avoids a significant number of false positives inactive compounds that interfere with antibody epitopes and antibodies. The procedure will be implemented on a Tecan Genesis LiHa/TeMo robotics system at UK. Specific Aim 2. To develop a high-throughput assay system to identify compounds to destabilize Abeta oligomer structure. Abeta oligomers are highly protease-resistant and thus poorly cleared from the brain. Compounds that destabilize oligomers allowing degradation by Abeta-metabolizing proteases would be useful in reducing oligomer levels and be of potential therapeutic value. Synthetic Abeta oligomers formed in the presence of compound or preformed and then treated with compound will be screened with trypsin and if positive digested with insulin-degrading enzyme and neprilysin proteases believed to degrade Abeta peptides in vivo. Selected positive compounds will be also tested for their effect on the protease sensitivity of soluble Abeta oligomers extracted from AD brain employing a new highly sensitive single site immunoassay configured for the Luminex-100(r) Beadlyte(tm) system. This method shows promise for the detection of oligomeric Abeta in biological fluids including animal models and clinical specimens to determine the effectiveness of anti-oligomer therapeutics. Specific Aim 3. To determine the performance of the assays developed in Specific Aims 1 and 2 on screening the LOPAC compound library and a targeted screen of the more extensive Hit-Finder(tm) pharmacophore collection. The LOPAC library will be used to troubleshoot the protocols optimized in Specific Aims 1 and 2 applied in a screening format. Results from this screen will be used to predict which compounds in the 16000 compound Maybridge Hit-Finder(tm) collection may be active in blocking oligomer formation. Although the intent of this exploratory/developmental proposal is primarily to validate the assays active compounds will provide tools that will be useful in probing the biological effects of Abeta oligomers since the pharmaceutical agents that make up LOPAC are compatible with cellular systems. Anti-oligomer compounds could potentially block the cognitive impairment symptoms that oligomers elicit in animal models and interfere with the progression of Alzheimer's disease.

project_terms:
Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Antibodies;Antibodies Blocking;Attention;Automation;Avidin;Binding (Molecular Function);Binding Sites;Biological;Biological Assay;Biology;Biotin;Brain;Cathepsins B;Cellular Assay;Chemistry Pharmaceutical;Clinical;Collaborations;Collection;Compatible;Cultured Cells;Detection;Development;Effectiveness;Endopeptidases;Enzymes;Epitopes;Evaluation;Immunoassay;Impaired cognition;In Vitro;Insulinase;Label;Lead;Libraries;Liquid substance;Measures;Mediator of activation protein;Methods;Neprilysin;Numbers;Peptide Hydrolases;Peptides;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Procedures;Process;Property;Protocols documentation;Publishing;Research Personnel;Resistance;Robotics;Science of Microbiology;Screening Result;Screening procedure;Site;Specimen;Staging;Streptavidin;Structure;Structure-Activity Relationship;Symptoms;System;Testing;Therapeutic;Treatment Effectiveness;Trypsin;abeta oligomer;amyloid formation;base;experience;high throughput screening;in vivo;inhibitor/antagonist;innovation;interest;monomer;neurotoxic;novel;pharmacophore;prevent;programs;secretase;small molecule;therapeutic target;tool


application_id: 7273515
project_number: 5R01AG022859-05
project_title: Species comparison of stem cell aging
administering_ic: NIA
award_notice_date: 2007-07-18
opportunity_number: RFA-AG-03-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 022859
program_official: MURTHY, MAHADEV
project_start_date: 2003-09-30
project_end_date: 2008-08-31
study_section: ZAG1-ZIJ-5(O1)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The replenishment of spent cells is a common theme in a newly appreciated and growing number of mammalian organs. In most cases stem cells fuel this process over a lifetime. Recent evidence suggests that an animal's absolute number of hematopoietic stem cells is conserved and is irrespective of body size and lifespan. What mechanistic strategies and adaptations allow the same-sized population of stem cells to replenish mature cell populations that in the human are several thousand-fold larger than those in the mouse over a lifespan that is forty-fold longer in humans than in mice? The first aim of this proposal will determine the changes in stem cell number cell cycle status responsiveness to cytokines and apoptosis rate from young to old age in both species. Human umbilical cord blood stem cells from newborns will be compared to bone marrow stem cells from humans greater than 75 years old. A parallel comparison will be made between bone marrow stem cells of 2 month old and 24 month old mice. Inter-species similarities and differences in these parameters during aging will provide insight to the physiological mechanisms employed at the cellular level. The second aim will determine the similar and contrasting inter-specific strategies employed at the molecular level. Hematopoietic stem cells from both humans and mice at young and old age will be purified by cell sorting. The repertoire of expressed genes in each stem cell population will be determined by extracting RNA from the purified populations and hybridizing it to gene sets of human and mouse respectively on microarrays. Comparative species analysis of gene expression during aging of stem cells is expected to reveal several patterns of special interest. Those genes whose expression is turned on increased or maintained during aging in human but not in the mouse suggest candidates that might account for maintenance of stem cell function over a long lifespan in humans. Those whose expression changes in a parallel pattern in both species suggests conserved genes fundamentally important for dealing with the rigors of aging. Those whose expression declines with age in the mouse but not the human suggests candidates that are responsible for the maintenance of the longevity of stem cell function. Patterns of gene expression in stem cells during aging will reveal molecular pathways important in defining longevity and may suggest molecular targets of intervention in the treatment of age-related disorders including cancer.

project_terms:
Accounting;Adult;Affect;Age;Aging;Animals;Antigens Differentiation;Apoptosis;Apoptotic;Blood;Blood Cells;Blood Circulation;Body Size;Bone Marrow;Bone Marrow Stem Cell;CD34 gene;Cell Aging;Cell Count;Cell Cycle;Cell Separation;Cell physiology;Cell surface;Cells;Censuses;Condition;Disease;Flow Cytometry;Gene Expression;Genes;Hematopoietic stem cells;Hour;Human;Immune;Infant Newborn;Intervention;Learning;Length;Life;Longevity;MATK gene;Maintenance;Malignant Neoplasms;Marrow;Measures;Molecular;Molecular Target;Mus;Numbers;Organ;Organism;Pathway interactions;Pattern;Phenotype;Physiological;Population;Population Sizes;Process;RNA;Rate;Sorting - Cell Movement;Source;Stem cells;Stress;Telomerase;Testing;Time;Tissues;Umbilical Cord Blood;age related;base;cell age;comparative;cytokine;day;expectation;falls;gastrointestinal epithelium;human stem cells;insight;interest;man;middle age;size;telomere


application_id: 7272599
project_number: 1R41AA016499-01A1
project_title: Transdermal Cannabidiol Delivery for Alcohol-Induced Neurodegeneration
administering_ic: NIAAA
award_notice_date: 2007-09-30
opportunity_number: PA-06-121
application_type: 1
activity_code: R41
ic: AA
serial_number: 016499
suffix: A1
program_official: NORONHA, ANTONIO
project_start_date: 2007-09-30
project_end_date: 2009-05-31
study_section: Special Emphasis Panel[ZRG1 MDCN-L (10)]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Treatment of alcohol use disorders (AUDs) commonly referred to as alcoholism has been hampered by alcohol's promiscuous pharmacological effects and the complex etiology of addiction. People drink in excess for a variety of reasons and an approach that targets more of these reasons will have greater commercial success than an approach that only targets a sole aspect. Excessive consumption of alcohol results in many changes in the brain that contribute to the development of addiction including progressive neurodegeneration and impaired executive function and dependence that leads to withdrawal-induced negative affect. However of the three drugs currently approved by the FDA for the treatment of excessive alcohol consumption none address neurodegeneration withdrawal or anxiety. Whereas recently success has been seen in a class of drugs that are neuroprotective in many neurodegenerative disease models the cannabinoids. Intriguingly this class of drugs and specifically cannabidiol (CBD) also has anticonvulsant (withdrawal) and anxiolytic properties that make it an ideal candidate for the treatment of AUDs. The cannabinoid class of compounds has been minimally studied because of the lack of a suitable drug delivery method. Oral delivery of drugs is usually the preferred administration route however the oral bioavailability of CBD is only about 6%. Therefore the transdermal delivery route will be used in order to provide substantial plasma CBD levels with the added convenience of controlled release delivery. This proposal will test the overall hypothesis that transdermal delivery of a cannabinoid cannabidiol may protect against alcoholic neural and behavioral pathologies by determining (1) if transdermal delivery of cannabidiol can prevent alcohol-induced neurodegeneration in an established rat model of binge drinking. In this aim we will refine transdermal delivery of CBD and examine its effects on both cell death via examination of Fluoro-Jade B labeling of degenerating cells and cell birth via examination of labeling of neural progenitor/stem cell proliferation and (2) whether transdermal delivery of cannabidiol can prevent alcohol-induced behavioral pathology in a rat model of binge drinking. Behavioral pathologies associated with AUDs include preoccupation with the drug (perseveration) and negative affect (anxiety) as the result of withdrawal from the drug. Both behaviors may then drive drug seeking to alleviate these symptoms and thus are leading candidates as targets of relapse prevention. Therefore in this aim we examine the effect of transdermal delivery of CBD on withdrawal severity including seizures withdrawal- induced anxiety on the Elevated Plus Maze and perseverative behavior on the Morris Water Maze following binge alcohol exposure. With over 8.5% of the population meeting the diagnostic criteria for alcohol use disorders (AUDs) alcohol use and abuse are one of the nation's major public health problems. Currently approved pharmacological treatments have only targeted the craving aspect of addiction an approach that has failed a large portion of alcoholics. Thus the treatment of alcoholism would benefit from a pharmacological approach designed to target multiple aspects of alcoholism: neurodegeneration withdrawal and anxiety. Cannabidiol administration in the appropriate delivery system has these benefits as a lead candidate in the search for novel alcoholism pharmacotherapies.

project_terms:
Address;Adverse effects;Affect;Alcohol abuse;Alcohol consumption;Alcohol withdrawal syndrome;Alcoholic Intoxication;Alcoholism;Alcohols;Anti-Anxiety Agents;Anticonvulsants;Anxiety;Behavior;Behavioral;Biological Availability;Birth;Brain;Bypass;Cannabidiol;Cannabinoids;Cell Death;Cell Death Inhibition;Cell Proliferation;Cells;Class;Clinical Trials;Clinical Trials Phase I;Cognitive deficits;Complex;Dependence;Development;Diagnostic;Disease model;Dose;Drug Delivery Systems;End Point;Ethanol;Etiology;Gel;Genetic;Heavy Drinking;Intake;Intoxication;Investigational New Drug Application;Label;Lead;Metabolism;Methods;Modeling;Naltrexone;Nerve Degeneration;Neurodegenerative Disorders;Neuroprotective Agents;Oral;Pathology;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Plasma;Play;Population;Process;Property;Rattus;Relapse;Research;Rewards;Role;Route;Seizures;Severities;Stem cells;Symptoms;System;Testing;United States Food and Drug Administration;Week;Withdrawal;acamprosate;addiction;alcohol abuse therapy;alcohol exposure;alcohol reward;alcohol use disorder;alcoholism pharmacotherapy;binge drinking;controlled release;craving;design;drinking;drug withdrawal;executive function;fluoro jade;gastrointestinal;morris water maze;neurogenesis;neurotoxicity;novel;prevent;prevention of later incidences of a disorder;problem drinker;progenitor;progressive neurodegeneration;prototype;public health medicine (field);relating to nervous system;success;theories


application_id: 7272176
project_number: 1R43AR055014-01
project_title: Nonsurgical Exogenous Crosslink Therapy for Intervertebral Disc Disease
administering_ic: NIAMS
award_notice_date: 2007-08-14
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: AR
serial_number: 055014
program_official: PANAGIS, JAMES S
project_start_date: 2007-08-15
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (10)]
contact_pi_person_id: 6575299
contact_pi: HEDMAN, THOMAS P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 602492451
duns_number: 602492451
fips: US
organization_id: 10009769
organization_name: ORTHOPEUTICS, LP
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111285
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-15
budget_end_date: 2008-01-31
project_abstract:
DESCRIPTION (provided by applicant): Degenerative disc disease and associated spinal instability are the major cause of chronic low back pain in western civilization. Surgical options including artificial discs have been disappointing and only a very small percentage of back pain sufferers (~1 in 20) elect to have surgery. The specific aims of this program focus on the design of a nonsurgical tissue engineering solution that would become the first line of therapy for degenerative disc disease. Orthopeutics' key innovation is the use of nontoxic injectable agents that increase collagen crosslinking in the extracellular matrix of the disc annulus fibrosus mimicking the body's own efforts to stabilize aged and mechanically unstable discs. Preliminary in vitro studies which form the basis of this Phase I proposal show a 2 to 3-fold improvement in durability a 4-fold improvement in joint stability and doubled nutritional supply/waste removal to center of the disc. In vivo proof of concept studies have demonstrated a mild treatment effect with no significant histological changes in the annulus fibrosus. This Phase I study will characterize several candidate reagents with regard to crosslinking effect and diffusive transport using an ex vivo bovine/porcine disc model. Crosslinking effect will be assessed through mechanical testing thermal analysis and protease digestion. Diffusive transport will be assessed through time lapse visualization studies using dyes of representative molecular weights as well as mapping of treated discs using thermal analysis. A Phase II study of the most promising formulation would focus on optimizing reagent activity durability of effect and safety; and developing a product suitable for human clinical trials.   
Back pain and disability associated with spinal degeneration and instability is one of the costliest and most prevalent health problems. Between 4.7 percent (medical records) and 9.4 percent (population surveys) of the US population seeks professional health care annually (1990) for low back pain a prospective patient population in excess of 15 million/year. In the face of this great unmet clinical need the development of regenerative medicine techniques to reverse the process of spinal disc degeneration has been recognized as an important research opportunity by NIAMS.

project_terms:
Address;Area;Back Pain;Bioflavonoid;Blood;Bos taurus;Carbodiimides;Cattle;Cerebrospinal Fluid;Cerebrum;Chronic low back pain;Civilization;Clinical;Clinical Trials;Clinical Trials Phase I;Clinical Trials Phase II;Collagen;Compatible;Development;Diagnostic Procedure;Diffusion;Digestion;Disease;Dyes;Endopeptidases;Environment;Evaluation;Excision;Extracellular Matrix;Face;Family suidae;Fatigue;Formulations Drug;Government;Half-Life;Health;Health Professional;Human;Imagery;In Vitro;Injectable;Injection of therapeutic agent;Inpatients;Internist;Intervertebral disc structure;Joints;L-threose;Low Back Pain;Maps;Mechanics;Medical Records;Methods;Modeling;Molecular Weight;Nutritional;Operative Surgical Procedures;Outpatients;Pain management;Patients;Peptide Hydrolases;Permeability;Persons;Phase;Population;Preparation;Proanthocyanidins;Procedures;Process;Purpose;Pyruvaldehyde;Range;Reagent;Recombinants;Regenerative Medicine;Research;Resistance;Risk;Safety;Site;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Solutions;Spinal;Spinal Fusion;Standards of Weights and Measures;Sterility;Sterilization for infection control;Structure;Surgeon;Techniques;Testing;Time;Tissue Engineering;Transglutaminases;United States Food and Drug Administration;aged;base;biomaterial compatibility;cofactor;concept;cost;crosslink;design;disability;geniposide;in vitro Model;in vivo;innovation;population survey;programs;prospective;radiologist;success;sugar;surfactant;treatment effect;usability;wasting


application_id: 7271321
project_number: 5R01GM064606-04
project_title: Regulation of HSF1 and HSF2 by SUMO-1 Modification
administering_ic: NIGMS
award_notice_date: 2007-08-02
application_type: 5
activity_code: R01
ic: GM
serial_number: 064606
program_official: ANDERSON, JAMES J
project_start_date: 2003-08-01
project_end_date: 2009-07-31
study_section: Physiological Chemistry Study Section[PC]
contact_pi_person_id: 7875217
contact_pi: SARGE, KEVIN D
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: 2007-08-01
project_abstract:
DESCRIPTION (provided by applicant):   The long-term goal of this application is to elucidate the mechanism(s) that regulate stress-induced and constitutive expression of heat shock proteins (hsps) which are critical not only for the cell's ability to survive exposure to stress conditions but also for normal protein folding in non-stressed cells. The stress-inducible vs. constitutive activities of the transcriptional regulatory proteins HSF1 and HSF2 are critical for this stress-activated and basal hsp gene expression but how their differentially-regulated activities are controlled is unknown. In the search for this mechanism we have identified differential regulation of SUMO-1 modification of HSF 1 and HSF2 leading to stress-induced and constitutive activation respectively. We propose that SUMO-1 modification of HSFs is pre-requisite for their transcriptional activities at the levels of their ability to interact with promoters of hsp genes (DNA-binding activities) for assembly of transcription complexes with other factors on these promoters (transactivation potential) and for their protection against degradation. In this application we will 1) determine the functional consequences of SUMO-1 modification for the DNA-binding and transactivation activities of HSF 1 and HSF2 2) characterize the role of this modification in regulating the turnover of HSF1 and HSF2 and 3) identify the mechanism(s) which mediate the differential regulation of stress-induced vs. constitutive SUMO-1 modification of HSF1 and HSF2 determine the significance of HSF sumoylation for protein misfolding in vivo and determine whether sumoylation of HSFs is altered by cellular aging. Results from the proposed studies will define the basis of the differential regulation of HSF 1 and HSF2 leading to stress-induced and constitutive expression of heat shock proteins and may provide a strategy for manipulating cellular heat shock protein expression a promising potential treatment of diseases caused by protein misfolding/aggregation such as Parkinson's Huntington's and Alzheimer's Disease.

project_terms:
Affinity;Alzheimer's Disease;Binding (Molecular Function);Cell Aging;Cell Death;Cells;Complex;Condition;DNA Binding;DNA Binding Domain;Disease;Elements;Enzymes;Event;Exposure to;Fostering;Gene Expression;Genes;Goals;Heat shock proteins;Heat-Shock Response;Human;Huntingtin protein human;Huntington Disease;Lysine;Mediating;Modeling;Modification;Molecular;Molecular Chaperones;N-terminal;Nuclear;Parkinson Disease;Phosphorylation;Positioning Attribute;Proline;Promotor (Genetics);Proteins;Rate;Regulation;Relative (related person);Role;Serine;Site;Stress;Testing;Thinking function;Trans-Activation (Genetics);Transcription Factor TFIIB;Transcription Regulatory Protein;Transcription Genetic;Translating;UC01;Ubiquitin;Ubiquitination;base;caspase-3;cell age;heat shock transcription factor;heat-shock factor 2 human;in vivo;monomer;prevent;protein aggregation;protein expression;protein folding;protein misfolding


application_id: 7270778
project_number: 1R43AI071618-01A1
project_title: ApoVax104-HPV as a Novel Vaccine for Cervical Cancer
administering_ic: NIAID
award_notice_date: 2007-07-31
opportunity_number: PA-06-134
application_type: 1
activity_code: R43
ic: AI
serial_number: 071618
suffix: A1
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2007-07-31
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1 IMM-G (10)]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-31
project_abstract:
DESCRIPTION (provided by applicant):  Various cancer vaccines based on tumor associated antigens (TAAs) or tumor specific antigens (TSAs) have shown efficacy in preclinical models. However their therapeutic efficacies have been rather limited in clinical trial settings. Although the reason for clinical inefficacy for these vaccines is not known the lack of an adjuvant with potent immunostimulatory capacity ineffective delivery of TAAs/TSAs into professional antigen presenting cells (APCs) and/or the presence of significant immune evasion mechanisms may contribute to this effect. The main objective of this proposal is to develop a novel cancer vaccine for cervical cancer which overcomes these problems. The vaccine designated ApoVax104-HPV is based on the use of a proprietary formulation of the costimulatory ligand 4-1BBL designed to specifically deliver TAAs/TSAs to APCs. This vaccine formulation also activates APCs for the generation of an effective anti-tumor immune response with therapeutic efficacy. This novel proprietary molecule consists of 4-1BBL chimeric with core streptavidin and is based on the company's platform technology ProtEx(tm) invented by the co-investigator of this application Dr. Haval Shirwan. The ApoVax104 technology has been shown in preliminary studies to have potent immunostimulatory activity for T effector cells and inhibitory activity for T regulatory cells that are implicated in tumor growth. A vaccine formulation consisting of ApoVax104 conjugated with the human papillomavirus (HPV)-16 viral oncoprotein E7 will be generated and tested for its efficacy to induce an immune response in C57BL/6 mice. Successful completion of the proposed experiments will be the first step along the critical path for the development of ApoVax104 as the second-generation platform technology for ApoImmune. If ApoVax104-HPV proves effective in these initial proof-of-concept experiments the Company will apply for a Phase II SBIR grant to further develop ApoVax104-HPV into a lead commercial product to test in a Phase I clinical trial. In addition ApoVax104 vaccines may not only protect against cancer but also against infectious diseases leading to the development of an entire line of ApoVax104-based vaccines with significant potential in the millions of dollars. Immune system-based treatment of cancer represents an alternative therapeutic approach to classic chemotherapy and radiation treatment and promises to yield a more definitive solution based on a true molecular approach to cancer. ApoImmune's novel immune system-based therapy ApoVax104 vaccine is a new innovative approach to treating cancer and malignant neoplastic diseases.


application_id: 7270361
project_number: 5R01DK071765-03
project_title: Mechanisms of S-adenosylmethionine in NASH
administering_ic: NIDDK
award_notice_date: 2007-07-27
application_type: 5
activity_code: R01
ic: DK
serial_number: 071765
program_official: DOO, EDWARD
project_start_date: 2005-09-15
project_end_date: 2010-07-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-01
project_abstract:
DESCRIPTION (provided by applicant): S-adenosylmethionine (SAMe) is an important methyl donor and antioxidant. Depressed SAMe levels are observed in multiple forms of experimental liver injury and SAMe therapy is an effective hepatoprotective agent in diverse forms of experimental liver injury. SAMe is available as a complementary and alternative medicine and is widely used to treat several forms of liver disease as well as depression. Likely therapeutic properties of SAMe include its effects on methylation antioxidant status mitochondrial function hepatocyte differentiation cytokine metabolism and/or antidepressive functions. In this proposal we will evaluate potential benefits of SAMe in an emerging major health problem in the U.S. non-alcoholic steatohepatitis (NASH). While the etiology of NASH still remains unclear most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation fibrosis or necrosis in order to develop NASH. The focus of our research group has been the interactions of cytokines oxidative stress with lipid peroxidation and mitochondrial dysfunction in the induction of steatohepatitis both alcoholic and nonalcoholic in origin. Recent research from other laboratories also supports increased cytokine activity oxidative stress and mitochondrial dysfunction in the pathogenesis of NASH. Our long-term goal is to further understand mechanism(s) of action of SAMe in liver disease. In this proposal we will evaluate specific mechanisms of action of SAMe in the human liver disease NASH. This is not a clinical trial but a mechanistic translational study. The specific objectives for this proposal are: 1 .Evaluate mechanisms for dysregulated TNF/cytokine production in patients with NASH and determine whether or not SAMe in vitro/ex vivo favorably modulates this abnormal cytokine metabolism; 2. Evaluate in vivo mechanisms of action of SAMe in NASH patients including antioxidant status cytokine metabolism liver function and quality of life issues; 3. Determine whether or not hepatic methyltransferases are decreased in NASH and improve with SAMe therapy; and 4. Determine by proteomic analysis of serum and liver biopsies the proteins (esp. oxidative stress oxidized and mitochondrial proteins) that may play a role in the diagnosis or etiology of NASH and which may be modified by SAMe therapy

project_terms:
Alcohol consumption;Amiodarone;Antioxidants;Body Weight decreased;Choline Deficiency;Classification;Clinical;Clinical Trials;Coin;Complementary and alternative medicine;Depressed mood;Development;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Diagnosis;Enzymes;Ethanol;Etiology;Evolution;Female;Fibrosis;Goals;Grants Applications;Health;Hepatic;Hepatitis Alcoholic;Hepatocyte;Hepatoprotective Agent;Human;Hyperlipidemia;Hypertension;In Vitro;Inflammation;Injury;Insulin Resistance;Knowledge;Laboratories;Lipid Peroxidation;Liver;Liver diseases;Liver neoplasms;Mental Depression;Metabolic;Metabolic syndrome;Metabolism;Methionine;Methylation;Methyltransferase;Mice Knockout;Mitochondria;Mitochondrial Proteins;Mus;Necrosis;Obesity;Operative Surgical Procedures;Organ;Oxidative Stress;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Polycystic Ovary Syndrome;Predisposition;Production;Property;Proteins;Proteomics;Protocols documentation;Quality of life;Research;Research Personnel;Role;S-Adenosylmethionine;Science of nutrition;Serum;Simulate;Steatohepatitis;Syndrome;TNF protein human;Tamoxifen;Therapeutic;Therapeutic Agents;Toxin;Translational Research;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;base;biopsy of liver;cytokine;diabetic;improved;in vivo;liver function;methionine adenosyltransferase;mitochondrial dysfunction;non-alcoholic;nonalcoholic steatohepatitis;problem drinker;programs;translational study


application_id: 7270125
project_number: 5R21AG026521-02
project_title: Oxidation of cysteine-proteases in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2007-02-28
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AG
serial_number: 026521
program_official: SUNEJA, SANOJ
project_start_date: 2006-08-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZRG1-CDIN-D(01)Q]
contact_pi_person_id: 3079616
contact_pi: GUTTMANN, RODNEY P
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease is the most common cause of dementia affecting nearly 18 million people worldwide and projected to double over the next 20 years. Without new and significant preventative or curative measures this growing problem will place a substantial burden on society in terms of both financial and emotional strains. Previous research has implicated over activation of thiol-proteases in AD progression. This is based primarily on the observation of an increased 'activation' state of various thiol-proteases in AD brain. However other data suggest that thiol-proteases are not fully proteolytically active and that inhibition of thiol-proteases is more likely to contribute to AD pathology. Thus there is an important discrepancy between the observed activation of thiol-proteases and their proteolytic activity in Alzheimer's disease. These contradictory findings regarding thiol-protease 'activation1 and thiol-protease 'activity' need to be resolved in order to move forward and determine the role of thiol-proteases in tau and Abeta accumulation as well as cell death/ dysfunction during Alzheimer's disease. To address this gap in our knowledge we will test the hypothesis that the 'activated' thiol-proteases are oxidatively inhibited at their active-site cysteines by specific oxidants in the hippocampus of Alzheimer's disease. Aim 1: Determine the activity of thiol-dependent proteases in Alzheimer's disease brain compared to age-matched controls within the vulnerable hippocampus and the non-vulnerable cerebellum. Based on our recently published work we will show that thiol-protease activity including calcium-dependent thiol-protease activity is oxidatively inhibited in the hippocampus of AD brain compared to age-matched controls. Because AD degeneration is progressive we will also determine the extent of thiol-protease oxidation over the progression of the disease using brain samples from various stages of Alzheimer's disease. Aim 2: Determine the oxidants responsible for thiol-protease oxidation in the hippocampus of AD brain. These studies will determine the extent of oxidation and the oxidants responsible for oxidation of active-site cysteines within individual thiol- dependent proteases in AD hippocampus. This hypothesis challenges an existing paradigm by suggesting thiol-protease activity in Alzheimer's disease is decreased (rather than increased) due to oxidation of the active site. The proposed research will have impact on future therapeutics involving anti-oxidant or protease inhibitor strategies in the treatment or prevention of Alzheimer's disease.

project_terms:
Address;Affect;Age;Alzheimer disease prevention;Alzheimer's Disease;Antioxidants;Area;Attention;Brain;Calcium;Calpain;Cell Death;Cerebellum;Condition;Conflict (Psychology);Cultured Cells;Cysteine;Cysteine Protease;Data;Dementia;Disease;Disease Progression;Emotional;Endopeptidases;Foundations;Functional disorder;Future;Hippocampus (Brain);In Vitro;Individual;Kentucky;Knowledge;Link;Measures;Neurodegenerative Disorders;Oxidants;Oxidation-Reduction;Oxidative Stress;Parkinson Disease;Pathology;Pathway interactions;Peptide Hydrolases;Predisposition;Protease Inhibitor;Published Comment;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Role;Sampling;Sites Active;Societies;Staging;Sulfhydryl Compounds;Testing;Therapeutic;Thinking function;Thiol Proteinases;Time;Universities;Work;abeta accumulation;base;experience;innovation;oxidation;tau Proteins


application_id: 7270108
project_number: 5R21AA015611-02
project_title: Matrix Metalloproteinases in Alcoholic Liver Injury
administering_ic: NIAAA
award_notice_date: 2007-04-25
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: AA
serial_number: 015611
program_official: RADAEVA, SVETLANA
project_start_date: 2006-08-01
project_end_date: 2009-05-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1861697
contact_pi: DEACIUC, ION
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Years of research on alcoholic liver disease (ALD) have clearly demonstrated the multifactorial nature of this disease and to date the list of factors that have been implicated as causative in the disease is still growing.  This is of no surprise because alcohol (ethanol) is a cytotoxic agent and as such is expected to affect many facets of liver cells' function. Therefore there is an ongoing necessity to search for novel aspects related to the mechanisms underlying ALD. This project's long-term objective is investigation into what may constitute yet another aspect of the disease mechanism(s): a potential role of matrix metalloproteinases (MMPs) in the development and progression of ALD. We postulate that MMPs play an important pathogenic role in the earlier phases of the disease by both mediating the transmigration of extrahepatic cells into the liver which in turn produce liver injury and by disturbing the liver structural architecture. If confirmed by experimental work this postulate may unravel a novel aspect of the disease mechanisms and bring into light a novel target for therapeutic interventions in ALD: the MMPs. This project has two specific aims:  1)To investigate the kinetics of expression of MMPs and their natural inhibitors tissue inhibitors of metalloproteinases (TIMP) in the liver of laboratory animals (mice treated with alcohol) from the onset of the disease and during its progression toward more advanced phases and 2) To investigate the effects of several synthetic inhibitors of MMPs on the occurrence and progression of ALD. These experiments will be performed on mice chronically fed alcohol to develop alcoholic liver injury resembling the ALD in humans. The data obtained will provide an enhanced insight into the mechanisms of ALD and may provide insights into novel therapeutic approaches of ALD.

project_terms:
Affect;Alcoholic Liver Diseases;Alcohols;Animals Laboratory;Architecture;Attenuated;Cell physiology;Cells;Chronic;Cytotoxic agent;Data;Development;Disease;Disease Progression;Enzymes;Ethanol;Extrahepatic;Hand;Hepatocyte;Human;Inhibition of Matrix Metalloproteinases Pathway;Injury;Investigation;Kinetics;Light;Liver;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediating;Mus;Nature;Onset of illness;Phase;Play;Proteins;Research;Role;Staging;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissue Inhibitor of Metalloproteinases;Tissues;United States Food and Drug Administration;Work;base;design;enzyme activity;feeding;inhibitor/antagonist;insight;mRNA Expression;novel;novel therapeutics;prevent;problem drinker;public health medicine (field);research study


application_id: 7269902
project_number: 5F31ES013360-04
project_title: Minority Predoctoral Fellowship program
administering_ic: NIEHS
award_notice_date: 2007-07-25
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: ES
serial_number: 013360
program_official: HUMBLE, MICHAEL C
project_start_date: 2004-08-01
project_end_date: 2007-09-30
study_section: Special Emphasis Panel[ZRG1-F10(29)L]
contact_pi_person_id: 6190682
contact_pi: NANEZ, ADRIAN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Benzo(a)pyrene (BaP) is a ligand for the aryl hydrocarbon receptor (Ahr) and a potent genotoxic carcinogen. Environmental exposure to BaP has been associated with tumorigenesis atherosclerosis and developmental deficits in several organ systems. The Ramos laboratory has recently shown that treatment of metanephric cultures with BaP is associated with Ahr-dependent disruption of nephrogenesis as evidenced by inhibition of glomerulogenesis and branching morphogenesis. Nephrogenesis is characterized by mesenchymal-to-epithelial transition and this process is regulated by the Wilm's tumor suppressor gene (Wt-1). Disruption of nephrogenesis by BaP involves interference with Wt-1 splicing and reductions in Wt-1 protein. Studies are proposed in this application to test the hypothesis that ligands of Ahr disrupt nephrogenesis in vivo by altering Wt-1 mRNA splicing. Aim 1 examines the impact of in utero BaP exposure on nephrogenesis and Wt-1 mRNA splicing. Aim 2 will determine the kinetic profiles of BaP-induced inhibition of nephrogenesis and altered Wt-1 splice variant expression. Aim 3 will characterize the mouse mesonephric M15 cell line as a model to evaluate downstream effects of increased -KTS/+KTS mRNA ratios.

project_terms:
Aryl Hydrocarbon Receptor;Atherosclerosis;Benzo(a)pyrene;Carcinogens;Cell Differentiation process;Cell Line;Complement;Cultured Cells;Development;Disruption;Embryonic Development;Environmental Exposure;Epithelial;Event;Exposure to;Fellowship Program;Genetic;Genotype;Goals;In Vitro;Kidney;Kinetics;Laboratories;Lead;Link;M15;Metanephric structure;Mice Knockout;Minority;Modeling;Molecular;Morphogenesis;Mus;Nephroblastoma;Nuclear;Organ Culture Techniques;Organism;Patient currently pregnant;Process;Protein Isoforms;Proteins;RNA Splicing;RNA Messenger;Regulation;Repression;Research;Role;System;Testing;Time;Tumor Suppressor Genes;Variant;Work;aryl hydrocarbon receptor ligand;body system;design;environmental chemical;epithelial to mesenchymal transition;gene function;genetic element;in utero;in vivo;interest;kidney cell;nephrogenesis;pre-doctoral;research study;transcription factor;tumorigenesis


application_id: 7269869
project_number: 5K01DK065039-05
project_title: Inhibition of NADPH oxidase by Anaplasma phagocytophila
administering_ic: NIDDK
award_notice_date: 2007-08-17
opportunity_number: PAR-02-065
application_type: 5
activity_code: K01
ic: DK
serial_number: 065039
program_official: ROY, CINDY
project_start_date: 2003-08-15
project_end_date: 2007-10-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 6434147
contact_pi: CARLYON, JASON A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Human granulocytic ehrlichiosis (HGE) is an emerging infection of the blood that results in leukopenia and thrombocytopenia. If left untreated the disease can manifest itself as severe neutropenia hypotension shock and may potentially be fatal due to myocarditis pancarditis or to opportunistic infections resulting from impaired host defense mechanisms. Recent evidence suggests that kidney and pancreas transplant recipients are at risk for contracting HGE. A. phagocytophila the etiologic agent of HGE persists within its mammalian host by colonizing neutrophils. Neutrophils are primary effector cells involved in phagocytosing and killing bacterial invaders. This bactericidal activity is partially dependent on the superoxide anion produced by the rapidly activatable multi-component enzyme NADPH oxidase. A. phagocytophila however utilizes multiple strategies to prevent superoxide anion production. It is established that the bacterium inhibits the mRNA expression of gp91phox a component of NADPH oxidase. Preliminary data presented here demonstrates that A. phagocytophila also prevents transcription of rac2 the key factor of NADPH oxidase. Aims 1 and 2 seek to define the mechanisms responsible for the inhibition of rac2 transcription. Evidence suggests that prior to preventing rac2 and gp91phox mRNA expression once inside the host cell A. phagocytophila initially inhibits activation of preformed NADPH oxidase components during invasion. Activation of Rac2 represents the initial integral step of NADPH oxidase assembly. Therefore Aim 3 will investigate whether A. phagocytophila inhibits Rac2 activation during invasion. Collectively these studies will decipher the complex means by which A. phagocytophila prevents the neutrophil respiratory burst. In addition these studies will lead to a more thorough understanding of neutrophil biology specifically he factors that regulate rac2 mRNA expression and NADPH oxidase activation.

project_terms:
Affect;Anaplasma phagocytophilum;Antibodies;Bacteria;Binding (Molecular Function);Biological Assay;Biology;Blood;CCAAT-Enhancer-Binding Proteins;Cell Line;Cell membrane;Cells;Complex;Contracts;Data;Disease;Effector Cell;Electrophoretic Mobility Shift Assay;Enzymes;Event;GTP Binding;Gdi2 protein mouse;Guanosine Diphosphate;Host Defense Mechanism;Human;Hypotension;Infection;Kidney;Killings;Lead;Left;Leukopenia;Mus;Myocarditis;NADPH Oxidase;Neutropenia;Opportunistic Infections;Pancreas;Pathogenesis;Phagocytosis;Production;Promotor (Genetics);RNA Messenger;Reporter;Respiratory Burst;Risk;Shock;Superoxides;Thrombocytopenia;Transcription Genetic;Transplant Recipients;bactericide;human granulocytic ehrlichiosis;mRNA Expression;migration;neutrophil;prevent;protein expression;transcription factor


application_id: 7269728
project_number: 1R43HL088760-01
project_title: Portable pneumatic driver for counterpulsation therapy
administering_ic: NHLBI
award_notice_date: 2007-07-17
opportunity_number: PA-06-120
application_type: 1
activity_code: R43
ic: HL
serial_number: 088760
program_official: MILLER, MARISSA A
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1 SBTS-E (10)]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-01
budget_end_date: 2008-07-31
project_abstract:
DESCRIPTION (provided by applicant): The incidence of congestive heart failure (CHF) is increasing worldwide with over one million new cases diagnosed annually. Over the past 30 years counterpulsation with an intra-aortic balloon pump (IABP) has been widely and successfully used as a short-term treatment for cardiac dysfunction. However counterpulsation is limited by its location within the descending thoracic aorta to short durations of therapy typically less than 14 days. To overcome this limitation Superficial Counterpulsation Research (SCR) Inc. has invented a novel system for extended application of counterpulsation therapy for heart failure. The system consists of a 32-ml counterpulsation device (CPD) that is designed to be implanted via a surface operation in the shoulder area (pacemaker pocket). The CPD a blood sac is anastamosed to the subclavian artery. A driver for controlling device inflation/deflation timing carried externally allowing complete patient mobility. Preliminary testing with a first generation prototype driver was conducted in mock circulation system and acute animal experiments to define driver performance characteristics. The driver was then re-designed to reduce size and weight improve force of counterpulsation delivery increase response to higher heart rates and extend device longevity. The CPD driver is in fabrication and ready for in vivo testing. The goal of this Phase I SBIR proposal is to compare the hemodynamic efficacy of the 32-ml CPD system (device and driver) to a 40- ml IABP system (catheter and driver). We will also demonstrate that engineering specifications of the new driver are met. This will be accomplished by completing the following specific aim: Aim-1: To demonstrate the efficacy of a 32-ml CPD driver in reducing ventricular afterload and augmenting diastolic perfusion to the heart and vasculature under a variety of clinically-relevant conditions - hypertension hypotension and heart failure. Our hypothesis is that the performance of the CPD system will be similar to a standard clinically-available IABP system. If successful in Phase II we will conduct driver reliability testing controller reliability testing and chronic in vivo testing to demonstrate the long-term effectiveness of the 32-ml CPD system. SCR Inc. (Louisville KY) is developing a novel mechanical device to treat early stage heart failure patients. The device can be implanted using a simple surgical procedure comparable to a pacemaker. Since comparable devices can only provide up to 2 weeks of support SCR is proposing to develop a portable pneumatic driver to provide up to two years of support.

project_terms:
Acute;Anastomosis - action;Animals;Area;Arrhythmia;Blood;Blood Circulation;Cardiac;Catheters;Characteristics;Chronic;Clinical;Condition;Coronary;Counterpulsation;Development;Devices;Diagnosis;Diastole;Early treatment;Economic Inflation;Effectiveness;Engineering;Evaluation;Experiments Animal;Functional disorder;Generations;Goals;Grant;Heart;Heart Failure Congestive;Heart Rate;Heart failure;Hypertension;Hypotension;Implant;Incidence;Intra-Aortic Balloon Pumping;Invasive;Location;Longevity;Mechanics;Modification;Myocardial;Numbers;Operative Surgical Procedures;Organ;Pacemakers;Patients;Performance;Perfusion;Peripheral;Phase;Physiological;Pump;Range;Recovery;Research;Shoulder;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Staging;Standards of Weights and Measures;Sternotomy;Structure of subclavian artery;Surface;System;Systole;Testing;Thoracic aorta;Time;Ventricular;Week;Weight;Workload;biomaterial compatibility;clinically relevant;day;design;heart rhythm;hemodynamics;improved;in vivo;novel;prototype;response;size;therapy duration;ventricular assist device


application_id: 7269723
project_number: 1R41AG030239-01
project_title: Development of a Diagnostic Test for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2007-06-04
opportunity_number: PA-06-121
application_type: 1
activity_code: R41
ic: AG
serial_number: 030239
program_official: BUCKHOLTZ, NEIL
project_start_date: 2007-06-15
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1 BDCN-A (11)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 614763006
duns_number: 614763006
fips: US
organization_id: 10010025
organization_name: SCOUT DIAGNOSTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402431805
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-15
budget_end_date: 2008-04-30
project_abstract:
DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective sensitive and specific biomarker of the disease particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this proposal is that levels of a novel protein-protein complex present in cerebrospinal fluid (CSF) are able to differentiate AD subjects from age-matched controls and subjects with non-AD neurologic disorders. In addition the biomarker complex appears to identify subjects with mild cognitive impairment (MCI) the earliest clinical manifestation of AD. Analysis of lumbar CSF from a small number of living probable AD and age-matched controls showed 100% sensitivity and 93% specificity in the identification of AD subjects. The proposed studies will enhance our understanding of the way in which the protein complex is generated and will further validate our initial findings by: 1) using Western blot analysis sequential immunoprecipitation and mass spectrometry to examine individual components of the protein complex in ventricular CSF from MCI LAD and age-matched control subjects; and 2) to quantify levels of the protein complex in small volumes of unprocessed CSF from autopsied MCI LAD and age-matched controls and lumbar CSF from living probable AD and age- matched controls using an enzyme linked immunoassay developed in our laboratory that is based on trapping one component of the complex and quantifying the other component. Together these studies will provide further validation of our preliminary findings and will provide support for wide scale testing of the protein-protein complex as an objective biomarker of AD and MCI. Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects.

project_terms:
4 hydroxynonenal;Acrolein;Affect;Age;Alzheimer's Disease;American;Amyloid beta-Protein Precursor;Antibodies;Autopsy;Binding Proteins;Biological Markers;Blotting Western;Buffers;Cause of Death;Cerebrospinal Fluid;Clinic;Clinical;Complex;Condition;Count;Coupled;Cuprozinc Superoxide Dismutase;Data;Development;Diagnosis;Diagnosis clinical;Diagnostic;Diagnostic Procedure;Diagnostic tests;Disease;Disease Progression;Electrophoresis;Elevation;Enzyme Immunoassay;Enzymes;Etiology;Fractionation;Frontotemporal Dementia;Future;Hippocampus (Brain);Immunoassay;Immunoprecipitation;Individual;Intervention;Interview;Laboratories;Legal patent;Lewy Body Disease;Life;Link;Lipid Peroxidation;Literature;Measures;Memory Disorders;Memory Loss;Methods;Modification;Molecular Weight;Nature;Nerve Degeneration;Numbers;Parahippocampal Gyrus;Parkinson Disease;Pathogenesis;Pathology;Peptides;Phase;Plasma;Population;Prealbumin;Primary Health Care;Process;Prostaglandins;Protein Processing Post-Translational;Proteins;Psyche structure;Range;Rate;Retinol Binding Proteins;Sampling;Scanning;Score;Senile Plaques;Sensitivity and Specificity;Series;Serotransferrin;Specificity;Specimen;Spectrum Analysis Mass;Staging;Staining method;Stains;Structure;Superoxide Dismutase;Supranuclear Palsy Progressive;Testing;Therapeutic Intervention;Thinking function;United States;Validation;Ventricular;amyloid pathology;base;beta-2 Microglobulin;carbonate dehydratase;copper zinc superoxide dismutase;crosslink;density;interest;link protein;mild cognitive impairment;nervous system disorder;neuroimaging;neuropsychological;novel;post gamma-globulins;pre-clinical;prevent;public health medicine (field);tau Proteins;two-dimensional


application_id: 7268974
project_number: 5P20RR018733-05
project_title: Center of Biomedical Research Excellence in Molecular Targets
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
program_official: CANTO, MARIA TERESA
project_start_date: 2003-09-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The University of Louisville Molecular Targets Center of Biomedical Research Excellence application (MTCOBRE) is focused on the identification of novel molecular targets for cancer therapy using the techniques of modern structural biology. The two major objectives of this proposal are to ensure the success of junior investigators who are members of the Molecular Targets Program at the University of Louisville and to discover new approaches to the therapy of cancer. The Specific Aims of the Molecular Targets COBRE application are to:  1. Foster successful independent research careers for each of the five principal investigators leading to independent R01 grants.  2. Further build our existing core facilities which will enhance the research capability of the five principal investigators and the other members of the program.  3. Continue to develop our Molecular Targets Program as a cohesive research program which will promote collaborative research projects and increase funding opportunities.  4. Develop an internationally and nationally recognized program which will attract the very best graduate students postdoctoral fellows and additional faculty.  5. Most importantly make discoveries leading to new and more effective treatments for patients with cancer.  The five related projects of this MT-COBRE application will address a broad spectrum of molecular targets. The specific problems being investigated are: 1) Characterization and manipulation of an inducible isoform of 6-phosphofructo-2-kinase (iPFK-2) a major controller of glucose metabolism in malignant cells. 2) Development and testing of small molecular antagonists of monocyte/macrophage migration inhibitory factor (MIF) recently found to play an important role in carcinogenesis. 3) Elucidation of the signaling mechanisms involved in the activation-dependent lipid signaling enzyme sphingosine kinase and its product sphingosine-l-phosphate in control of cell proliferation survival and migration. 4) Use of triplex forming oligonucleotides to target Bleomycin to the Her2/neu gene. 5) A crystallographer/biologist is being recruited to study molecular interactions important in the TRAF signaling pathway. The overarching theme of this program is the use of structural biology to develop novel strategies for therapy of neoplastic disease. We believe that these five projects along with those of the other members of the program represent a coherent approach to the application of modern structural biology to translational cancer research.


application_id: 7268952
project_number: 5R01DK046923-11
project_title: PROLACTIN AND BILE SECRETORY FUNCTION
administering_ic: NIDDK
award_notice_date: 2007-06-29
application_type: 5
activity_code: R01
ic: DK
serial_number: 046923
program_official: SERRANO, JOSE
project_start_date: 1994-05-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-B(04)M]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Lactation is a physiological state characterized by a 4-5-fold increase in energy demand and a 2-3-fold increase in food consumption to meet this demand. We have demonstrated a coordinated up-regulation of expression of the hepatic sodium/taurocholate cotransporter (ntcp) and bile salt export pump (bsep) and of the intestinal apical sodium-dependent bile acid transporter (asbt) during lactation in the rat. There is also a 3-fold increase in the size of the bile acid pool during lactation. We postulate that these increases function to enhance absorption of dietary lipids to meet the energy demands of the lactating dam and for incorporation into milk. However the increased bile acid pool occurs at times when expression of Cyp7a1 the major regulated enzyme in the synthesis of bile acids from cholesterol is decreased and ntcp expression is increased. We will test the following hypotheses: 1) hepatic expression of enzymes involved in the alternate bile acid synthesis pathway is increased at the time of maximal expansion of the bile acid pool; 2) the expanded bile acid pool leads to activation of FXR and increased hepatic expression of bsep and SHP; and 3) while increased expression of SHP leads to repression of Cyp7a1 prolactin-mediated activation of the Jak2/Stat5 signal transduction pathway activates ntcp and overrides SHP-mediated repression. Specific Aims designed to test these hypotheses will use control female and lactating rats at various times postpartum to characterize 1) the size and composition of the bile acid pool and in lipid and cholesterol absorption; 2) expression of bile acid transporters and key enzymes in the synthesis of bile acids from cholesterol and expression; 3) signaling pathways that regulate bile acid synthesis and transport. The lactating female is unique in terms of the high-energy demands; investigation in this model offers an opportunity for increased understanding of the regulation of cholesterol and bile acid homeostasis under stressful conditions. In addition to the need to understand the changes that potentially occur in nursing women this model may enable identification of new regulatory pathways not otherwise observed and which may be exploited for therapeutic purposes. The high burden of disease related to elevated cholesterol makes this a highly significant and compelling opportunity.

project_terms:
ASBT protein;Acids Bile;Apical;Bile Acid Biosynthesis Pathway;Bile fluid;Birth;Cholesterol;Cholesterol Homeostasis;Condition;Coupled;Cytochrome P450;Dietary Fats;Discipline of Nursing;Enterocytes;Enzymes;Female;Food;Goals;Grant;Hepatic;Hepatocyte;Homeostasis;Hydrophobicity;Intestines;Investigation;Laboratories;Lactation;Lipids;Liver;Mediating;Metabolic;Milk;Mixed Function Oxygenases;Modeling;Nutrient;Pathway interactions;Patient currently pregnant;Pattern;Physiological;Postpartum Period;Pregnancy;Process;Process of absorption;Production;Prolactin;Proteins;Pump;Purpose;RNA Messenger;RXR;Rattus;Regulation;Regulatory Pathway;Relative (related person);Repression;Salts Bile;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Sodium;Sterols;Testing;Therapeutic;Time;Transcriptional Activation;Up-Regulation (Physiology);Woman;bile acid binding proteins;bile acid transporter;burden of illness;cholesterol absorption;cholesterol transporters;concept;design;energy balance;food consumption;indexing;insight;protein expression;response;size;sodium-bile acid cotransporter;steroidogenic acute regulatory protein;transcription factor;vitamin D3 25-hydroxylase


application_id: 7268126
project_number: 5R21DK075473-02
project_title: Proteomic identification of diabetes biomarkers
administering_ic: NIDDK
award_notice_date: 2007-06-19
opportunity_number: PA-04-081
application_type: 5
activity_code: R21
ic: DK
serial_number: 075473
program_official: SECHI, SALVATORE
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-EMNR-K(90)S]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The central hypothesis to be tested in this proposal is that the development of Type 2 diabetes induces alterations in the protein composition of lipid rafts in monocytes and in lipoproteins. Furthermore we hypothesize that these changes will serve as biomarkers for both the development of diabetes (pre-diabetic to diabetic transition) and serve as biomarkers for the development of subsequent cardiovascular complications. The goal of this proposal is to elucidate proteins that are altered in monocyte lipid rafts and lipoproteins in patients with impaired glucose tolerance and newly diagnosed type 2 diabetics compared to patients with normal glucose tolerance. A unique aspect of this proposal is the use of pediatric patients. Type 2 diabetes has historically been an adult disease but unfortunately a large and growing number of children have type 2 diabetes. Although the mechanisms and progression of the disease appear similar in adults and children a major difference between adult and pediatric patients is that the pediatric patients do not have as extensive co-morbidities such as atherosclerosis renal failure and neuropathy. A major problem in identifying biomarkers for type 2 diabetes are confounds created by patients having multiple diseases and taking multiple medications. For the most part these confound is not a major problem in pediatric patients. For these reasons we have chosen to use pediatric patients. Three Specific Aims are proposed. Aim 1: To elucidate the complete proteome of lipid rafts in monocytes and in isolated lipoproteins (LDL and HDL) isolated from patients with normal glucose tolerance. Aim 2: To identify a subset of proteins that associate or disassociate with lipid rafts in monocytes and in lipoproteins (LDL and HDL) isolated from patients with impaired glucose tolerance. Aim 3: To characterize the proteome of lipid rafts in monocytes and in lipoproteins (LDL and HDL) isolated from newly diagnosed Type 2 diabetics.

project_terms:
Adult;Affect;Atherosclerosis;Biological Markers;Blindness;Cardiovascular Diseases;Cardiovascular system;Cell physiology;Child;Childhood;Development;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Disease;Disease Progression;Disruption;Goals;Heart Diseases;High Blood Pressure;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Inflammatory;Kidney Failure;Lipoproteins;Low-Density Lipoproteins;Membrane Microdomains;Modification;Morbidity - disease rate;Nerve;Neuropathy;Newly Diagnosed;Numbers;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Proteins;Proteome;Proteomics;Risk;Risk Factors;Role;Signal Transduction;System;Testing;cardiovascular disorder risk;diabetic;glucose tolerance;impaired glucose tolerance;macrophage;monocyte;non-diabetic;particle;stroke


application_id: 7267020
project_number: 5R01RR020357-04
project_title: Zebrafish Mutant Mapping Facility
administering_ic: NCRR
award_notice_date: 2007-07-13
opportunity_number: PAR-02-142
application_type: 5
activity_code: R01
ic: RR
serial_number: 020357
program_official: O'NEILL, RAYMOND R
project_start_date: 2004-08-01
project_end_date: 2009-07-31
study_section: Special Emphasis Panel[ZRG1-CDF-4(50)R]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to accelerate the identification of zebrafish genes discovered during mutagenesis screens. This proposal is in response to PAR-02-142 to develop "Tools for Genetic Studies in Zebrafish." A major focus of this PA is to use novel screens to identify mutants of interest. However an essential part of this effort is to identify the genes responsible for the novel phenotypes generated. While thousands of mutants already have been described only 167 genes are listed in the zebrafish database (ZFIN) for which mutations are known (although there are probably some not listed). The major reason for this is the time consuming nature of the positional cloning strategy that must be used. The major bottleneck in gene discovery by positional cloning is the need to do whole genome linkage mapping. This takes considerable resources and time as well as technical expertise. This goal of this proposal is to eliminate this bottleneck by setting up a high throughput mapping facility. The usual laborious task of screening sometimes hundreds of markers to find one that is linked to the mutation of interest will be accomplished in 2 days. This will be done using fluorescence sequencers to automate genotyping of SSLPs (short sequence length polymorphisms) that span the genome. The mapping will be done in two main stages. First an approximate location will be determined using bulk segregant analyses. Second once closely flanking markers are identified 500-1000 individual mutant embryos will be genotyped to identify the region containing the mutant gene. Third for a small number of mutants the genes will be identified. The core will map a minimum of 100 mutants per year and identify the gene in 5-10 although both these numbers are likely to increase dramatically once the genome sequence is completed. The service will be modular so that investigators can have the initial mapping phases done by the facility and then complete the mutant gene isolation in there own laboratories. This project will have considerable impact because it will greatly accelerate the discovery of genes that already have been shown to be models of human diseases. The facility is committed to full and open access and all data pertaining to mapping will be made available at publication. Given the importance of zebrafish as a model organism this facility will have an immediate impact on the rate at which mutant genes are discovered which will provide new insights into the genetic underpinnings of important biochemical pathways involved in disease.

project_terms:
Animal Model;Biochemical Pathway;Candidate Disease Gene;Chemicals;Chromosome Mapping;Chromosomes;Commit;Computer Retrieval of Information on Scientific Projects Database;Core Facility;DNA;Data;Databases;Disease;Dyes;Embryo;Event;Expertise Technical;Fees;Fluorescence;Funding;Genes;Genetic;Genome;Genotype;Goals;Grant;Individual;Inheritance Patterns;Internet;Label;Laboratories;Length;Link;Location;Maps;Modeling;Molecular;Mutagenesis;Mutation;Nature;Numbers;Parents;Phase;Phenotype;Polymerase Chain Reaction;Polymorphism Genetic;Publications;Publishing;Range;Rate;Reagent;Recombinants;Recombination Genetic;Research Personnel;Resolution;Resources;Rights;Screening procedure;Services;Site;Staging;Standards of Weights and Measures;Time;Tissues;Transfer Agreement;United States National Institutes of Health;Zebrafish;base;cost;day;gene discovery;genome sequencing;human disease;insight;interest;male;mutant;novel;positional cloning;programs;response;size;tool


application_id: 7266898
project_number: 5R44EY015584-03
project_title: Retina Implantation Instrument Kit
administering_ic: NEI
award_notice_date: 2007-06-07
opportunity_number: PA-06-006
application_type: 5
activity_code: R44
ic: EY
serial_number: 015584
program_official: WUJEK, JEROME R
project_start_date: 2004-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-F(12)]
contact_pi_person_id: 1893843
contact_pi: ARAMANT, ROBERT B
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 127181209
primary_uei: U9KYX2EZS585
duns_number: 127181209
uei: U9KYX2EZS585
fips: US
organization_id: 3904701
organization_name: OCULAR TRANSPLANTATION, LLC
organization_city: CRESTWOOD
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400148741
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to develop a retina implantation instrument kit that will allow: 1) retinal surgeons to harvest dissect and transplant sheets of undifferentiated fetal retinal tissue with its retinal pigment epithelium (RPE) and then transplant these cografts into the subretinal space 2) other transplant protocols for microchips and RPE/choroid patches and 3) delivery of encapsulated slow-releasing drugs or cell suspensions. The tools in the kit consist of an implantation instrument (a hand piece and nozzles that fit over mandrels) a special microscissors to allow easy harvest and dissection of consistently good preparations of retina/RPE sheets and a dilator probe to allow easier and more accurate insertion of the implantation instrument into the eye. Results of the Phase I research demonstrate the implantation instrument provides the precise handling and maneuverability required for the transplant procedure and that the nozzles can load and unload tissue without damage to either the cograft sheets or recipient eye. The goal of Phase II is to develop a production-ready retina implantation instrument kit suitable for clinical trials and commercial manufacture and perform testing in preparation for Food and Drug Administration (FDA) approval. A production-ready hand piece will be developed along with a standardized production process for disposable nozzles and mandrels for cograft implantation. In an extension of the design prototypes of nozzles/mandrels suitable for other applications will be developed. The other tools in the kit a furrowed-edge microscissors and a dilator probe will also be developed. Testing will then be performed in preparation for FDA approval. Following a Phase III effort that includes FDA approval and multi-center clinical trials a commercial retina implantation instrument kit will be available for transplant applications ranging from fetal cografts to microchips to RPE/choroid patches. Retinal diseases such as macular degeneration retinal dystrophies and retinitis pigmentosa (RP) afflict more than 8.5 million Americans. As the population ages this number will grow significantly and many people will suffer from vision loss due to degeneration of photoreceptors and/or RPE. With surgeons equipped with the versatile tools in this kit and trained in their use retinal transplantation will emerge as a near-term viable technique for the growing number of patients in need of vision preservation and restoration. Retinal diseases such as macular degeneration retinal dystrophies and retinitis pigmentosa afflict more than 8.5 million Americans. As the population ages this number will grow significantly and many people will suffer from vision loss due to degeneration of photoreceptors and/or retinal pigment epithelium. With surgeons equipped with the versatile tools in this kit and trained in their use retinal transplantation will emerge as a near- term viable technique for the growing number of patients in need of vision preservation and restoration.

project_terms:
Age;American;Biomedical Engineering;Blindness;Cells;Choroid;Clinical Trials;Delayed-Action Preparations;Dilator;Dissection;Encapsulated;Evaluation;Eye;Funding;Goals;Government;Hand;Harvest;Indigenous;Macular degeneration;Manuals;Marketing;Multi-Institutional Clinical Trial;Numbers;Patients;Persons;Phase;Photoreceptors;Population;Preparation;Preservation Biological;Procedures;Process;Production;Protocols documentation;Purpose;Range;Readiness;Research;Retina;Retinal;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Safety;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Staging;Stem cell transplant;Structure of retinal pigment epithelium;Surgeon;Suspension substance;Suspensions;Techniques;Technology;Testing;Tissues;Training;Transplantation;Undifferentiated;United States Food and Drug Administration;Vision;Vitamins;base;design;fetal;gene therapy;human subject;implantation;instrument;photoreceptor degeneration;prototype;restoration;retina implantation;retina transplantation;retinal progenitor cell;tool


application_id: 7266735
project_number: 3R01DE014142-05S1
project_title: Opportunistic Oral HSV-- Mechanisms of Reactivation
administering_ic: NIDCR
award_notice_date: 2006-07-28
opportunity_number: RFA-DE-00-002
application_type: 3
activity_code: R01
ic: DE
serial_number: 014142
suffix: S1
program_official: RODRIGUEZ-CHAVEZ, ISAAC R
project_start_date: 2001-08-01
project_end_date: 2008-11-30
study_section: ZDE1
contact_pi_person_id: 1883677
contact_pi: MILLER, CRAIG S
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION: (Provided by Applicant) Human Immunodeficiency Virus (HIV)                                  infection is characterized by recurrent oral disease caused by HSV-1. The           defining hallmark of HSV-1 is reactivation from latency. Following stress           (heat trauma ultra violet light etc.) viral transcription is induced             resulting in HSV-1 reactivation. The mechanism regulating the switch between        latency and reactivation is poorly understood. The broad objectives of this         proposal are to determine the viral gene sequences required for HSV-1               reactivation in vitro and in vivo during normal and compromised immune              function. The central hypothesis to be tested is that stress induced HSV-1          genes are critical for reactivation from latency. Aim one will test the             hypothesis that specific HSV-1 genes are induced by stress. Transient               transfection of neurally differentiated (ND)-PC12 cells and the firefly             lucifease (LUC) assay will be used to determine whether HSV-1 (i.e. alpha          genes: alpha 0 alpha 4 alpha 22 alpha 27 and alpha 47 beta genes: ul9          ul23 ul39 and the gamma gene ul48 and LAT) are transcriptionally induced by        heat stress and forskolin treatment in the absence of other viral gene              products. Aim 2 will identify cis elements that mediate stress responsiveness       of HSV-1 promoters using the LUC assay electrophoretic mobility shift assay        (EMSA) and DNA footprinting. Sequentially deleted constructs of HSV-1 promoters     will be analyzed for loss of stress responsiveness in the (ND)-PCI2 cells using     the LUC assay. Regions identified by standard competition and super shift EMSA     and foot printing will be assessed for stress responsiveness by mutational          analysis in the LUC assay. Aim 3 will test the hypothesis that stress response      elements in HSV-1 genes are required for reactivation in vitro and in vivo. The     cis regulatory elements of HSV-1 genes governing the stress response will be        mutated and introduced into the viral genome using recombination techniques.        Mutant viruses will be tested in parallel with the rescued virus and parental       virus in the PC12 cell culture model for quiescent HSV infection that was           developed during their previous NIH funding. Mutant viruses that maintain wild      type lytic growth properties and display at least 50 percent reduction in           reactivation phenotype will be tested in the immunocompetent and                    immunosuppressed mouse and rabbit eye models of reactivation to determine           whether altered reactivation in vitro correlates with that seen in vivo. The        coordinate sequential pattern of gene expression (immediate early early late)     of the parental mutant and rescued viruses during the establishment and            reactivation phases of quiescence will be analyzed by RT-PCR. These studies         will advance the understanding of the molecular biological principals that          govern the process of HSV-1 reactivation in immunocompetent and                     immunosuppressed individuals and could lead to the development of novel             antiviral agents that block reactivation in patients with Acquired                  Immunodeficiency Syndrome (AIDS).

project_terms:
DNA footprinting;HIV infections;PC12 cells;binding sites;biological signal transduction;disease /disorder model;gel mobility shift assay;gene expression;gene mutation;genetic promoter element;herpes simplex virus 1;human immunodeficiency virus;hyperthermia;immunosuppression;laboratory mouse;laboratory rabbit;latent virus infection;luciferin monooxygenase;mutant;opportunistic infections;polymerase chain reaction;protein binding;transcription factor;virus genetics;virus infection mechanism


application_id: 7266676
project_number: 3R01CA108696-03S1
project_title: An Appalchian Cervical Cancer Prevention Project
administering_ic: NCI
award_notice_date: 2006-07-24
opportunity_number: PA-02-169
application_type: 3
activity_code: R01
ic: CA
serial_number: 108696
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2004-09-01
project_end_date: 2008-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Despite its nearly preventable status 13000 new cases of invasive cervical cancer are diagnosed each year with 4600 deaths. While nationally women have experienced a 75% reduction in cervical cancer mortality in the past 5 decades rural Appalachian women continue to sustain low rates of Pap testing and disproportionately high cervical cancer rates. To reduce this cervical cancer burden experienced by middle aged and older Appalachian women we propose to undertake a community participatory tailored faith based intervention entitled "Faith Moves Mountains." While extensive literature has established the association between rural culture and religiosity aside from programs involving African-American churches surprisingly few scientifically based interventions have located disease prevention activities within the trusted sustainable rural religious institutions of rural Appalachia. To address this missed opportunity this project will develop a random stratified sample of 50 congregations with 600 participants to: (1) Examine the factors (both barriers and assets) that influence the use of Pap tests; (2) Administer a faith-based lay health advisor intervention that is community-participatory theoretically informed and culturally consistent; (3) Evaluate the efficacy of the intervention in a group-randomized experimental design. These 3 aims correspond to 3 phases a developmental ethnographically oriented phase; a community-participatory intervention phase; and a qualitative and quantitative evaluation phase. With a multidisciplinary team of social scientists community leaders physicians and cancer control experts the results from the proposed project will enable researchers and communities to better address the barriers that prevent rural women from receiving Pap tests and recommended follow-up care; draw on local community assets to promote the use of Pap tests; and establish a community-based model that can be extrapolated to other rural underserved communities for cancer prevention.

project_terms:
cancer prevention;cervical /vaginal smear;cervix neoplasms;clinical research;community;culture;early diagnosis;focus groups;geographic site;health care service utilization;human subject;information systems;interdisciplinary collaboration;interview;medically underserved population;religion;rural area


application_id: 7264707
project_number: 2R56AA013205-05
project_title: Response Signatures of Alcohol-Related Birth Defects
administering_ic: NIAAA
award_notice_date: 2007-05-29
application_type: 2
activity_code: R56
ic: AA
serial_number: 013205
program_official: HERELD, DALE
project_start_date: 2001-09-29
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1 BDA-A (02)]
contact_pi_person_id: 1866555
contact_pi: PISANO, M. MICHELE
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): Maternal alcohol use during pregnancy is a significant public health problem. It affects 1% infants and is the leading preventable cause of mental retardation. This project addresses the mechanisms of target organ susceptibility to prenatal alcohol exposure. Eye defects such as coloboma microphthalmia and optic nerve hypoplasia are a cardinal feature of the Fetal Alcohol Syndrome (FAS) and reflect lesions induced by maternal alcohol exposure during early development. Our hypothesis states that mitochondria react to alcohol-induced oxidative stress by invoking a conserved checkpoint for developmental plasticity. The checkpoint fine-tunes cellular remodeling but may disrupt morphogenetic remodeling under stressful conditions. The signal is started by the mitochondrial Bzrp/TspO protein an oxygen-sensing signal generator and recasts signaling networks. Receptor-mediated cell adhesion pathways appear most sensitive; as such mitochondria intercept the flow of molecular regulatory information between nucleus and cell surface. Preliminary studies show that the C57BL/6J background (B6J) is at high risk for alcohol-induced eye defects whereas the C57BL/6N background (B6N) carries a low risk. B6J embryos are protected from alcohol-related eye defects with PK11195 a potent pharmacological ligand for Bzrp/TspO. Specific Aim 1 will determine if genetic predisposition to PK11195-responsive eye defects is linked to the maternal disposition for Fetal Alcohol Syndrome in pregnant mice. Specific Aim 2 will establish a causal link between Bzrp/TspO and alcohol-induced eye defects using genetic (B6J B6N) pharmacological (PK11195) and molecular (antisense) manipulation in whole embryo culture. Specific Aim 3 will identify microRNA (miRNA) signatures for receptor-mediated cell adhesion systems altered during the pathogenesis of alcohol-induced eye defects. Specific Aim 4 will sustain 'Birth Defects Systems Manager' (BDSM) as an ongoing bioinformatics-knowledge management system to enable secondary analysis of relevant developmental and genomic data. Achieving these Specific Aims will lead to a better understanding of the disease risks associated with maternal alcohol consumption and can advance new diagnostics for individual susceptibility to alcohol-related birth defects in general and pediatric ophthalmic disorders in particular.

project_terms:
Address;Affect;Alcohol consumption;Alcohol-related birth defects;Alcohols;Animal Model;Benzodiazepine Receptor;Bioinformatics;Cell Adhesion;Cell Nucleus;Cell surface;Childhood;Coloboma;Condition;Congenital Abnormality;Data;Defect;Development;Disease;Embryo;Eye;Eye Development;Fetal Alcohol Exposure;Fetal Alcohol Syndrome;Genetic;Genetic Predisposition to Disease;Genomics;Individual;Infant;Information Resources Management;Intercept;Lead;Learning;Lesion;Ligands;Link;Mediating;Mental Retardation;MicroRNAs;Microphthalmos;Mitochondria;Molecular;Mus;Nature;Optic Nerve;Organ;Oxidative Stress;Oxygen;PK 11195;Pathogenesis;Pathway interactions;Patient currently pregnant;Peripheral;Pharmaceutical Preparations;Predisposition;Pregnancy;Proteins;Research Personnel;Risk;Risk Factors;Signal Transduction;Site;Specificity;Staging;System;Testing;alcohol exposure;disorder risk;embryo culture;malformation;novel;novel diagnostics;programs;public health medicine (field);receptor;research study;response


application_id: 7264257
project_number: 3R01CA102285-03S1
project_title: Role of MIF in Rb inactivation and Tumorigenesis
administering_ic: NCI
award_notice_date: 2006-07-26
application_type: 3
activity_code: R01
ic: CA
serial_number: 102285
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2004-07-01
project_end_date: 2009-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Many human cancers require the production of soluble growth factors for tumor initiation promotion and survival. These extracellular factors contribute to and promote most stages of tumor development. For example tumors of the mammary gland are strongly influenced by the activity of epidermal growth factor (EGF) receptor family members. EGF binding to its cognate receptor is thought to contribute to breast cancer cell cycle regulation by activating signaling pathways that facilitate cyclin D1 expression cyclin dependent kinase 4 or 6 (Cdk4t6) activation and ultimately retinoblastoma (Rb) inactivation. While Rb inactivation is critically important for oncogene-induced malignancies the nature of the signals induced by oncogenes to facilitate this are incompletely understood. We recently discovered that the pro-inflammatory cytokine migration inhibitory factor (MIF) is both necessary and sufficient for mitogen and oncogene-induced cyclin D1 transcription Cdk4 activity and Rb inactivation. Moreover our results reveal that MIF is strongly induced by tumor promoting oncogenes and cells from MIF-deficient mice are resistant to oncogene-induced  malignant transformation. Despite these findings more work is needed to investigate in detail the influence mechanism and effectors of MIFs contribution to Rb inactivation malignant growth properties and de novo tumorigenesis. We hypothesize that MIF promotes both normal and neoplastic cell growth by stimulating RhoA GTPase activity that leads to the activation of the canonical MAP kinase pathway and resulting in cyclin D1 transcription and Rb inactivation. To test the fundamentals of our hypothesis and fulfill the stated objectives of this application the following specific aims are proposed: 1) Examine the regulatory and effector requirements for MIF in cyclin D1 transcription focusing on Rho GTPase activated pathways; 2) Test the requirements for MIF in human breast carcinoma Rho activation cyclin D1 expression and Rb inactivation and; 3) Investigate the contribution and functional requirements for MIF in de novo mammary tumorigenesis. This work should contribute to a greater understanding of the physiologic and pathologic importance of soluble growth factors to cell cycle regulation and neoplastic processes and may reveal a novel target for future cancer therapies.

project_terms:
3T3 cells;MCF7 cell;athymic mouse;breast neoplasms;cyclin dependent kinase;cyclins;enzyme activity;gene induction /repression;genetic transcription;genetically modified animals;guanine nucleotide binding protein;mammary epithelium;migration inhibition factor;mitogen activated protein kinase;molecular oncology;neoplastic cell;neoplastic growth;neoplastic transformation;protein structure function;retinoblastoma;tumor suppressor genes


application_id: 7264055
project_number: 2R01DA013425-04A2
project_title: Naltrexone Prodrugs for Transdermal Delivery
administering_ic: NIDA
award_notice_date: 2007-04-10
application_type: 2
activity_code: R01
ic: DA
serial_number: 013425
suffix: A2
program_official: PARK, MOO KWANG
project_start_date: 2000-07-01
project_end_date: 2011-03-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L
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_terms:
6 beta-hydroxynaltrexone;Addiction Opiate;Adverse effects;Alcohol abuse;Alcohol dependence;Alcoholism;Amines;Carbamates;Carbonates;Cavia;Data;Databases;Diffusion;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Goals;Heating;Human;Hydrogen Bonding;In Vitro;Knowledge;Lead;Measures;Molecular;Molecular Weight;Mono-S;Naltrexone;Narcotic Antagonists;Opioid;Oral;Penetration;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Population;Prodrugs;Property;Rate;Recovery;Reporting;Research;Research Personnel;Rest;Series;Skin;Solubility;Solvents;Structure;System;Tablets;Therapeutic;United States;alcohol craving;carboxylate;clinical application;cost;craving;design;improved;in vivo;in vivo Model;lipophilicity;melting;problem drinker;research and development;tool


application_id: 7263026
project_number: 5T35HL071486-05
project_title: From Bench to Bedside: Introduction to Clinical Research
administering_ic: NHLBI
award_notice_date: 2007-07-06
application_type: 5
activity_code: T35
ic: HL
serial_number: 071486
program_official: SILSBEE, LORRAINE M
project_start_date: 2003-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-ICP(01)S]
contact_pi_person_id: 3133207
contact_pi: HORNUNG, CARLTON A
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant)The "From Bench to Bedside: Introduction to Clinical Research" is a 10-week summer program designed to introduce rising second and rising fourth year medical students to the challenges and rewards of patient-oriented population-based research. It is anticipated that introducing medial students to the field of clinical research early in their medical school education will be the most effective way of stimulating their interest in pursuing a career in clinical research. The program involves a series of lectures and didactic sessions given by members of the core faculty of the K30 sponsored Clinical Research Epidemiology and Statistics Training (CREST) Program and by other leading researchers at the UofL Health Science Center. In addition to formal instruction in epidemiology Biostatistics and the responsible conduct of research trainees participate in a research project under the direction of a team of mentors. The trainee's mentoring team is composed of a basic scientist a clinician scientist and a member of the CREST core faculty. Trainees will work in the laboratory of the basic science researcher and with the clinician scientist to see how basic science translates into clinical practice and with what consequences (i.e. costs and benefits) for the health of the population. The ultimate objective of the summer program is to recruit medical students into the joint MD-MSPH degree program within CREST or into the post MD masters and PhD training in the clinical investigation sciences.

project_terms:
Adverse event;Age;Ambulatory Care;Animals;Authorship;Basic Science;Belief;Bioethics;Biometry;Bioterrorism;Budgets;Cardiology;Cardiovascular Diseases;Career Choice;Case-Control Studies;Child health care;Class;Clinical;Clinical Data;Clinical Medicine;Clinical Research;Clinical Trials;Clinical Trials Design;Cohort Studies;Collection;Community Medicine;Complex;Cost-Benefit Analysis;Costs and Benefits;County;Databases;Development;Device or Instrument Development;Disadvantaged;Disease;Doctor of Philosophy;Drug Industry;Educational aspects;Endocrinology;Ensure;Epidemiologist;Epidemiology;Ethics;Ethics Committees Research;Evidence Based Medicine;Faculty;Family;Foundations;Funding;Genetic;Genetic Research;Geriatrics;Grant;Gray unit of radiation dose;Guidelines;Health;Health Policy;Health Sciences;Healthcare;Heart;Hematology;Hospitals;Hospitals Pediatric;Hour;Human;Institutes;Instruction;Intellectual Property;Internal Medicine;Investigation;Issues Ethical;Jewish follower of religion;Joints;Journals;Label;Laboratories;Laboratory Study;Laws;Lead;Learning;Legal patent;Length;Life;Literature;Logic;Marketing;Master of Public Health;Medial;Medical;Medicine;Mentors;Meta-Analysis;Methods;Monitor;National Research Service Awards;Nephrology;Neurology;Numbers;Occupations;Odds Ratio;Operative Surgical Procedures;Oral;Outcomes and Health Services Research;Paper;Patients;Pediatrics;Persons;Pharmaceutical Preparations;Philosophy;Physicians;Policies;Population;Population Attributable Risks;Principal Investigator;Process;Psychiatry;Publications;Publishing;Quality of Care;Quality of life;Quality Data;Randomized;Rate;Recording of previous events;Recruitment Activity;Regulatory Affairs;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Review Systematic (PT);Rewards;Rights;Risk;Risks Relative;Rotation;Running;Safety;Schedule;Schools Medical;Science;Science of Statistics;Scientist;Series;Social Sciences;Source;Students;Students Medical;Techniques;Testing;Time;Training;Training Programs;Translating;Travel;United States Agency for Healthcare Research and Quality;United States Food and Drug Administration;United States Health Resources and Services Administration;United States National Institutes of Health;Universities;Victoria Austrailia;Week;Women's Health;Work;animal facility;base;bench to bedside;career;clinical epidemiology;cooking;cost effectiveness;design;desire;experience;falls;health economics;human subject;interest;lecturer;lectures;member;oncology;patient oriented;patient safety;posters;programs;prospective;public health medicine (field);rehearsal


application_id: 7262455
project_number: 7R34MH073071-03
project_title: Outcomes of Teacher Training on Autism
administering_ic: NIMH
award_notice_date: 2007-07-31
opportunity_number: PAR-03-078
application_type: 7
activity_code: R34
ic: MH
serial_number: 073071
program_official: MARRO, MARY ACRI
project_start_date: 2005-09-15
project_end_date: 2009-07-31
study_section: Services Research Review Committee[SRV]
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 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 EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed project is pilot research aimed at developing "novel service delivery models designed to target children with complex comorbid and/or chronic conditions in school and community-based settings." It is timely and responds to the National Institute of Mental Health PA: PAR-03-078 "From intervention development to services: Exploratory research grants"1 and a concern of the lag between research and practice for children with autism. This gap is significant because of the increasing numbers of children with autism identified by public service agencies and a lack of trained community and school-based personnel. The proposed study will evaluate the effects of an innovative treatment approach for children with autism who participate in community-based public school programs. Guidelines of effective practice and recommendations for research generated by the National Research Council (NRC) in 2001 are incorporated. Caregiver teacher and school variables as well as child effects will be evaluated. The evaluation of this intervention is longitudinal and focuses on important child outcomes over a period of one school year as well as parent/caregiver and teacher outcomes. The aims of this proposal are: (1) To generate pilot data and effect size estimates of the impact of a child-specific consultation approach (COMPASS) vs. "usual" educational program development practice by prospectively following a random sample of 60 children whose teachers received COMPASS and whose teachers did not receive COMPASS and (2) to generate pilot data of additional factors (school organization teacher parent and child) that may account for variance in teacher child and family outcomes.

project_terms:
Accounting;Autistic Disorder;Behavior;Behaviors Adaptive;Caregivers;Child;Chronic;Collaborations;Communities;Complex;Condition;Consultations;Data;Development;Educational aspects;Evaluation;Family;Funding;Goals;Guidelines;Human Resources;Intervention;Knowledge;Language;Leadership;Modeling;National Institute of Mental Health (U.S.);National Research Council (U.S.);Numbers;Outcome;Parents;Process;Program Development;Randomized;Recommendation;Research;Research Personnel;Research Project Grants;Sampling;School Health Services;Schools;Services;Severities;Stress;Teachers School;Training;base;demographics;design;improved;innovation;model design;novel;programs;response;size;teacher;therapy development;treatment planning


application_id: 7262438
project_number: 5R01CA113371-04
project_title: Biochemical basis of WRN and RecQ helicase function
administering_ic: NCI
award_notice_date: 2007-08-01
application_type: 5
activity_code: R01
ic: CA
serial_number: 113371
program_official: PELROY, RICHARD
project_start_date: 2004-08-10
project_end_date: 2009-10-31
study_section: Special Emphasis Panel[ZRG1-CMAD(01)Q]
contact_pi_person_id: 7034221
contact_pi: ORREN, DAVID KEITH
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: 2007-08-01
project_abstract:
DESCRIPTION (provided by applicant): RecQ helicases act to maintain genomic stability by an as yet unknown mechanism. When their function is lost levels of illegitimate recombination increase significantly. Not surprisingly the human hereditary RecQ deficiency diseases (Werner Bloom and Rothmund-Thomson syndromes caused by defects in WRN BLM and RECQL4 respectively) demonstrate early onset and increased frequency of cancer. Importantly Werner syndrome also shows accelerated development of many age-related problems. Although these diseases have distinct phenotypes RecQ family members maintain a high degree of homology within and C terminal to the conserved central helicase domain suggesting that they may have a common mechanistic function and/or DNA substrate specificity. We refer to this extended sequence conservation as the RecQ expanded core. Their illegitimate recombination phenotypes suggest that RecQ helicases function in recombination or anti-recombination pathways or possibly in resolution of replication fork blockage. Our laboratory has recently uncovered strand pairing and strand exchange activities in WRN and other RecQ helicases consistent with putative roles in these pathways. We hypothesize that the RecQ expanded core forms a functional unit that encompasses DNA binding and catalytic activities. Further we propose that the function of the RecQ expanded core is to coordinate DNA binding and unwinding to achieve strand exchange reactions in complex recombination or replication intermediates. This hypothesis fits with the putative roles for RecQ members and current biochemical knowledge regarding these proteins. In this proposal WRN is used as a model RecQ helicase for 1) characterizing strand exchange activity reflecting putative coordination between strand pairing and unwinding activities 2) examining DNA binding properties and substrate specificity for replication and recombination intermediates and 3) generating site-directed mutants that pinpoint the DNA binding enzymatic and physiological functions of the RecQ expanded core and its individual domains. Our findings with WRN will be highly relevant to elucidating its DNA metabolic role and specific mechanisms underlying carcinogenesis and certain aging phenotypes. Sequence conservation between RecQ helicases also indicates that our findings will be applicable to the functions of other RecQ helicases (including BLM and RECQL4) and their relationships to human health.

project_terms:
Affinity;Age;Aging;Bacteria;Binding (Molecular Function);Biochemical;C-terminal;Cells;Complex;DNA;DNA Binding;DNA Damage;DNA Sequence;Defect;Deficiency Diseases;Development;Disease;Enzymes;Family member;Frequencies (time pattern);Genome Stability;Genomic Instability;Health;Hereditary Disease;Human;Hypersensitivity;Incidence;Individual;Inherited;Joints;Knowledge;Laboratories;Length;Malignant Neoplasms;Metabolic;Metabolism;Modeling;Mutagenesis Site-Directed;Numbers;Pathway interactions;Phenotype;Physiological;Property;Proteins;RECQL4 gene;Reaction;Recombination Genetic;Research Personnel;Resolution;Role;Rothmund-Thomson syndrome;Site;Specificity;Substrate Specificity;WRN gene;Werner Syndrome;age related;base;carcinogenesis;early onset;helicase;in vivo;member;migration;mutant;programs;recombinational repair


application_id: 7262407
project_number: 5U19DA017548-05
project_title: Developmemt of Novel Treatments for Nicotine Addiction
administering_ic: NIDA
award_notice_date: 2007-06-21
opportunity_number: RFA-MH-03-008
application_type: 5
activity_code: U19
ic: DA
serial_number: 017548
program_official: RAPAKA, RAO
project_start_date: 2003-09-30
project_end_date: 2009-06-30
study_section: ZMH1-BRB-S(08)
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Tobacco smoking is the number one health problem accounting for more illnesses and deaths in the US than any other factor. Despite efficacy of some current pharmacotherapies (i.e. nicotine replacement and bupropion) relapse rates continue to be high indicating that novel medications are needed. Research in the current application proposes to develop a new class of subtype-selective nicotinic receptor (nAChR) antagonists as therapeutic agents with efficacy for tobacco use cessation and for treatment of nicotine dependence. As much as tobacco use behavior and nicotine addiction have links to depression these novel drug candidates may also prove to be new treatments for depression. Based on the observations that the bupropion acts as a nAChR antagonist and that the nonselective nAChR antagonist mecamylamine has some efficacy as a tobacco use cessation agent but is limited by its peripherally-mediated side-effect of constipation we predict that the subtype-selective nAChR antagonists which we propose to develop may have therapeutic advantages and efficacy as tobacco use cessation agents in the treatment of nicotine addiction. We hypothesize that quaternizing the pyridine-N atom of the nicotine molecule with a lipophillic N-substituent to afford N-nicotinium analogs and/or by connecting these quaternary ammonium moieties with a lipophillic linker to afford NN'-bis-analogs will result in subtype-selective nAChR antagonists which will inhibit either nicotine-evoked dopamine norepinephrine or serotonin release and thus inhibit nicotine-induced behaviors indicating their potential as nicotine addiction treatments. Brain bioavailability pharmacokinetics and metabolism of the lead candidates will also be evaluated. Comparison of results using native and recombinant nAChRs will provide new insights into the subunit composition of nAChRs mediating these functions. Drug candidates will be assessed for their ability to decrease nicotine self-administration to decrease nicotine-induced reinstatement of nicotine seeking behavior and to precipitate withdrawal in nicotine-dependent animals. Thus an integrative approach (i.e. medicinal chemistry pharmacokinetics metabolism pharmacology psychology and neuroscience) will be used to increase our understanding of the underlying mechanisms of tobacco use and nicotine addiction with focus on pharmacotherapeutic candidate development.

project_terms:
Accounting;Adverse effects;Ammonium;Animals;Area;Arts;Basic Science;Behavior;Behavioral;Behavioral Model;Biological Availability;Brain;Bupropion;Cessation of life;Chemistry Pharmaceutical;Class;Communities;Conceptions;Constipation;Consultations;Data;Dependence Nicotine;Development;Discipline;Dopamine;Drug Discovery Groups;Drug Kinetics;Drug abuse;Environment;Evaluation;Experimental Designs;Faculty;Generations;Goals;Grant;Health;Human Resources;Individual;Intellectual Property;Internet;Investigation;Journals;Kentucky;Laboratories;Lead;Learning;Link;Mecamylamine;Mediating;Mental Depression;Metabolic;Metabolism;Mood Disorders;Neurosciences;Nicotine;Nicotinic Receptors;Norepinephrine;Numbers;Operative Surgical Procedures;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Protocols Treatment;Psychology;Publications;Rate;Recombinants;Relapse;Research;Research Personnel;Research Project Grants;Research Evaluation;Resources;Route;Science of neurochemistry;Self Administration;Serotonin;Site;Structure;Students;Teleconferences;Testing;Therapeutic;Therapeutic Agents;Tobacco Use Cessation;Tobacco smoking;Tobacco use;Translations;Travel;United States National Institutes of Health;Universities;Withdrawal;Withholding Treatment;Work;analog;base;data integration;day;dosage;drug discovery;innovation;insight;interdisciplinary collaboration;metabolic abnormality assessment;molecular modeling;nicotine replacement;novel;novel strategies;pre-clinical;prevention of later incidences of a disorder;programs;psychopharmacologic;pyridine;research clinical testing


application_id: 7262182
project_number: 3R01CA034627-21S1
project_title: Pharmacogenetics of drug and carcinogen metabolism
administering_ic: NCI
award_notice_date: 2006-09-05
application_type: 3
activity_code: R01
ic: CA
serial_number: 034627
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 1989-09-01
project_end_date: 2008-06-30
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
DNA damage;acetyl coA acetyltransferase;acetylation;adduct;biphenyl compounds;breast neoplasms;carcinogenesis;chemical carcinogen;cyclic amine;cytotoxicity;enzyme activity;gene environment interaction;gene interaction;genetic polymorphism;genetic susceptibility;genotype;human subject;laboratory rat;molecular cloning;nucleic acid purification;pharmacogenetics;polymerase chain reaction;smoking;tissue /cell culture;transfection /expression vector


application_id: 7261266
project_number: 5R01NS044157-05
project_title: Cox-2 deficient mice are resistant to MPTP neurotoxicity
administering_ic: NINDS
award_notice_date: 2007-06-04
application_type: 5
activity_code: R01
ic: NS
serial_number: 044157
program_official: REFOLO, LORENZO
project_start_date: 2003-07-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-4(01)S]
contact_pi_person_id: 7875115
contact_pi: BING, GUOYING
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc). Loss of SNpc dopaminergic neurons results in the depletion of striatal dopamine levels and produces symptoms such as tremor muscle rigidity and bradykinesia. The etiology of PD is unknown but chronic inflammatory processes microglial activation and oxidative stress are thought to play prominent roles in the degeneration of dopaminergic neurons in the SNpc. Microglia are thought to contribute to neurodegeneration by releasing cytotoxic agents such as pro-inflammatory cytokines and reactive oxygen species that increase inflammation and oxidative stress. N-Methyl-4-phenyl-1236-tetrahydropyridine (MPTP) is a neurotoxin found to mimic many of the features of PD in animal models including loss of dopaminergic neurons in SNpc and activation of microglia. Recent observations indicate that cyclooxygenase-2 (COX-2) deficiency in mice reduces the susceptibility of SNpc dopaminergic neurons to MPTP toxicity and diminishes MPTP-induced microglial activation. The purpose of this study is to test the hypothesis that COX-2-regulated inflammatory processes exacerbate MPTP neurotoxicity by activating microglia and increasing oxidative stress that contributes to the degeneration of dopaminergic neurons in the SNpc. To test this hypothesis mice deficient in the COX-2 gene will be treated with MPTP to determine the role of COX-2 in MPTP-induced neurodegeneration. Furthermore wild-type mice will be administered exogenous COX-2 inhibitors prior to MPTP treatment to evaluate the protective effects of COX-2 inhibitors against MPTP neurotoxicity. Following these experiments dopaminergic neuron survival microglial activation striatal dopamine levels and functional recovery will be assessed. In addition protein modification generation of reactive oxygen species expression of inflammatory cytokines and apoptosis-related genes and activation of specific signaling molecules will be evaluated to determine the molecular mechanisms by which COX-2 exacerbates MPTP neurotoxicity. The goals of this study are to elucidate the changes in inflammatory processing affected by COX-2 deficiency to explore the etiology and molecular mechanisms underlying Parkinsonian symptoms in the experimental MPTP model and to develop novel therapeutic treatments for PD and other neurodegenerative diseases.

project_terms:
Activation Gene;Affect;Agonist;Animal Model;Apoptosis;Attenuated;Behavioral;Blotting Western;Bradykinesia;Cell Death;Chromatography High Pressure Liquid;Chronic;Complex;Computer Systems;Corpus striatum structure;Coxibs;Cytotoxic agent;Data;Dopamine;Dopaminergic Cell;Endoribonucleases;Enzyme-Linked Immunosorbent Assay;Etiology;Generations;Genes;Goals;Inflammation;Inflammatory;Injection of therapeutic agent;Lead;MAPK14 protein human;Macrophage-1 Antigen;Measurement;Measures;Mediating;Microglia;Modeling;Molecular;Motor Activity;Movement Disorders;Mus;Muscle Rigidity;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotoxins;Optical Methods;Oxidative Stress;Pancreatic ribonuclease;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Peroxisome Proliferator-Activated Receptors;Phosphorylation;Play;Predisposition;Principal Investigator;Process;Protein Processing Post-Translational;Proteins;Purpose;Reactive Oxygen Species;Recovery of Function;Resistance;Ribonucleases;Role;Signal Transduction Pathway;Signaling Molecule;Substantia nigra structure;Symptoms;Testing;Thinking function;Toxic effect;Tremors Muscle;Tyrosine 3-Monooxygenase;Wild Type Mouse;behavior measurement;cyclooxygenase 2;cytokine;dopaminergic neuron;improved;inhibitor/antagonist;mitogen-activated protein kinase p38;neurotoxicity;novel therapeutics;pars compacta;programs;protective effect;research study;response;stress-activated protein kinase 1


application_id: 7260348
project_number: 5R01HL070911-04
project_title: Sleep and Sleep Disorders in Children
administering_ic: NHLBI
award_notice_date: 2007-06-29
application_type: 5
activity_code: R01
ic: HL
serial_number: 070911
program_official: BLAISDELL, CAROL J
project_start_date: 2004-07-15
project_end_date: 2009-05-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1959297
contact_pi: MOLFESE, DENNIS L
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-01
project_abstract:
DESCRIPTION (provided by applicant): The goal of this research is to investigate the effects of sleep restriction and sleep prolongation on cognitive processes in preschool and school-age children as measured by event-related potentials (ERPs). Children throughout the USA frequently face mild sleep restrictions due to a host of pressures - demands of homework school activities peer interactions family activities - that reduce the number of hours of sleep children experience from day-to-day or week-to-week. Such changes can impact the child's ability to attend to classroom studies or other areas that place additional cognitive processing demands on the child. To pursue this goal 480 children half females from 4 through 8 years of age will participate in a number of cognitive tasks while their brain electrical activity is recorded. It is anticipated that changes in the topographic recordings of brain electrical patterns across the scalp will change as a function of sleep deprivation and sleep prolongation. Such changes will be characterized by latency shifts that reflect the rapidity in which the brain responds to information. Analyses will also attempt to localize the hypothesized sources within the brain where information is processed. This work will greatly enhance knowledge concerning the role sleep plays in brain and behavior and can lead to the development of a means to identify children potentially at cognitive risk because of chronic sleep restrictions. This is an important first step in minimizing potential negative risks of sleep restriction on cognitive development during the childhood years.

project_terms:
Academic achievement;Accounting;Acting Out;Address;Age-Years;Agitation;Area;Attention;Attention deficit hyperactivity disorder;Beds;Behavior;Behavior Control;Behavioral;Brain;Brain region;Child;Childhood;Chronic;Cognitive;Computer information processing;Condition;Control Groups;Country;Data;Decision Making;Development;Diffuse;Disease;Electrodes;Event-Related Potentials;Exhibits;Face;Family;Female;Figs - dietary;Goals;Grouping;Hour;Hyperactive behavior;Investigation;Knowledge;Lead;Learning;Link;Localized;Maps;Measures;Modeling;Monitor;Neurocognitive;Numbers;Organizational Change;Pattern;Physiological;Play;Pressure- physical agent;Process;Range;Reaction Time;Research;Research Personnel;Response Latencies;Restriction Mapping;Risk;Role;Scalp structure;School-Age Population;Schools;Schools Nursery;Science of neurophysiology;Series;Signal Transduction;Site;Sleep;Sleep Deprivation;Sleep Disorders;Source;Speech Perception;Time;Week;Work;awake;brain behavior;brain electrical activity;concept;day;density;design;experience;indexing;peer;response;skills;sleep regulation;social;social skills;success;voltage


application_id: 7260336
project_number: 5R01OH007650-05
project_title: Health Effects of Occupational Exposures in PGDP Workers
administering_ic: NIOSH
award_notice_date: 2007-07-30
application_type: 5
activity_code: R01
ic: OH
serial_number: 007650
program_official: KARR, JOAN
project_start_date: 2005-07-01
project_end_date: 2009-06-30
study_section: ZOH1-SPC(12)S
contact_pi_person_id: 1871961
contact_pi: TOLLERUD, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
The Paducah Gaseous Diffusion Plant (PGDP) is located in Western Kentucky about 10 miles west of the City of Paducah. It currently employs approximately 1700 workers; some 8000 individuals have worked at the plant since it was opened in 1952. The plant is located in a rural area adjacent to protected conservation wildlife and recreation areas. The primary function of the PGDP has been to produce enriched uranium for use by commercial reactors or as feed material for other plants that further enrich the uranium. Workers government officials and the surrounding community have raised concerns about potential health effects from current and past exposures at the plant. The studies proposed here will complete an ongoing mortality investigation to help address those concerns by combining work histories with historical exposure data to create an exposure metric for each worker at the plant throughout the history of the facility. In Specific Aim 1 we will validate the worker roster against other existing name lists and source documents. In Specific Aim 2 we will develop a comprehensive list of jobs and job historiesfor the workforce from paper records and electronic files. In Specific Aim 3 we will create a Job Exposure Matrix for chemical and radiation exposures throughout the history of the plant. In Specific Aim 4 we will link the Work History data with the Job Exposure Matrix to estimate individual worker exposure metrics. In Specific Aim 5 we will evaluate worker Mortality for relationships with workplace exposures usingstandardized mortality ratios and risk assessment approaches. In Specific Aim 6 we will communicate thestudy results to employees and management. The overarching goal of these investigations is to evaluate the impact of historical exposures on worker mortality. The PGDP is the only remaining gaseous diffusion plant in the US that has not undergone a comprehensive occupational health study. The data generated by the PGDP investigations will be available to merge with the two prior studies at the Portsmouth and Oak Ridge gaseous diffusion plant facilities. The Paducah data will add substantially to the statistical power of the combined database to address the pressing health concerns of uranium enrichment workers.


application_id: 7259944
project_number: 3R01DA002243-29S1
project_title: Degradation of Opioid Peptides
administering_ic: NIDA
award_notice_date: 2006-07-20
application_type: 3
activity_code: R01
ic: DA
serial_number: 002243
suffix: S1
program_official: RAPAKA, RAO
project_start_date: 1978-09-30
project_end_date: 2007-02-28
study_section: Special Emphasis Panel[ZRG1]
contact_pi_person_id: 7875201
contact_pi: HERSH, LOUIS B
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION(From applicant's abstract):                                             The long range objective of this project is to develop methods to modulate          opioid peptide action through the peptidases which inactivate them. A recent        effort has been made to develop a method to isolate endogenous substrates for       metallopeptidases. The enkephalin degrading puromycin sensitive aminopeptidase      is the initial system to be studied. Mutations which eliminate catalytic            activity while having little effect on binding will be introduced into this         aminopeptidase. Immobilized mutant enzyme will then be used as an affinity          matrix to isolate endogenous substrates and inhibitors from tissue extracts.        This technology will be extended to two other zinc containing neuropeptidases      insulysin and nardilysin.                                                                                                                                               A second objective of this project will be to study a novel mechanism for           regulation of the peptidase nardilysin. This enzyme contains a unique acidic        domain which binds amines and either increases or decreases the reaction rate       dependent on the particular substrate. Preliminary evidence suggests that           nadilysin forms hetero-oligomers through binding to the acidic domain. We           propose to isolate the proteins which interact with nardilysin and to study         their effect on nardilysin activity as well as the activity of the interacting      protein(s).                                                                                                                                                             The third objective focuses on the isolation and characterization of a new          membrane enzyme which degrades -endorphin. This is the only membrane peptidase      which acts on -endorphin thus its tissue distribution and potential                physiological role(s) will be studied.                                                                                                                                  Lastly we will continue our work toward obtaining the three dimensional             structure of three of the neuropeptidases the puromycin sensitive                  aminopeptidase insulysin and nardilysin. Initial crystals of the                  aminopeptidase have been obtained. These structures will provide important          mechanistic information and should lead to the design of potent and selective       inhibitors which can be used to modulate peptidase activity.

project_terms:
Mammalia;X ray crystallography;aminopeptidase;binding proteins;dynorphins;endogenous opioid;endorphins;enzyme activity;enzyme substrate;molecular biology information system;neprilysin;neuropharmacology;protein degradation;protein localization;protein purification;protein sequence;protein structure function;receptor expression;recombinant proteins;tissue /cell culture


application_id: 7258566
project_number: 7R01DK071349-03
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2006-08-07
opportunity_number: RFA-DK-04-010
application_type: 7
activity_code: R01
ic: DK
serial_number: 071349
program_official: LAUGHLIN, MAREN R
project_start_date: 2005-06-01
project_end_date: 2009-05-31
study_section: ZDK1-GRB-N(J2)S
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: Not Applicable
congressional_district: 06
department: ADMINISTRATION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity is the most common and powerful force for creating insulin resistance and metabolic syndrome however the molecular basis of this association is not well understood. In this proposal three independently funded researchers-Philip Kern MD a clinical investigator and Charlotte Peterson PhD and Robert McGehee PhD with significant experience in muscle and adipocyte biology respectively-will formalize a collaborative effort as a natural extension of previous work and shared interests in the fields of obesity insulin resistance and tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further we hypothesize that excess IMCL accumulation is dependent on secretary proteins derived from a complex interplay between adipocytes and macrophages in adipose tissue. To test these hypotheses we will examine the interactions among adipocytes macrophages and muscle cells isolated and cultured from subjects that are moderately obese with insulin resistance and impaired glucose tolerance (IGT) but who do not yet have fasting hyperglycemia. This study population has elevated IMCL and is at high risk for obesity complications but avoids the pathophysiologic complications of glucotoxicity. These subjects will be compared to moderately obese subjects with normal glucose tolerance (NOT). Aim 1 will explore mechanisms that contribute to IMCL and elucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obese subjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activity under differing extracellular fatty acid concentrations. Lipid accumulation and oxidation and insulin-mediated glycogen synthesis and signaling will be assessed. Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretary proteins. We will use co-cultures of adipocytes myoblasts and adipose stromal vascular cells to examine IMCL and the development of insulin resistance. Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine expression. Aim 4 will determine if improved glucose tolerance in response to a 10- week treatment with pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Coculture studies will also be used with muscle and stromal cells before and after pioglitazone treatment. These experiments will provide mechanistic insight into the link between obesity and muscle function leading to metabolic syndrome.


application_id: 7258396
project_number: 5T32DA007304-10
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2007-07-20
application_type: 5
activity_code: T32
ic: DA
serial_number: 007304
program_official: KHALSA, JAGJITSINGH H
project_start_date: 1998-08-01
project_end_date: 2008-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 7875177
contact_pi: GARRITY, THOMAS F
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    This training program co-directed by Thomas Garrity and Carl Leukefeld proposes to support three pre- and three postdoctoral trainees with a training faculty of 21 drawn from seven different academic and research units of the University. The environment is rich with opportunities for biobehavioral research in facilities such as the Center on Drug and Alcohol Research the Center for Prevention Research and the Residential Research Facility. Trainees will be housed in offices of the Department of Behavioral Science and the Center on Drug and Alcohol Research with 24-hour/day access to laboratories and computer facilities; some trainees will have additional work space in the project areas of their faculty supervisors. This program is designed to prepare trainees to assume research responsibilities in academic and other scientific organizations concerned with drug abuse and the behavioral aspects of health and medical care. Postdoctoral fellows will either have a doctorate in a behavioral science discipline and will be preparing for a research role in the drug abuse field or they will be health professionals who are seeking a behavioral science research orientation in drug abuse. Predoctoral trainees will concentrate in behavioral science aspects of drug abuse as part of their program for a doctorate in a biobehavioral science discipline. Basic elements of the program include (I) research training designed to provide experience in utilizing the basic building blocks of research laboratory methods case study experimental design development and pretesting of instruments data analysis) and independent research competence; (2) a multidisciplinary orientation which takes students beyond their basic discipline and provides exposure to key theoretical concepts and methodological issues of the related biobehavioral sciences along wish a biobehavioral conceptualization; (3) a program of enculturation and orientation to drug abuse health and mental health settings; (4) opportunities to explore drug abuse topics from a medical behavioral perspective through courses offered by training faculty; and (5) opportunities for independent research around relevant questions in drug abuse behavior that can constitute significant learning experiences for postdoctoral fellows and a dissertation project for predoctoral trainees. The program for postdoctoral fellows will be individually geared to the Objectives of the fellows and will build on their previous knowledge and experience.


application_id: 7257892
project_number: 5R01GM065459-05
project_title: Novel feedback-regulation of xenobiotic bioactivation
administering_ic: NIGMS
award_notice_date: 2007-06-12
opportunity_number: PA-99-016
application_type: 5
activity_code: R01
ic: GM
serial_number: 065459
program_official: OKITA, RICHARD T
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
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
project_abstract:
DESCRIPTION (provided by applicant):  Background: Xenobiotic metabolism hinges on a delicate balance between phase I (bioactivation) and phase II (detoxification) enzymatic activity.  Suppression of bioactivation has been shown to protect against drug-induced liver injury.  In humans cytochrome P4502E 1 (CYP2E1) is suppressed by IFN-( and other mediators of the inflammatory response.  A mechanism for this decrease in activity and its role in affording host advantage has not yet been proposed.  Preliminary Findings: Based on our preliminary studies of CYP2E1 expression we now propose a novel mechanism of feedback-regulation.  Within the proximal promoter of the human CYP2E1 gene is a nucleotide sequence ((-interferon activation sequence GAS) responsible for y-interferon ((-IFN)-dependent suppression of gene transcription.  A naturally occurring polymorphism G(-71)T within this sequence renders the CYP2E1-promoter insensitive to suppression by (-IFN.  General Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter.  In order to test this hypothesis it is first necessary to demonstrate a viable mechanism.  Thus our Working hypothesis for this proposal is: Interferon-( suppresses CYP2E1 transcription by acting through the GAS element.  This mechanism limits the intracellular pool of CYP2E1 enzyme and decreases the production of reactive metabolic intermediates.  Polymorphism of the GAS structure prohibits IFN-(-dependent regulation of CYP2E1 and therefore increases risk of toxicity due to accumulation of reactive metabolic intermediates Approach: To test this hypothesis we will; i) Characterize the molecular mechanisms of IFN-(-mediated suppression of CYP2E1 in humans; ii) Define the influence of IFN-( on the metabolism and toxicity of substrates bioactivated by CYP2E1; iii) Define the clinical significance of the CYP2E1*7B allele in selected human diseases linked to the bioactivity of CYP2E1; and iv) Demonstrate that control of CYP2E1 expression is linked to inflammation caused by toxic injury in a physiologic model.  Significance: This research will identify a novel and perhaps general mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1.  These findings may lead to an approach for identifying susceptible individuals and provide insight into potential therapeutic or preventive strategies.


application_id: 7257081
project_number: 5R01DA012964-08
project_title: Novelty Dopamine and Response to Amphetamine
administering_ic: NIDA
award_notice_date: 2007-06-27
application_type: 5
activity_code: R01
ic: DA
serial_number: 012964
program_official: LYNCH, MINDA
project_start_date: 2000-03-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-4(05)M]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): Evidence indicates that repeated early life exposure to an enriched environment produces changes in response to novelty and response to drugs of abuse later in life. The overall working hypothesis of this proposal is that exposure to novel environmental stimulation during development decreases responding for nondrug and drug reinforcers during adulthood and that this behavioral change is due at least in part to enhanced basal DA activity in the mesocorticolimbic reward system. The specific aims of the proposed experiments are to determine if environmental enrichment alters: (1) extinction or reinstatement of amphetamine seeking behavior; (2) the ability of nondrug reinforcers to decrease amphetamine self-administration; (3) neuronal processing in the nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) in response to nondrug reinforcers; and (4) activity of the DA transporter (DAT) and vesicular monoamine transporter (VMAT2) in mPFC.      In the proposed experiments rats will be raised from 21 days of age in either an enriched condition (EC) social condition (SC) or imporverished condition (IC). At 50 days of age rats from each condition will be trained to self-administer amphetamine at one of various doses. Extinction and reinstatement of responding for amphetamine will be examined and the ability of a concurrent alternative nondrug reinforcer (sweet solution or visual novelty) to reduce amphetamine self-administration will be examined in EC SC and IC rats. To identify the critical neural mechanisms that underlie these enrichment-induced behavioral changes separate groups of EC and IC rats will be examined for single-unit neuronal activity in the mPFC Nacc core and Nacc shell while having access to sweet solution or novelty. Other experiments will use in vivo voltammetry or in vitro binding/uptake to access potential changes in DAT or VMAT2 in EC and IC rats.     To the extent that both novelty and drugs of abuse activate the same mesocorticolimbic DA circuitry this would suggest that novel stimulation might substitute for drug reward. Novelty-induced reductions in amphetamine self-administration would provide the impetus for examining the effectiveness of presenting enriching stimulation in drug abuse prevention interventions in humans prone to abuse drugs. The long-term objective of our work is to design biologically relevant behavioral treatment and prevention strategies that can be evaluated in a controlled human study.

project_terms:
Age;Amphetamines;Behavior;Behavior Therapy;Behavioral;Binding (Molecular Function);Brain region;Condition;Decision Making;Development;Dopamine;Dose;Drug abuse;Effectiveness;Environment;Environmental Risk Factor;Exposure to;Extinction (Psychology);Funding;Genetic;Genetic Predisposition to Disease;Human;In Vitro;Individual;Life;Medial;Metabolism;Molecular;Motivation;Neurons;Nucleus Accumbens;Pharmaceutical Preparations;Prefrontal Cortex;Presynaptic Terminals;Prevention intervention;Prevention strategy;Process;Rattus;Research;Rewards;Self Administration;Self-Administered;Social Conditions;Solutions;Stimulus;Sucrose;System;Technology;Testing;Training;Visual;Work;day;design;dopamine transporter;drug abuse prevention;drug of abuse;drug reward;executive function;human study;in vivo;neuromechanism;novel;reinforcer;research study;response;uptake;vesicular monoamine transporter


application_id: 7256321
project_number: 5R01CA108696-04
project_title: An Appalachian Cervical Cancer Prevention Project
administering_ic: NCI
award_notice_date: 2007-06-19
opportunity_number: PA-02-169
application_type: 5
activity_code: R01
ic: CA
serial_number: 108696
program_official: CHOLLETTE, VERONICA
project_start_date: 2004-09-01
project_end_date: 2010-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Despite its nearly preventable status 13000 new cases of invasive cervical cancer are diagnosed each year with 4600 deaths. While nationally women have experienced a 75% reduction in cervical cancer mortality in the past 5 decades rural Appalachian women continue to sustain low rates of Pap testing and disproportionately high cervical cancer rates. To reduce this cervical cancer burden experienced by middle aged and older Appalachian women we propose to undertake a community participatory tailored faith based intervention entitled "Faith Moves Mountains." While extensive literature has established the association between rural culture and religiosity aside from programs involving African-American churches surprisingly few scientifically based interventions have located disease prevention activities within the trusted sustainable rural religious institutions of rural Appalachia. To address this missed opportunity this project will develop a random stratified sample of 50 congregations with 600 participants to: (1) Examine the factors (both barriers and assets) that influence the use of Pap tests; (2) Administer a faith-based lay health advisor intervention that is community-participatory theoretically informed and culturally consistent; (3) Evaluate the efficacy of the intervention in a group-randomized experimental design. These 3 aims correspond to 3 phases a developmental ethnographically oriented phase; a community-participatory intervention phase; and a qualitative and quantitative evaluation phase. With a multidisciplinary team of social scientists community leaders physicians and cancer control experts the results from the proposed project will enable researchers and communities to better address the barriers that prevent rural women from receiving Pap tests and recommended follow-up care; draw on local community assets to promote the use of Pap tests; and establish a community-based model that can be extrapolated to other rural underserved communities for cancer prevention.

project_terms:
Address;African American;Aftercare;Age Group Unspecified;Aging;Appalachian Region;Cancer Burden;Cancer Control;Caring;Cessation of life;Church;Communities;Development;Diagnosis;Early Diagnosis;Experimental Designs;Health;Health Promotion;Institution;Intervention;Invasive;Life;Literature;Malignant neoplasm of cervix uteri;Modeling;Mortality Vital Statistics;Numbers;Pap smear;Participant;Phase;Physicians;Population;Prevention;Prevention of Cervical Cancer;Prevention program;Procedures;Protocols documentation;Quantitative Evaluations;Randomized;Rate;Religion and Spirituality;Research Personnel;Research Proposals;Risk;Role;Rural;Rural Community;Sampling;Scientist;Screening Result;Screening procedure;Standards of Weights and Measures;Treatment Efficacy;Trust;Woman;Women's Group;anticancer research;base;cancer diagnosis;cancer prevention;disorder prevention;experience;falls;follow-up;improved;middle age;multidisciplinary;older women;prevent;programs;rural area;social


application_id: 7256296
project_number: 5R01NS046242-04
project_title: Structure/Function of N-ethylmaleimide Sensitive Factor
administering_ic: NINDS
award_notice_date: 2007-06-29
application_type: 5
activity_code: R01
ic: NS
serial_number: 046242
program_official: TALLEY, EDMUND M
project_start_date: 2004-09-20
project_end_date: 2009-06-30
study_section: Synapses, Cytoskeleton and Trafficking Study Section[SYN]
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
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant):   
The homohexameric N-ethylmaleimide Sensitive Factor (NSF) is a key element in most physiologically important vesicular trafficking and exocytosis events (i.e. neurotransmission hemostasis immune responses). As an AAA ATPase NSF acts as a "protein helicase" unwinding spent SNARE (SNAP receptor) complexes after they have mediated membrane fusion. Dysfunction of NSF leads to stark phenotypes such as paralysis or growth arrest. NSF protomers have three contiguous domains (NSF-N NSF-D1 and NSF-D2); each contributes uniquely to activity. Despite our advances little is known about which structural elements are required for NSF to bind its adaptor protein alpha SNAP (Soluble NSF Attachment Proteins) and to use the chemical energy from ATP hydrolysis to disassemble SNARE complexes. This proposal's Specific Aims focus on these key unanswered questions. The Aims are: 1) To determine which structural features of NSF-N are required for SNAP-SNARE complex binding and SNAP-mediated stimulation of the ATPase activity of NSF. 2) To determine what structural elements of NSF-D1 promote SNAP-dependent enhancement of nucleotide hydrolysis and facilitate the conformational changes needed for SNAP-SNARE binding and disassembly. 3) To determine the conformational changes that occur in NSF as it progresses through the different nucleotide states of its ATP hydrolysis cycle. For the first two aims structure-based mutagenesis will be combined with a battery of functional assays to assess the importance of specific regions of NSF. For the third aim cryo-electron microscopy and single particle image analysis will be used to generate 3D maps of the NSF hexamer in the different nucleotide-induced conformations (ADP ATP and ADP-Pi). These structures will then be compared to determine what parts of the NSF hexamer change and how they might shift conformations during the ATP hydrolysis cycle. From the knowledge generated by the experiments in these three specific aims it will be possible to better understand the catalytic mechanism of NSF as well as that of a number of other cellular ATPases of the AAA family.

project_terms:
ATP Hydrolysis;ATP phosphohydrolase;Adaptor Signaling Protein;Address;Adenine;Binding (Molecular Function);Binding Proteins;Binding Sites;Biological Assay;Cell physiology;Cells;Chemicals;Complex;Cryoelectron Microscopy;Data;Elements;Enzymes;Event;Exocytosis;Family;Functional disorder;Goals;Growth;Hemostatic function;Hydrolysis;Image Analysis;Immune response;Indium;Individual;Integral Membrane Protein;Knowledge;Maps;Mechanics;Mediating;Membrane Fusion;Membrane Protein Traffic;Methods;Molecular Conformation;Mutagenesis;Mutation;N Domain;N-ethylmaleimide-sensitive protein;Nucleotides;Numbers;Paralysed;Phenotype;Protein Binding;Proteins;Protomer;Recycling;Role;SNAP receptor;Site;Structure;Surface;Testing;base;helicase;mutant;neurotransmission;novel;particle;receptor;receptor binding;research study;sensor;soluble NSF attachment protein;trafficking


application_id: 7255466
project_number: 5R01AG021981-05
project_title: RESPONSE OF THE AGING NERVOUS SYSTEM TO TRAUMA
administering_ic: NIA
award_notice_date: 2007-07-20
application_type: 5
activity_code: R01
ic: AG
serial_number: 021981
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2003-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)Q]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-01
project_abstract:
DESCRIPTION (provided by applicant): Abundant clinical data indicate increased morbidity and mortality following trauma to the aging nervous system. Little is currently known about the cellular substrates underlying this amplified adverse response. The proposed studies lead to testing of the hypothesis that age-related changes associated with traumatic brain injury (TBI) can be negated by enhancing the ability of neurons to produce ATP. This idea is based on the theory that age-related changes in brain mitochondria lead to a disruption of ATP necessary to meet the energy demands of neurons following trauma. Mitochondria are the major source of ATP required for neuronal function. Age-related defects in mitochondrial oxidative phosphorylation result in deceased energy production impaired cellular calcium buffering activation of proteases and phospholipases and the generation of increased free radicals. All of these pathways can lead to enhanced cell death depending on the severity of the insult. Preliminary data from our laboratory demonstrate age-related differences following experimental TBI supporting its usefulness as an aging animal model. We also present data that a diet supplemented by creatine provides a neuroprotective intervention for TBI. Because of a lack of sufficient information on aged animal models of TBI this study will first characterize age-related changes. Specific aim #1 will characterize age-related decline in morphologic and behavioral changes following TBI employing an animal model of controlled cortical contusion. Specific aim #2 will characterize age-related changes in synaptic and non-synaptic mitochondria following TBI. Specific aim #3 will explore age-related changes in the generation of lactic acid and free fatty acids sensitive markers of secondary injury and changes in isoprostanes and neuroprostanes markers of lipid peroxidation following TBI. Specific aim #4 will use a 'creatine-supplemented' dietary intervention that enhances cytosolic phosphocreatine and increases the ability of neurons to produce ATP an intervention to reverse the age-related response to TBI.

project_terms:
Affect;Age;Age-associated memory impairment;Aging;Animal Model;Animals;Behavioral;Brain;Buffers;Calcium;Cell Aging;Cell Death;Cell Survival;Cell physiology;Clinical Data;Cortical Contusions;Creatine;Creatine Supplement;Data;Defect;Diet;Dietary Intervention;Dietary Supplements;Disruption;Endopeptidases;Fatty Acids Nonesterified;Foundations;Free Radicals;Generations;Grant;Hippocampus (Brain);Injury;Intervention;Isoprostanes;Laboratories;Lactic acid;Lead;Link;Lipid Peroxidation;Metabolic;Mitochondria;Mitochondrial Swelling;Modeling;Monitor;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Mutation;Nervous system structure;Neurons;Outcome;Oxidative Phosphorylation;Oxidative Stress;Pathway interactions;Peptide Hydrolases;Phosphocreatine;Phospholipase;Production;Rattus;Reactive Oxygen Species;Research Design;Rodent;Science of neurochemistry;Severities;Source;Synapses;Synaptosomes;Techniques;Testing;Tissues;Trauma;Traumatic Brain Injury;Work;age related;age related cognitive change;aged;aging brain;base;controlled cortical impact;feeding;improved;mitochondrial dysfunction;mitochondrial genome;research study;response;response to injury;theories


application_id: 7255434
project_number: 5F30NS048716-04
project_title: Reconstruction of the nigrostriatal pathway
administering_ic: NINDS
award_notice_date: 2007-06-20
opportunity_number: PA-01-100
application_type: 5
activity_code: F30
ic: NS
serial_number: 048716
program_official: SIEBER, BETH-ANNE
project_start_date: 2004-07-01
project_end_date: 2008-05-10
study_section: ZNS1-SRB-M(01)
contact_pi_person_id: 7789861
contact_pi: ZIEMBA, KRISTINE S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The long-term objective of this research proposal is to develop a means to reconstruct the neural circuit that degenerates in Parkinson's disease (PD) - that is the nigrostriatal pathway. While current therapy (levadopa treatment) for PD may alleviate symptoms for a while there is still no way to halt or reverse the neurodegeneration. Since 1% of the population over the age of 65 is affected by PD and the prevalence increases with increasing age research into better therapies and an eventual cure for PD is important for our aging population. Cellular replacement is not a new idea in PD research but this proposal differs from most previous efforts by attempting an anatomically and physiologically correct reestablishment of the nigrostriatal pathway effecting a more complete behavioral recovery. Molecular cues to guide growth of dopaminergic neurons will be identified in vitro and adenoviral vectors will be used to express these molecules between the substantia nigra (SN) and the striatum in hemiparkinsonian rats. When dopaminergic neurons are subsequently transplanted into the SN their axons should grow along the growth-supportive pathway ending in the striatal target. Success will be evaluated with detailed histological and behavioral analyses.


application_id: 7254910
project_number: 5R03OH008651-02
project_title: A Model-Based Estimate of Carbon Monoxide Uptake by Heart Muscle During Exercise
administering_ic: NIOSH
award_notice_date: 2007-08-03
opportunity_number: PA-04-021
application_type: 5
activity_code: R03
ic: OH
serial_number: 008651
program_official: KARR, JOAN
project_start_date: 2006-07-01
project_end_date: 2010-06-30
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 1918429
contact_pi: BRUCE, EUGENE N
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Intermittent exposures to carbon monoxide (CO) concentrations that exceed permissible levels are thought to contribute to the increased incidence of cardiovascular disease in exposed workers. A valid assessment of the cardiac risk associated with these exposures has proved difficult in part because of limited information regarding the degree of hypoxia that occurs in heart tissue during these exposures. Although the Coburn-Forster-Kane Equation (CFKE) is often used to predict CO uptake by and removal from hemoglobin (Hb) it can not estimate CO uptake by extravascular tissues such as muscle a potentially large storage site for CO as muscle accounts for approximately 41% of body weight in young adult males. Therefore we developed and validated with human data a mathematical model of CO uptake and washout that unlike the CFKE includes a muscle compartment. Our model predicts that the CO concentration in muscle increases soon after the onset of the exposure and rises steadily as carboxyhemoblobin (COHb) increases. When used to assess CO washout under hyperoxia the common treatment strategy for toxic CO exposures our model predicts a further rise in CO uptake by muscle myoglobin (Mb) even as COHb levels fall suggesting an increased risk for hypoxic injury to the myocardium. Based on these results we hypothesize that a mathematical model that could predict COMb levels in cardiac muscle would provide a more accurate estimate of risk for cardiac hypoxia than COHb alone. Accordingly the objectives of this proposal are to use data sets obtained from two human CO exposure experiments to: 1) enhance our model to enable it to predict COHb and COMb during exercise and washout under hyperoxia and 2) evaluate the correlation between the predicted CO dose to the heart and subtle ECG changes during exercise and washout under hyperoxia. To accomplish these objectives we will expand the model to include a separate myocardial compartment optimize our method for fitting the model and estimating myocardial COMb at rest and during exercise in each subject and correlate model estimates of myocardial COMb levels with degree of cardiac electrical instability. Relevance: To understand the increased risk for heart disease in workers exposed to carbon monoxide we will use our mathematical model to analyze existing data from exposed humans to determine the exposure conditions likely to damage the heart. We will also determine whether treatment with 100% oxygen may be harmful in some cases.


application_id: 7254710
project_number: 5R01CA084036-08
project_title: Screening for Ovarian Cancer: Psychobehavioral Outcomes
administering_ic: NCI
award_notice_date: 2007-06-19
application_type: 5
activity_code: R01
ic: CA
serial_number: 084036
program_official: NELSON, WENDY
project_start_date: 2000-03-01
project_end_date: 2009-06-30
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1874012
contact_pi: ANDRYKOWSKI, MICHAEL A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Transvaginal sonography (TVS) can facilitate early detection of ovarian cancer (OC) however like all cancer screening tests TVS yields a proportion of "abnormal" findings. While the vast majority of abnormal TVS results are benign the impact of this potentially stressful screening experience upon affective cognitive and behavioral outcomes has not been adequately examined. The proposed research builds on our current study (R01 CA84036) of psychological and behavioral outcomes associated with routine TVS screening by focusing explicitly on the impact of an abnormal TVS result. Women (n=400) receiving an abnormal TVS result during routine screening (Abnormal Screening (AS) group) and returning for a repeat TVS test four-eight weeks later will be matched (age prior screening history) with women (n=400) receiving a normal TVS result during routine screening (Routine Screening (RS) group). All women will complete a baseline assessment prior to either routine (RS group) or repeat (AS group) TVS screening and follow-up assessments 14 and 18 months post-baseline. Some women (n=120) in the AS group will complete an additional "true" baseline assessment prior to the routine TVS test yielding their abnormal result. Measures of dispositional variables (optimism monitoring emotional approach coping) are obtained at baseline and affective (e.g. OC-specific distress) cognitive (e.g. OC risk perception TVS efficacy beliefs benefit finding) and behavioral (e.g. OC-specific monitoring behavior emotional approach coping participation in screening for breast/colon cancers) endpoints will be assessed longitudinally. Adherence with recommendations for routine TVS screening will be monitored by OC screening program records. Several contemporary theoretical models of response to stressful events (Cognitive-Social Health Information Processing Monitoring Process Social-Cognitive Processing) guide selection of study variables and provide specific hypotheses for testing. Three specific aims will be addressed: (1) characterize the impact of an abnormal TVS result with regard to the nature magnitude valence and trajectory of outcomes; (2) identify clinical demographic dispositional and psychosocial variables associated with magnitude and persistence of these outcomes; and (3) develop and pilot test an appropriate psycho educational intervention for minimizing negative outcomes after an abnormal TVS result. Results will enhance understanding of response to abnormal results in response to screening for OC and will also enhance understanding of response to abnormal screening results for other malignant and nonmalignant conditions.

project_terms:
Accounting;Address;Adherence (attribute);Affective;Age;Behavior;Behavior monitoring;Behavioral;Belief;Benign;Breast;Cessation of life;Clinical;Cognitive;Colon Carcinoma;Colorectal Cancer;Computer information processing;Condition;Diagnosis;Distress;Educational Intervention;Emotional;End Point;Exposure to;Family;Family history of;Feeling;Future;Goals;Health;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Modeling;Monitor;Nature;Non-Malignant;Outcome;Perception;Personal Satisfaction;Process;Psychosocial Factor;Recommendation;Recording of previous events;Records;Reporting;Research;Research Activity;Research Personnel;Screening Result;Screening for Ovarian Cancer;Screening for cancer;Screening procedure;Social Environment;Social support;Stress;Stressful Event;Test Result;Testing;Theoretical model;Ultrasonography;Week;Woman;cancer risk;coping;experience;follow-up;optimism;programs;psychoeducational intervention;psychologic;response;social


application_id: 7253482
project_number: 1R15GM076079-01A1
project_title: Photoreceptors Involved in Chlamydomonas reinhardtii Circadian Entrainment
administering_ic: NIGMS
award_notice_date: 2007-05-08
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 076079
suffix: A1
program_official: TOMPKINS, LAURIE
project_start_date: 2007-06-01
project_end_date: 2011-05-31
study_section: Cellular Signaling and Dynamics Study Section[CSD]
contact_pi_person_id: 8670163
contact_pi: JACOBSHAGEN, SIGRID
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
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of this research is to elucidate the biochemical mechanisms underlying the circadian clock in Chlamydomonas reinhardtii. This green alga serves as a model system for a number of cell processes in animals and plants. Understanding its circadian clock will contribute to an understanding of circadian clock evolution and thus also help to better understand the circadian clock in humans. A precise knowledge of the circadian clock in humans is important for understanding health problems related to a defective clock like certain sleep disorders and depressions. The specific aim of this research is to identify the photoreceptor(s) responsible for adjusting the circadian clock to the daily light/dark cycles. The extent of adjustment will be monitored based on the circadian rhythm of phototaxis (swimming towards light) because its measurement has been automated. First experiments will determine the optimal time for giving a light pulse to yield the largest phase shifts in wild-type cells as well as the wavelength dependency at this optimal time. Previous analyses were performed with a cell-walless mutant and there is evidence that a wild-type strain shows major differences. To determine whether a particular photoreceptor is involved in entrainment knockout strains with no photoreceptor protein or RNA interference strains with reduced photoreceptor levels will be tested for impaired abilities to phase shift upon light pulses. Two kinds of photoreceptors will be analyzed: rhodopsins and cryptochromes. Cryptochromes might also function as part of the central oscillator of the circadian clock. Cryptochrome-impaired strains might therefore exhibit rhythm impairments instead. If blue light entrains the circadian clock in wild-type cells the single phototropin photoreceptor will also be tested. Rhodopsin knockout strains will be available from Peter Hegemann. RNA interference strains with reduced plant-like cryptochrome will be created by cloning available genomic and cDNA in reverse orientation and testing transformants with the available antiserum. The potential animal-like cryptochrome gene will be tested for expression by RT-PCR. Amplified cDNA will be cloned into an expression vector and the protein purified from E. coli to have antiserum made. Once all tools are available RNA interference strains for animal-like cryptochrome can be created. RNA interference strains are already available for phototropin. Preliminary experiments indicate that they can be used in this study. The project will engage four undergraduates and two Master level graduate students stimulating their excitement for careers in the sciences biomedical or otherwise. Understanding the circadian or biological clock in organisms like a green alga will help understand the clock in humans. This research should therefore also contribute to health-related questions like the role the clock plays in tumor suppression and how its defects can cause mental problems like some forms of depression and sleep disorders. It should also contribute to a better understanding of health problems due to shiftwork or jet lag and how to optimize work schedules or prepare for time zone travels in order to keep these problems to a minimum.

project_terms:
Algae Green;Animal Model;Animals;Arabidopsis;Biochemical;Biological Clocks;Biological Models;Cell physiology;Cells;Chlamydomonas reinhardtii;Circadian Rhythms;Class;Cloning;Communication Personal;DNA Photolyase;DNA Complementary;Daily;Defect;Dependency (Psychology);Escherichia coli;Evolution;Exhibits;Genes;Genome;Genomics;Health;Human;Immune Sera;Impairment;Insecta;Investigation;Jet Lag Syndrome;Knock-out;Knowledge;Light;Mammals;Measurement;Mental Depression;Methyl Green;Monitor;Numbers;Organism;Pacemakers;Phase;Photoreceptors;Physiologic pulse;Plants;Play;Proteins;Psyche structure;Publishing;Pulse taking;RNA Interference;Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Rhodopsin;Role;Schedule;Science;Signal Transduction;Sleep Disorders;Students;Swimming;Testing;Time;Travel;Tumor Suppression;Vascular Plant;Work;base;career;cell type;circadian pacemaker;cryptochrome;expression vector;falls;follow-up;interest;light entrainment;mutant;phototropin;receptor;research study;response;tool


application_id: 7253304
project_number: 5R01AA012600-08
project_title: Development of screens for drugs in alcohol dependence
administering_ic: NIAAA
award_notice_date: 2007-06-08
application_type: 5
activity_code: R01
ic: AA
serial_number: 012600
program_official: EGLI, MARK
project_start_date: 1999-09-23
project_end_date: 2008-09-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): The absence of accepted simple screens with predictive validity is one of several barriers to the discovery of novel drugs for alcohol dependence. For example modulation of the glutamate - NMDA receptor (NMDAR) is a clear molecular target for drugs that might decrease relapse rates and/or reduce alcohol-associated neurotoxicity but there is no accepted way of preclinically evaluating such drugs for potential value against these therapeutic targets. The original aims of the project were (a) to establish a hierarchy of screens for these therapeutic targets validating the screens with drugs believed or known to be effective and (b) to generate a library of novel active compounds to be evaluated using the screening hierarchy. The screening hierarchy is almost complete with the exception of validation of behavioral screens for alcohol-associated neurotoxicity. Additionally over 600 compounds based on endogenous modulators of the NMDAR have been synthesized and screened for appropriate molecular effects. Two novel and potent structural series have emerged based on tryptamine and agmatine derivatives which are believed to modulate NMDAR function in different ways. Similar naturally occurring compounds have previously been demonstrated to reduce drug-seeking behavior and/or to be neuroprotective. Some of the novel synthetic compounds have now been screened for neuroprotective properties in vitro and anti-seizure properties during withdrawal in vivo. Active compounds will next be evaluated for effects on rat drinking in an "alcohol deprivation effect" paradigm for effects on mouse behavior in a "conditioned pseudowithdrawal" paradigm and in behavioral screens of neuroprotection in rats when these have been validated. The specific aims of this competing renewal are thus to complete the screening hierarchies and to continue to test the two novel compound series in these. Additionally since it may now be possible to identify novel compounds with potential therapeutic value in alcohol dependence further research is necessary to protect the intellectual property in these and to bring them to the stage of toxicity testing prior to clinical evaluation. The overall objective remains to demonstrate the legitimacy of this approach to medications development in alcohol dependence by establishing the reproducibility and predictive validity of the screening hierarchies for evaluation of novel compounds. Even if this objective is not fully achieved the novel compounds and their performance in the different screens will help to elucidate the roles of NMDARs and their modulators in relapse and in alcohol-associated neurotoxicity.

project_terms:
Acute;Adult;Agmatine;Alcohol dependence;Alcohol withdrawal syndrome;Alcohols;Animal Model;Behavior;Behavioral;Binding (Molecular Function);Chemical Structure;Chronic;Complex;Computer Programs and Programming;Condition;Data;Databases;Development;Drug Evaluation Preclinical;Drug Industry;Evaluation;Future;Glutamates;Housing;In Vitro;Industry;Intellectual Property;Kentucky;Laboratories;Learning;Legitimacy;Libraries;Mediating;Memory;Methods;Microfluidics;Modeling;Molecular;Molecular Target;Mus;N-Methyl-D-Aspartate Receptors;Nerve Degeneration;Performance;Pharmaceutical Preparations;Polyamines;Process;Program Development;Property;Rate;Rattus;Relapse;Reproducibility;Research;Research Personnel;Robotics;Rodent;Role;Screening procedure;Seizures;Series;Staging;Structure;System;Testing;Therapeutic;Toxic effect;Toxicity Tests;Tryptamines;Universities;Validation;Withdrawal;alcohol exposure;base;deprivation;drinking;drug seeking behavior;in vivo;neuroprotection;neurotoxicity;novel;pharmacophore;programs;radioligand;receptor;receptor function;research and development;research clinical testing;response;scale up;therapeutic target;tryptamine


application_id: 7253155
project_number: 5R01EY014366-05
project_title: Characterization of uveitogenic T cells
administering_ic: NEI
award_notice_date: 2007-06-21
application_type: 5
activity_code: R01
ic: EY
serial_number: 014366
program_official: SHEN, GRACE L
project_start_date: 2003-08-01
project_end_date: 2008-02-29
study_section: Special Emphasis Panel[ZRG1-VISA(01)Q]
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
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): Immunization of Lewis rats with myelin basic protein (MBP) and its peptides induces autoimmune encephalomyelitis (EAE) as well as an anterior uveitis (AU) that closely mimics human anterior uveitis. This reflects the observation in humans that a significant percentage (20%) of multiple sclerosis patients suffer from AU. This proposal stems from the observation that MBP-induced eye disease was more persistent than the disease of the CNS and the uveitogenic activity of MBP-reactive T cells does not always parallel with the encephalitogenic activity of the cell indicating that the mechanism involved in the pathogenesis and tolerance induction of the two diseases differ. These proposed studies will exploit a large volume of data and T cell lines obtained in my laboratory during the previous study of EAE and MBP to characterize uveitogenic T cells and to elucidate the pathogenic mechanism by which MBP-induces different autoimmune diseases in the CNS and in the eye. We propose to determine whether uveitogenic and encephalitogenic T cells are distinct or overlapping subset(s) of MBP-specific T cells and to determine whether uveitogenic T cells have augmented activation in the eye leading to prolonged disease expression. Finally we will determine whether the regulatory T cells elicited by MBP-specific encephalitogenic T subsets are less effective in neutralizing uveitogenic T cell activity and whether non-specific inhibitory cells like NKT cells will be more effective in down-regulating diverse uveitogenic T cells. Our proposal will be greatly promoted by the MBP-specific T cells lines already available in my laboratory and the experience of isolation and characterization of autoimmune regulatory T cells and autoreactive T cells elicited by whole MBP antigen and altered peptides. This project will enhance our ability to understand the mechanisms for the development of autoimmune diseases and also identify targets for the therapeutics in uveitis.

project_terms:
Alanine;Anterior uveitis;Antigens;Autoantigens;Autoimmune Diseases;Autoimmune Process;Cell Line;Cells;Central Nervous System Diseases;Data;Development;Disease;Encephalomyelitis;Epitopes;Event;Experimental Autoimmune Encephalomyelitis;Eye;Eye diseases;Future;Human;Immune Tolerance;Immunization;Infiltration;Inflammatory;Intercellular adhesion molecule 1;Knowledge;Laboratories;Mediating;Modeling;Models Experimental;Molecular;Multiple Sclerosis;Myelin Basic Proteins;Myelin Proteins;Nature;Pathogenesis;Patients;Pattern;Peptides;Range;Rattus;Research Personnel;Resistance;Rodent;Role;Structure;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;Uveitis;autoreactive T cell;chemokine;cytokine;experience;novel therapeutics;programs;stem;therapeutic target


application_id: 7252437
project_number: 5R01DA017186-05
project_title: Neurochem Chip: Methodology to Study Untethered Rats
administering_ic: NIDA
award_notice_date: 2007-07-05
opportunity_number: PAR-03-017
application_type: 5
activity_code: R01
ic: DA
serial_number: 017186
program_official: PILOTTE, NANCY S
project_start_date: 2003-09-30
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-4(03)R]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This Stage II CEBRA application involves the development of Neurochem Chip microelectrodes for neurochemical recordings of neurotransmitter release in rats and mice. The long-term goals of this project are to develop Neurochem Chips for rapid in vivo recordings of glutamate GABA acetylcholine and choline in the CNS of freely moving rats and mice. In developing the technologies we will first implement and improve the technologies of Neurochem Chips in rats and mice. First we plan to optimize the recording approaches in the anesthetized rat and mouse. This will involve microelectrode development in corporation with Thin Film Technologies Hybrid Circuits Inc. and Cleveland Medical Devices Inc. Instrumentation development will occur in cooperation with PCB Assembly Inc. We will carry out extensive in vitro and in vivo recordings of glutamate GABA choline and acetylcholine release and uptake in the prefrontal cortex striatum and hippocampus of anesthetized rats. There are numerous microelectrode instrumentation and recording details that must first be optimized to develop reliable Neurochem Chips. These microelectrodes recordings will be compared with microdialysis measures of glutamate and choline to try and further validate the techniques. As this grant progresses the refined and adapted technologies will be applied to studies in awake behaving rats and mice. Freely moving tethered systems will be developed for 4-channel measures in awake rats and 2-channel recordings in mice. In addition a biotelemetric system will be developed to record from rats with a totally untethered system. This should contribute to 1) increased signal-to-noise of the recordings 2) increased freedom of movement of the rats and 3) the potential for monitoring large numbers of rats. The major goal of these studies is to develop Neurochem Chips that are reliable sensitive and selective for the rapid (second-by-second) determination of neurochemicals in the extracellular space of the brain. This technology could have a major impact on basic science studies of neurotransmitter systems involving drug abuse disease models and behavior. This CEBRA Stage II mechanism is needed due to the number of technical issues that must be addressed before these techniques can be disseminated to other researchers.

project_terms:
Acetylcholine;Address;Adult;Animals;Basic Science;Behavior;Bite;Brain;Ceramics;Characteristics;Choline;Corpus striatum structure;Development;Disease model;Drug abuse;Electrodes;Enzymes;Extracellular Space;Film;Freedom;Glutamates;Goals;Grant;Hippocampus (Brain);Hybrids;Implant;In Vitro;Measures;Medical Device;Methodology;Microdialysis;Microelectrodes;Miniaturization;Monitor;Movement;Mus;Neurotransmitters;Noise;Numbers;Performance;Polychlorinated Biphenyls;Prefrontal Cortex;Property;Purpose;Rattus;Research Personnel;Science of neurochemistry;Screening procedure;Series;Signal Transduction;Site;Staging;Surface;System;Techniques;Technology;Work;awake;base;data acquisition;design;drug of abuse;gamma-Aminobutyric Acid;improved;in vivo;instrumentation;miniaturize;neurotransmitter release;uptake


application_id: 7251719
project_number: 1R15MH076788-01A1
project_title: Improving memory after hippocampal cell loss
administering_ic: NIMH
award_notice_date: 2007-05-02
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: MH
serial_number: 076788
suffix: A1
program_official: HUPALO, SOFIYA
project_start_date: 2007-05-01
project_end_date: 2011-04-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is a resubmission of an application for a new R15 AREA (Academic Research Enhancement Award) grant. The original application was reviewed in October 2005. A consistent literature has demonstrated the presence of hippocampal abnormalities in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease (AD) and in both disorders changes in hippocampal function and structure have been linked to memory impairment. But to our knowledge an animal model of reduced hippocampal volume has not been used to assay new treatments for memory deficits. The development and use of such a model is important since existing animal models of memory loss involving systemic decreases in acetylcholine or glutamate function may not adequately emulate the pathophysiology of memory deficits caused by hippocampal dysfunction. The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies performed since the original application that thioperamide a highly selective antagonist at histamine H3 receptors clearly alleviates injury-induced deficits in spatial working memory. As a result of this data we hypothesize that thioperamide and related H3 antagonists will improve spatial working memory in rats with adult and neonatal excitotoxic injury to the hippocampus. The specific aims of this proposal are intended to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury & 3) Can H3 antagonists alleviate changes in spatial working memory prepulse inhibition and locomotor activity in rats with neonatal-onset hippocampal injury? The results of these studies should improve our understanding of memory deficits specifically linked to hippocampal dysfunction and suggest new treatment strategies for such deficits in neuropsychiatric disorders. The funding of this application will also expand student research in behavioral neuroscience and psychopharmacology and better enable students from Kentucky a state traditionally underrepresented in biomedical sciences to successfully advance into biomedical graduate programs. Memory loss associated with clinical disorders such as Alzheimer's Disease or schizophrenia has been linked to reductions in the size of specific brain regions. The proposed studies are designed to study memory in laboratory rats with similar changes in regional brain size and to identify new treatments for the memory impairment associated with these size changes. The results may shed light on new directions in the treatment of memory disorders and the proposed work will also enhance education in biomedical research among college undergraduates in Kentucky.

project_terms:
Academic Research Enhancement Awards;Acetylcholine;Adult;Alzheimer's Disease;Animal Model;Animals;Behavioral;Biological Assay;Biomedical Research;Brain region;Chronic;Clinical;Cognitive;Data;Development;Disease;Dorsal;Educational aspects;Functional disorder;Funding;Glutamates;Goals;Grant;Hippocampus (Brain);Infusion procedures;Injury;Institution;Kentucky;Knowledge;Light;Link;Literature;Medial;Memory;Memory Disorders;Memory Loss;Memory impairment;Memory Short-Term;Modeling;Motor Activity;Neonatal;Nerve Degeneration;Neurosciences;Performance;Pilot Projects;Prefrontal Cortex;Psychopharmacology;Purpose;Radial;Rat Laboratory;Rattus;Receptors Histamine H3;Research;Research Design;Rewards;Role;Schizophrenia;Science;Structure;Students;Testing;Training;United States National Institutes of Health;Universities;Upper arm;Work;base;brain size;ciproxifan;college;day;drug testing;hippocampal cell loss;human study;improved;neurodevelopment;neuropsychiatry;postnatal;prepulse inhibition;programs;size;thioperamide


application_id: 7250162
project_number: 5R01HL073693-05
project_title: HIV protease inhibitors marcophage function/estrogen
administering_ic: NHLBI
award_notice_date: 2007-06-06
application_type: 5
activity_code: R01
ic: HL
serial_number: 073693
program_official: MCDONALD, CHERYL
project_start_date: 2003-07-09
project_end_date: 2010-06-30
study_section: AIDS and Related Research 6[AARR-6]
contact_pi_person_id: 1859333
contact_pi: WILSON, MELINDA E
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): Protease inhibitor therapy has greatly increased the lifespan of individuals infected with the human immunodeficiency virus (HIV). Unfortunately one of the deleterious side effects of protease inhibitor therapy is dyslipidemia which is known to be closely associated with development of atherosclerosis. The development of atherosclerosis is a multifactorial process in which macrophage lipid metabolism plays a central role. In the healthy population premenopausal women have a lower incidence of atherosclerosis as compared to men. Women on protease inhibitor therapy however have similar dyslipidemia as men on protease inhibitor therapy suggesting that the cardioprotective effects of estrogen are lost. Additionally preliminary studies in mice show that female mice have significantly fewer atherosclerotic lesions accompanied by a reduced disruption of lipid metabolism in macrophages. Therefore this proposal will test the hypothesis that the gonadal steroid estrogen modulates the effects of HW protease inhibitors on macrophage lipoprotein metabolism and thus atherosclerotic lesion formation. Aim 1 will determine the ability of 17??estradiol to suppress HIV protease inhibitor-induced macrophage sterol accumulation. We will use the human monocyte/macrophage cell line THP-1 to define the effects 17??estradiol on the HIV protease inhibitors ritonavir and amprenavir induced alterations of CD36 expression and CD36-dependent function by measuring lipoprotein uptake and cholesterol efflux. Aim 2 will investigate potential mechanisms by which 17??estradiol prevents macrophage dysfunction induced by HW protease inhibitors. An estrogen receptor antagonist will be administered to THP-1 cells to assess the role of estrogen receptors in the regulation of the scavenger receptor CD36 expression and function in the presence of ritonavir and/or amprenavir. We wilt also examine the expression and function of peroxisome proliferating activated receptor gamma (PPAR?) and PPAR? mRNA following estrogen treatment. Aim 3 will determine if 17??estradiol alters the development of atherosclerotic lesions induced by HW protease inhibitors in vivo. We will examine the atherosclerotlc lesion size and lipid metabolism in peritoneal macrophages from intact LDL receptor null mice as well as ovariectomized and estrogen replaced female mice. To determine if estrogen receptors are needed in vivo LDL receptor null mice will be crossed with estrogen receptor null mice to determine if the estrogen receptors are required for estrogen to prevent atheroscterotic lesions and macrophage dysfunction following HIV protease inhibitor treatment. The data obtained from these studies will be critical to enhancing our understanding of the actions of estrogen in the cardiovascular system as well as estrogen function during HIV infection and protease inhibitor therapy.

project_terms:
Abnormal Macrophage;Acquired Immunodeficiency Syndrome;Address;Adverse effects;Age;Amprenavir;Animals;Arterial Fatty Streak;Atherosclerosis;Biological Assay;CD36 gene;Cardiovascular system;Cell Line;Cells;Cholesterol;Data;Development;Disruption;Dyslipidemias;Estradiol;Estrogen Receptor alpha;Estrogen Receptors;Estrogens;Female;Foam Cells;Functional disorder;Genes;Gonadal Steroid Hormones;HIV;HIV-1;Human;ICI 182780;Incidence;Individual;Lesion;Lipids;Lipoprotein Binding;Lipoproteins;Longevity;Low Density Lipoprotein Receptor;Macrophages Peritoneal;Measures;Mediating;Metabolism;Mice Knockout;Mus;PPAR gamma;Peroxisome Proliferator-Activated Receptors;Plasma;Play;Population;Premenopause;Process;Proliferating;Protease Inhibitor;RNA Messenger;Regulation;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Ritonavir;Role;SR-BI receptor;Serum;Sex Characteristics;Sterols;Surface;Testing;Time;Virus;Virus Diseases;Woman;experience;gonad function;in vivo;lipid metabolism;low density lipoprotein inhibitor;mRNA Expression;macrophage;male;men;monocyte;peroxisome;prevent;programs;receptor;scavenger receptor;size;uptake


application_id: 7250146
project_number: 5R01EY014599-04
project_title: Regulation of the Ocular Immune Response by Retinal Pigment Epithelium
administering_ic: NEI
award_notice_date: 2007-06-20
application_type: 5
activity_code: R01
ic: EY
serial_number: 014599
program_official: SHEN, GRACE L
project_start_date: 2004-08-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-AED(01)Q]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the pathogenesis of uveitis a T cell-mediated autoimmune disease in the eye using experimental autoimmune uveitis (EAU) as an experimental model. Using in vitro co-culture of uveitigeneic T cells derived from rats with uveitis (EAU) and retinal pigment epithelial (RPE) a major parenchymal cell that might be targeted by uveitogeneic T cells we have demonstrated that normal RPE cells are capable of inhibiting uveitogeneic T cell functions including proliferation and cytokine production as evidenced by that T cells are rendered hypo-responsive to their specific antigens presented by APCs when they are pre-exposed to RPE. On the other hand activated RPE  
is capable of promoting T cell responses by expression of MHC molecules and production of cytokines upon confronting uveitogenic T cells. The reciprocal interaction of uveitogeneic T cell and activated RPE elicit significant amounts of inflammatory mediators such as TNF-a IFN-r and NO which may increase target tissue damage.  
The underlying hypothesis of this project is that the outcome of interactions between uveitogenic T cells and the RPE play a critic role in the pathogenesis of the disease. Experiments are designed to determine whether uveitogenic T cells have an increased ability compared to their nonpathogenic counterparts to escape the suppression mediated by RPE or they are more resistant to the apoptotic cell death induced by RPE (Specific Aim 1). We will also test an alternative possibility that uveitogenic T cells are more capable of inducing cascading responses upon interacting with RPEs. Uveitogenic T cells may induce increased expression of MHC class II or co-stimulatory molecules on RPE cells which in turn activate the T cells and result in excessive production of inflammatory cytokines and chemokines (Specific Aim 2). The expertise of this laboratory in generating both autoreactive T cells and RPE cells and the availability of various functional tests assessing interaction between T cells and RPE will provide a competitive advantage in the proposed studies. The results of our studies will provide new insights into the pathogenesis of uveitis.

project_terms:
Antigens;Apoptosis;Apoptotic;Autoimmune Diseases;Autoimmune Responses;Belief;Blindness;Cell Communication;Cell Death;Cell physiology;Cells;Coculture Techniques;Condition;Disease;Epithelial;Evolution;Eye;Genes MHC Class II;Goals;Hand;Immune response;In Situ;In Vitro;Inflammation;Inflammatory;Interferons;Invaded;Knowledge;Laboratories;Lead;Mediating;Mediator of activation protein;Models Experimental;Nitric Oxide;Outcome;Pathogenesis;Patients;Physiological;Play;Prevention;Production;Protein Overexpression;Rattus;Recruitment Activity;Recurrence;Regulation;Research;Research Personnel;Resistance;Retinal;Retinal Pigments;Role;Series;Structure of retinal pigment epithelium;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Uveitis;Virus Diseases;autoimmune uveitis;autoreactive T cell;base;chemokine;cytokine;design;insight;interstitial retinol-binding protein;prevent;programs;research study;response


application_id: 7249191
project_number: 3P50NS039787-06A1S1
project_title: Restoration of Dopaminergic Function in Parkinson's Disease
project_terms: Parkinson&apos;s disease;dopamine;nervous system regeneration;neurotrophic factors
administering_ic: NINDS
award_notice_date: 2006-07-11
opportunity_number: PAR-03-004
application_type: 3
activity_code: P50
ic: NS
serial_number: 039787
suffix: A1S1
program_official: MURPHY, DIANE
project_start_date: 1999-09-30
project_end_date: 2010-07-31
study_section: ZNS1
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
project_abstract:
DESCRIPTION (provided by applicant):   
  
The neurorestorative and neuroprotective trophic actions of glial cell line-derived neurotrophic factor (GDNF) on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease (PD; Gill et al. 2003). Currently a Phase I FDA-approved trial in later stage PD patients is taking place in our Udall Center (Slevin et al. 2003). Based on previous studies and our Center studies over the last 4 years we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: A) Upregulation of existing DA neurons (Projects 1 2 and 3); B) Repair of DA neurons and connections (Projects 1 2 and 3); and C) Neurogenesis and or gliogenesis (Project 3). We will investigate these three mechanisms in the proposed experiments in MPTP-treated nonhuman primates that best simulate the human parkinsonian state. In addition in the next 5 years we plan to address two key issues. 1) We propose to chronically deliver GDNF in the freely-moving MPTP-lesioned monkey to evaluate multisite delivery of GDNF (putamen vs. putamen and substantia nigra) to improve the functional restoration of DA systems. 2) We will use the improved delivery approach to investigate the effects of GDNF infusion on mild parkinsonian vs. severe parkinsonian monkeys to determine if early intervention of GDNF treatment may contribute to better functional recovery of the nigrostriatal system. The highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons determine mechanisms of action of GDNF and they will provide data that can be used to improve the use of GDNF in patients with PD. Project 1 will use microdialysis postmortem HPLC-EC methods and Western immunoblot methods to study the nigrostriatal pathway of GDNF-treated unilateral MPTP-lesioned monkeys. Project 2 will investigate the behavioral consequences of the GDNF infusions and study potential functional changes to DA neurons using fMRI methods. Project 3 will carryout immunohistochemical measures of DA neurons in the same groups of monkeys. Cores A-C will provide needed support for the experiments outlined in Projects 1-3. Finally Core D is a new translational Core added to address the potential cognitive and sensory effects of GDNF in patients with advanced PD as part of an ongoing FDA-approved Phase-I clinical trial.    
  
Project 1  
  
Title:Quantitative Neuropharmacological Studies of the Effects of Chronic Delivery of   
GDNF in Rhesus Monkeys   
  
PI:  Greg Gerhardt PhD  
  
DESCRIPTION (provided by applicant):   
  
The neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide a promising therapeutic approach for the treatment of Parkinson's disease (PD) which is being addressed in part through a Phase I FDA-approved clinical trial in our Udall Center. Based on our past work we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: 1) Upregulation of existing DA neurons; 2) Repair of DA neurons; and 3) Neurogenesis and/or gliogenesis. Project 1 will investigate upregulation of DA function and repair of DA neurons. These studies will be carried out in nonhuman primates which best simulate the human parkinsonian state. It is our central hypothesis that dualsite chronic intraputamenal/intranigral delivery of GDNF will improve function and restoration of damaged DA neurons with greater efficacy and reduced side effects as compared to other methods of delivery. In addition we predict based on preliminary data that GDNF treatment in mild parkinsonian animals a model of early stage PD patients will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl- 1236-tetrahydropyridine (MPTP)-Iesioned monkey to evaluate the two major issues. Project 1 will perform quantitative neurochemical assessments using in vivo microdialysis Western immunoblot assays and high performance liquid chromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems in the striatum (putamen and caudate nucleus) and substantia nigra of rhesus monkeys that have received chronic GDNF infusions. These neurochemical changes to the monkey striatum during chronic delivery of GDNF will be performed in conjunction with behavioral immunohistochemical histological and functional MRI (fMRI) studies with Projects 2 and 3. In addition Project 1 will begin studies of glutamate regulation in 6-OHDA-lesioned rats as a new area of scientific growth of the Center. The investigation of the role of glutamate in relation to DA function will improve our understanding of the essential role of this neurotransmitter to basal ganglia function in PD and provide an improved understanding of the functional effects of GDNF on nigrostriatal circuitry.


application_id: 7248678
project_number: 5F30NS048770-03
project_title: Postnatal Intermittent Hypoxia and Respiration: Potenti*
administering_ic: NINDS
award_notice_date: 2007-06-08
opportunity_number: PA-04-032
application_type: 5
activity_code: F30
ic: NS
serial_number: 048770
program_official: MITLER, MERRILL
project_start_date: 2005-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-B(21)L]
contact_pi_person_id: 7798502
contact_pi: REEVES, STEPHEN R
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):  Intermittent hypoxia (IH) is a frequent condition in clinical medicine (e.g. sleep apnea SIDS) which bears substantial morbidity and mortality. Furthermore organismal adaptations to IH suggest the formation of specific forms of neuronal plasticity. While substantial study of the effects of IH has been performed in the mature mammal little if any work has been done during the early phases of post-natal development a unique period of neuronal vulnerability and adaptation. Therefore we hypothesized that post-natal intermittent hypoxia such as occurs in sleep apnea may impose long-term modifications in respiratory control thereby leading to a form of metaplasticity of respiratory patterning. The latter modification of the respiratory network induced by early post-natal IH could impose either a functionally favorable or a maladaptive alteration of the respiratory response system. To examine this issue we will: (i) characterize the effects of post-natal IH on normoxic ventilation and on hypoxic and hypercapnic ventilatory responses in freely behaving rats.; (ii) assess the effects of IH on phrenic motor nerve long-term facilitation (LTF).; (iii) determine the potential role of signaling pathways particularly protein kinase C (PKC) in the long-term modification of ventilation imposed by IH through development. This work will therefore contribute to the understanding of potential mechanisms mediating not only early adaptations to IH but also provide insights to long-lasting changes in ventilation that may develop when a conditioning stimulus is applied during critical phase of maturation.

project_terms:
Clinical Medicine;Condition;Development;Environmental air flow;Hypoxia;Mammals;Mediating;Modification;Morbidity - disease rate;Mortality Vital Statistics;Motor;Nerve;Neuronal Plasticity;Neurons;Pathway interactions;Pattern;Phase;Protein Kinase C;Rattus;Respiration;Role;Signal Pathway;Sleep Apnea Syndromes;Stimulus;Structure of phrenic nerve;Sudden infant death syndrome;System;Ursidae Family;Work;awake;conditioning;insight;post-natal intermittent hypoxia;postnatal;respiratory;response


application_id: 7248566
project_number: 5R01HL070897-05
project_title: Mechanisms of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2007-06-09
application_type: 5
activity_code: R01
ic: HL
serial_number: 070897
program_official: LIANG, ISABELLA Y
project_start_date: 2003-07-01
project_end_date: 2009-06-30
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: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant): We have recently found that HO-1 serves as an obligatory mediator of three different forms of late preconditioning (PC) suggesting a central cardioprotective role of this protein.  Despite this and despite the fact that HO-1 is one of the most frequently induced proteins known to exist the regulation of cardiac HO-1 and the mechanism of its cardioprotective actions are unknown.  The objective of this proposal is to elucidate the molecular mechanisms underlying the newly discovered cardioprotective role of HO-1 and to use this knowledqe to develop novel therapies.  We will test the hypothesis that diverse PC stimuli upregulate HO-1 via eNOS-dependent generation of NO and subsequent activation of a cluster of stress-responsive transcription factors and that the salubrious effects of HO-1 are due to CO-dependent inhibition of apoptosis and modulation of other co-induced proteins (iNOS COX-2).  We propose that CO far from being a toxic waste product plays a fundamental role in protecting the heart against ischemia and apoptosis.  Three different forms of late PC elicited by a pathological (ischemia) physiological (exercise) and pharmacological (NO donor) stimulus will be interrogated in an effort to develop a comprehensive pathophysiologic paradigm.  A broad multidisciplinary approach will be used that will combine diverse techniques (integrative physiology protein chemistry biochemistry pathology confocal microscopy immunohistochemistry molecular biology gene targeting and transgenesis) and will integrate genetic and biochemical information at the molecular level with physiological information at the whole animal level.  A total of 16 genetically engineered mouse lines will be studied.  The effects of late PC and HO-1 on infarct size apoptosis and necrosis will be determined using HO-1-/- and HO-1 transgenic mice in conjunction with state-of-the-art pathology immunohistochemistry and confocal microscopy techniques.  The effects of CO on myocardial ischemia/reperfusion injury and apoptosis will be determined by using a novel class of compounds (CO-releasing molecules) that have potential therapeutic applications.  The role of specific transcription factors (NF-kappaB HIF-1alpha HSF1 STAT1 and STAT3) in HO-1 upregulation will be established by the use of a novel transdominant IkappaBalpha  mutant mouse with cardiac-specific repression of NF-kappaB activity knockouts for HIF-1alpha HSF1 and three specific NF-kappaB subunits (p50 RelB and c-Rel) and a novel conditional STAT3 knockout mouse.  The functional interactions of HO-1 with the other two co-mediators of late PC (iNOS and COX-2) will be deciphered in vivo by cardiac-specific overexpression and targeted disruption of each of these three genes.  This project should produce important new insights into the role of apoptosis vis-a-vis necrosis in late PC and the mechanism of HO-1-dependent cytoprotection.  If the studies of CO donors confirm our preliminary data they may pave the way for the development of novel antiischemic and antiapoptotic therapies predicated upon the supplementation of exogenous CO to patients with coronary artery disease.

project_terms:
Ablation;Analysis of Variance;Animals;Apoptosis;Arts;Biochemical Genetics;Biochemistry;Biological Assay;Cardiac;Cardiovascular system;Catabolism;Class;Coronary Arteriosclerosis;Cyclic GMP;Cytoprotection;Data;Development;Diethyldithiocarbamate;Disruption;Dose;EMSA;Enzyme Immunoassay;Exercise;Gene Targeting;Gene Transfer Techniques;Generations;Genes;Genetic;Genetic Techniques;Genetically Engineered Mouse;HIF1A gene;Heart;Heme;Heme Oxygenase (Decyclizing);Hypoxia Inducible Factor;I Kappa B-Alpha;I-kappa B Proteins;Immunohistochemistry;Individual;Infarction;Inhibition of Apoptosis;Interferon Activation;Investigation;Ischemia;Janus kinase;Knock-out;Late Effects;Lead;Left ventricular structure;Lipopolysaccharides;Measures;Mediating;Mediator of activation protein;Mice Knockout;Mice Mutant Strains;Mice Transgenic;Microscopy Confocal;Modeling;Molecular;Molecular Biology;Molecular Genetics;Multiprotein Complexes;Mus;Myocardial Ischemia;Myocardium;Myosin Heavy Chains;N-acetylpenicillamine;NF-kappa B;Necrosis;Neuro-Oncological Ventral Antigen 2;Nitric Oxide Synthase;Nitroglycerin;Nuclear;Occlusions Coronary;PTGS2 gene;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Phase;Phenotype;Physiological;Physiological reperfusion;Physiology;Play;Polymerase Chain Reaction;Prevention;Process;Property;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Chemistry;Protein Kinase C;Protein Overexpression;Proteins;Recruitment Activity;Regulation;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Repression;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Reverse Transcription;Ribonucleases;Role;S-nitro-N-acetylpenicillamine;STAT1 gene;STAT3 gene;Signal Transduction;Site;Stimulus;Stress;Structure;Supplementation;TNFRSF5 gene;Techniques;Testing;Therapeutic;Thromboxane B2;Time;Time Study;Tissues;Transcription Coactivator;Transgenic Organisms;UC01;Up-Regulation (Physiology);Ventricular Cardiac alpha-Myosin;Waste Products;cell type;concept;cyclooxygenase 1;cyclooxygenase 2;diethylenetriamine;dimer;heat shock transcription factor;in vivo;inhibitor/antagonist;insight;interdisciplinary approach;knockout gene;mutant;novel;preconditioning;progesterone 11-hemisuccinate-(2-iodohistamine);protective effect;response;size;therapeutic gene;transcription factor;tumor


application_id: 7248233
project_number: 3R01HL071010-04S1
project_title: Mechanism of Vascular Remodeling in Hyperhomocysteinemia
administering_ic: NHLBI
award_notice_date: 2006-06-19
application_type: 3
activity_code: R01
ic: HL
serial_number: 071010
suffix: S1
program_official: ERSHOW, ABBY
project_start_date: 2002-06-01
project_end_date: 2007-05-31
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant): The long-term objective of this project is to further the understanding of contribution of homocysteine in vascular disease. Previous studies have indicated a decrease in the bioavailability of endothelial nitric oxide and an increase in the concentration of nitrotyrosine in the aortic wall associated with hyperhomocysteinemia. The plasma levels of homocysteine have shown to be inversely related to peroxisome proliferator activated receptor (PPAR) a nuclear receptor which ameliorates vascular dysfunction. The central hypothesis of this proposal is that increased levels of homocysteine suppress the activity of PPAR by increasing the generation of nitrotyrosine and metalloproteinase activity and decreasing the endothelial nitric oxide concentration. The central hypothesis will be addressed by the following four specific aims: 1) To determine whether the homocysteine binds to PPAR the competitive binding of homocysteine and agonist (fibrate) to PPAR will be measured using homocysteine-cellulose affinity chromatography and aortic nuclear extracts. Bound PPAR will be eluted with fibrate and characterized by antibody to PPAR. 2) To determine whether the increase in PPAR expression decreases nitrotyrosine levels and increases endothelial nitric oxide concentration in a murine model of hyperhomocysteinemia the concentrations of PPAR and nitrotyrosine in the aortas of hyperhomocysteinemic mice treated with and without fibrate will be measured by Western blot analysis. The levels of nitric oxide will be measured by estimating the total nitrate/nitrite concentration. 3) To determine whether the increase in PPAR decreases the levels of metalloproteinase and elastinolysis the matrix metalloproteinase activity will be measured using specific substrate gel zymography and the elastinolysis by identifying elastin fragments using anti-elastin antibody. 4) To determine whether an increase in PPAR expression reverses the homocysteine-mediated vascular dysfunction the aortic contractile function will be measured. The proposed studies will elucidate the molecular cellular and extracellular mechanism by which homocysteine promotes arterial lesions and should provide new insights to therapeutic ramifications for vessel wall disease.

project_terms:
affinity chromatography;antihyperlipoproteinemic agent;atherosclerotic plaque;cardiovascular injury;clofibrate;elastin;homocystinuria;laboratory mouse;metalloendopeptidases;nitric oxide;peroxisome proliferator activated receptor;receptor binding;receptor expression;tyrosine;vasomotion;western blottings


application_id: 7244444
project_number: 5R01GM050388-14
project_title: Lysophosphatidic Acid: Synthesis Actions & Inactivation
administering_ic: NIGMS
award_notice_date: 2007-06-26
application_type: 5
activity_code: R01
ic: GM
serial_number: 050388
program_official: IKEDA, RICHARD A
project_start_date: 1994-08-01
project_end_date: 2008-09-14
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: 2007-07-01
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:
Accounting;Actins;Adenovirus Vector;Agonist;Atherosclerosis;Award;Biochemical;Blood Vessels;Cancer Cell Growth;Cancer cell line;Cell membrane;Cell model;Cells;Cellular Morphology;Chemicals;Class;Clinical;Cytoskeletal Modeling;Data;Development;Differentiation and Growth;Enzymes;Epithelial;Extracellular Space;Fibroblasts;Filopodia;Funding;G-Protein-Coupled Receptors;Genes;Genetic;Goals;Homologous Gene;Hydrolysis;In Vitro;Inflammation;Integral Membrane Protein;Lead;Lipid Binding;Localized;Lysophospholipids;Malignant Neoplasms;Mediating;Mediator of activation protein;Membrane;Mus;Mutation;Myocytes Smooth Muscle;Pathway interactions;Phospholipase D;Physiological;Play;Process;Production;Protein Binding;Protein Dephosphorylation;Protein Overexpression;Proteins;Proteolytic Processing;Publishing;RNA Interference;Range;Regulation;Reproduction;Research;Research Personnel;Resolution;Role;Signal Transduction;Structure;System;Testing;Thrombosis;Work;Wound Healing;alkylglycerophosphoethanolamine phosphodiesterase;alpha-glycerophosphoric acid;base;cancer cell;cell motility;cell type;clinically relevant;cytokine;design;extracellular;immune function;in vivo;inhibitor/antagonist;lipid mediator;lipid phosphate phosphatase;lysophosphatidic acid;migration;neoplastic cell;novel;novel strategies;programs;protein function;receptor;research study;response;response to injury


application_id: 7243427
project_number: 5R01HL071071-05
project_title: Sphingolipid Signaling in Endothelial Function
administering_ic: NHLBI
award_notice_date: 2007-06-21
application_type: 5
activity_code: R01
ic: HL
serial_number: 071071
program_official: GOLDMAN, STEPHEN
project_start_date: 2003-07-01
project_end_date: 2009-03-31
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 6981385
contact_pi: LEE, MENQ-JER
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: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Sphingosine-1-phosphate (S1P) a bioactive sphingolipid regulates a variety of cellular functions such as proliferation survival chemotaxis etc. Recently it has been shown that S1P is the high affinity ligand for the G-protein coupled receptor EDG-1 (Endothelial Differentiation Gene-1). Importantly a novel function of S1P/EDG-1 in blood vessel development and maturation has been proposed recently. For example S1P promotes morphogenesis of endothelial cells in vitro and potentiates VEGF and FGF-induced angiogenesis in vivo. Furthermore deletion of EDG-1 resulted in embryonic lethality due to the formation of immature vasculature. However the molecular mechanisms underlying S1P/EDG-1 regulated angiogenesis remain elusive. Thus our long-term goal is to understand the signaling and roles of this sphingolipid in endothelial functions. In this proposal we will characterize signaling pathways regulated by the EDG-1 receptor. Initially by utilizing the affinity purification procedure a panel of cellular polypeptides was found to specifically associate with the third intracellular loop (i3 domain) of EDG-1 receptor. Among them two protein kinases with apparent molecular masses of 120- and 56-kDa and a 21-kDa phosphoprotein were identified. We hypothesize that these EDG-1 associated kinases/polypeptides are critical for the S1 P/EDG-1 signaling in particular in regulating the function of endothelial cells. Preliminary data suggest that pp120 kinase may be functionally important in EDG-1 signaling. Thus we propose to prioritize and focus on determining the identity and functions of pp120 kinase in EDG-1 signaling in the context of vascular biology. The research aims are I) purify and clone the pp120EDG-1 associated kinase II) characterize the relevance of pp120 kinase in S1 P/EDG-1 signaling III) study the functions of pp120 kinase in endothelial cells activation and IV) determine the structure-function relationship of EDG-I-i3. The completion of these studies is anticipated to better our knowledge of molecular mechanisms underlying angiogenesis which ultimately may lead to future therapeutic development.

project_terms:
Adenovirus Vector;Affinity;Antibody Affinity;Binding (Molecular Function);Binding Sites;Biology;Blood Vessels;Cell physiology;Chemotaxis;Chromatography Affinity;DNA Complementary;Data;Development;Dominant-Negative Mutation;Embryo;Endothelial Cells;Future;G-Protein-Coupled Receptors;Genes;Goals;In Vitro;Indium;Knowledge;Lead;Ligands;Mediating;Molecular;Morphogenesis;Mutagenesis Site-Directed;Phosphoproteins;Phosphorylation;Phosphotransferases;Plasmids;Procedures;Protein Kinase;Research;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Sphingolipids;Structure-Activity Relationship;Techniques;Technology;Therapeutic;Vascular Endothelial Growth Factors;angiogenesis;base;in vivo;inhibitor/antagonist;molecular mass;mutant;novel;particle;polypeptide;receptor;sphingosine 1-phosphate


application_id: 7242874
project_number: 1R01AG029885-01
project_title: Dietary restriction and proteasome-mediated protein degradation in the aging CNS
administering_ic: NIA
award_notice_date: 2007-08-21
opportunity_number: PA-06-167
application_type: 1
activity_code: R01
ic: AG
serial_number: 029885
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2007-09-01
project_end_date: 2007-12-24
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis. Inhibition of the proteasome-proteolytic pathway is thought to occur as a part of normal aging in most tissues. Proteasome inhibition likely contributes to numerous age-related alterations in the proteome and thereby promotes a variety of cell disturbances during aging although the lack of rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) increases average and maximal lifespan in mammals and suppresses a variety of deleterious age-related alterations at both the cellular and systems level. Our data suggests that DR ameliorates age-related impairments in proteasome function within the central nervous system (CNS). The focus of this proposal is to test the hypothesis that DR ameliorates age-related impairments in proteasome function in the CNS as the result of direct effects on the proteasome complex. Additionally we hypothesize that this preservation of proteolysis by DR contributes to maintenance of the proteome and inhibition of cellular disturbances during aging of the CNS. The specific aims are as follows: (1) to test the hypothesis that DR alters age-related alterations in the biogenesis composition and oxidation of proteasome complexes in selective regions of the CNS; (2) to test the hypothesis that DR alters age-related changes in proteasome function in selective regions of the CNS; (3) to identify which proteins in the CNS exhibit decreased degradation following proteasome inhibition; (4) to test the hypothesis that DR ameliorates age-related elevations in key proteasome substrates within the CNS. Together these data will significantly contribute to our understanding of the molecular basis for DR-induced effects in the CNS and contribute to our understanding of how DR ameliorates age-related impairments in proteasome function in the CNS. Additionally these data will contribute to our understanding of how proteasome inhibition promotes disruptions in the proteome and ultimately contributes to cellular dysfunction in the CNS. Such data may not only be important to our understanding of aging in the CNS but may identify novel therapeutic targets for aging and age-related diseases of the CNS.


application_id: 7241461
project_number: 5R01CA102301-04
project_title: CSN5 Mediates HIF-alpha Stability and Tumor Growth
administering_ic: NCI
award_notice_date: 2007-06-01
application_type: 5
activity_code: R01
ic: CA
serial_number: 102301
program_official: KNOWLTON, JOHN R
project_start_date: 2004-09-01
project_end_date: 2009-06-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 1959966
contact_pi: ZUNDEL, WAYNE S
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Hypoxia-Inducible transcription factors (HIFs) are thought to regulate multiple facets of solid tumor progression. Using genetic and biochemical screens for proteins able to modify HIF-1alpha responses we have isolated the CSN5 subunit of the COP9 Signalosome (CSN). We have further found that CSN5 associated directly and constitutively with the pVHL tumor suppressor. This proposal seeks to define the precise mechanism(s) in which CSN5 regulates pVHL-mediated HIF-alpha stability. To accomplish this we propose to: 1) test if CSN5 regulates global or specific 26S-dependent protein degradation; 2) test if CSN5 binds HIF-1a or pVHL in association with the CSN holocomplex or as a component of another protein complex and which CSN5-associated complex (es) are able to prevent HIF-la ubiquitylation; 3) test if mutations in CSN components that influence CSN assembly or activity can alter HIF-la stability; and 4) examine the mechanism(s) by which CSN5 directly alters HIF-1a stabilization. Accomplishment of these specific aims will reveal novel pathways of HIF-1alpha and pVHL regulation and will suggest potential mechanisms by which these pathways could be manipulated for therapeutic benefit.

project_terms:
Binding (Molecular Function);Biochemical Genetics;Complex;Disruption;Doctor of Philosophy;EP300 gene;Failure (biologic function);Family;Genetic Screening;Goals;Hypoxia;Hypoxia Inducible Factor;Hypoxia Pathway;Mediating;Mutation;Neoplasm Metastasis;Pathway interactions;Primary Neoplasm;Protein Analysis;Proteins;Proteomics;Radiation;Regulation;Research Personnel;Solid Neoplasm;Testing;Therapeutic;Thinking function;Trans-Activation (Genetics);Transcription Coactivator;Tumor Suppressor Proteins;chemotherapy;novel;prevent;programs;protein degradation;response;transcription factor;tumor;tumor growth;tumor progression;ubiquitin-protein ligase


application_id: 7241372
project_number: 1R56AI059165-01A2
project_title: Role of Hsp27 in regulation of Neutrophil Apoptosis
project_terms: apoptosis;clinical research;neutrophil;phosphorylation;proteins;role
administering_ic: NIAID
award_notice_date: 2006-06-27
application_type: 1
activity_code: R56
ic: AI
serial_number: 059165
suffix: A2
program_official: DONG, GANG
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Erythrocyte and Leukocyte Biology Study Section[ELB]
contact_pi_person_id: 6799635
contact_pi: RANE, MADHAVI J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Activated neutrophils (PMNs) play a critical role in sepsis ischemia-reperfusion injury and immune complex-mediated diseases. The broad long-term objective of our laboratory is to elucidate the role of Akt in regulating PMN functions. This proposal will test the hypothesis that Hsp27 modulates neutrophil apoptosis by functioning as a scaffolding protein for Akt activation and induction of neutrophil survival pathways. The specific aims of this proposal are: Specific Aim 1-To identify proteins whose association with the Akt signaling complex is regulated by Hsp27.Specific Aim 2-To determine the effect of protein changes following disruption of Akt-Hsp27complex on the regulation of Akt activation and neutrophil apoptosis. Specific Aim 3 -To identify signaling pathways that underlie Akt-Hsp27 disruption-induced neutrophil apoptosis. Specific Aim 4- To identify Akt auto-phosphorylation sites and determine their effect on assembly of Akt-Hsp27 signal complex Akt activation and neutrophil apoptosis. In specific aim 1 we will disrupt Akt/Hsp27 interaction by 3 separate approaches. A) By transducing TAT-scrambled or TAT- Akt117-128 peptide which encompasses Hsp27 binding site on Akt. B) We will introduce control or anti-Hsp27 antibody into PMNs. C) Transfecting HK-11 cells with scrambled or Hsp27 siRNA. Protein lysates will be subjected to Akt and Hsp27 immunoprecipitation 2D SDS-PAGE MALDI-MS and LC-ESI-MS/MS analysis to identify proteins changes within Akt-Hsp27 complex in the presence or absence of Akt-Hsp27 interaction. Specific aim 2 experiments will determine if proteins (identified in specific aim 1) that associate/ dissociate from Akt-Hsp27 complex affect Akt activity and neutrophil apoptosis. In specific aim 3 we will identify signaling cascades that induce neutrophil apoptosis in the absence of Akt-Hsp27 interaction. In specific aim 4 site-directed mutagenesis and mass spectroscopic techniques will be used to identify in vitro Akt auto-phosphorylation sites. Phospho-specific antibodies to Akt auto-phosphorylation sites will be generated commercially to identify in vivo phosphorylation sites in neutrophils and to determine its effect on assembly of Akt signal module Akt activation and neutrophil apoptosis. These studies will lead us to new targets for disrupting neutrophil-mediated tissue damage in inflammatory diseases.


application_id: 7240589
project_number: 5P20RR015592-08
project_title: Center of Biomedical Research Excellence- Women's Health
administering_ic: NCRR
award_notice_date: 2007-06-21
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
program_official: SAYRE, MICHAEL
project_start_date: 2000-09-15
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
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_abstract:
DESCRIPTION (provided by applicant):    
The objectives of the Center of Biomedical Research Excellence in Women's Health (COBRE-WH) are to deepen our understanding of the unique role of gender and female reproductive hormones in the manifestation of health and disease and use this multi-disciplinary focus as a platform to develop research teams comprised of senior and junior level investigators capable of successfully competing for NIH grant support as independent research centers. We will achieve these objectives by: (1) assembling a cadre of junior and senior level scientists paired together as a research team to examine timely and important questions related to gender reproductive hormones and hormone action (2) providing junior faculty with state-of-the-art multidisciplinary training in concepts relevant to women's health (3) mentoring junior faculty in research projects focused on women's health that will insure that they successfully establish independent NIH-funded research careers (4) supporting shared core facilities to optimize use by COBRE-WH faculty in cutting edge methods and (5) building research teams that will be competitive for extramural funding to establish stand alone Centers. A critical challenge for the COBRE-WH during the next funding period is to become an independent extramurally supported Center(s). To meet this challenge we have structured our COBRE-WH program in a manner that we will have 5 "research teams" or projects that interact with each other in terms of concepts and methods. Each project will be directed by a senior investigator that will incorporate current or previous COBRE-WH supported junior investigators into the project. These research projects are included because they attack critical questions in women's health. Thus junior investigators will be mentored by established NIH-funded faculty who utilize a broad spectrum of state-of-the-art integrative clinical cellular and molecular approaches to probe critical questions in women's health research. This organizational structure will insure that the proposed COBRE-WH program will meet the challenge of increasing the NIH-funded research in the Commonwealth of Kentucky while pursuing the goal of developing the COBRE-WH into as many as 3 separate yet interactive independent program projects or Centers.


application_id: 7239631
project_number: 5R01DA021155-02
project_title: Agonist Replacement Therapy for Cocaine Dependence: Identifying Novel Medications
administering_ic: NIDA
award_notice_date: 2007-03-23
application_type: 5
activity_code: R01
ic: DA
serial_number: 021155
program_official: OVERSBY, STEVEN
project_start_date: 2006-06-01
project_end_date: 2010-03-31
study_section: HIV and Substance Use Research Study Section [NIDA-E]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-04-01
project_abstract:
DESCRIPTION (provided by applicant):     
Cocaine abuse and dependence continue to be significant public health concerns. The number of Americans that used cocaine in the past month the percentage of 12th- 10th- and 8th-graders that used cocaine in the past year and the percentage of treatment admissions involving cocaine has remained stable in recent years. In 1996 cocaine use cost society over $45 billion due to medical consequences lost productivity and crime. Because of the public-health concerns and costs associated with its abuse identifying a pharmacotherapy for cocaine dependence is a priority with the National Institute on Drug Abuse (N.I.D.A.). A pharmacological adjunct for cocaine dependence has not yet been identified. The results of clinical trials suggest that agonist replacement therapies (e.g. d-amphetamine) may be effective for cocaine dependence. Because d-amphetamine reduces cocaine use these clinical findings can be used as a reference to identify human laboratory procedures for screening putative pharmacotherapies. Identifying procedures for assessing the efficacy of putative pharmacotherapies is important because human laboratory studies can be conducted more rapidly/and/efficiently than clinical trials. The present project has two specific aims. The first specific aim is to demonstrate the sensitivity and predictive validity of human laboratory procedures commonly used to screen putative pharmacotherapies for cocaine dependence. To accomplish this aim we will conduct two "proof-of -concept" studies. We will first demonstrate the safety and tolerability of d-amphetamine-cocaine combinations (Exp. 1). We will then demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of cocaine (Exp. 2). The ability to attenuate the reinforcing effects of cocaine may be an important characteristic of an effective pharmacotherapy. The results of these studies will help elucidate the optimal conditions (e.g. dose) under which d-amphetamine might be expected to be effective. The second specific aim is to determine the efficacy of atomoxetine (Strattera(r)) as a putative agonist replacement pharmacotherapy for cocaine dependence. To accomplish this aim we will conduct two experiments to determine the effects of cocaine during atomoxetine maintenance. We will first demonstrate the safety and tolerability of atomoxetine-cocaine combinations (Exp. 3). Finally we will determine the reinforcing effects of intranasal cocaine during atomoxetine maintenance (Exp. 4). Atomoxetine a potent norepinephrine uptake blocker was chosen for study because its pharmacological and behavioral effects overlap to some extent with those of d-amphetamine but it appears to have less abuse potential. Identifying novel agonist replacement therapies is important because clinicians may be reluctant to use d-amphetamine because of its abuse potential.

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


application_id: 7238591
project_number: 5R01HL073085-05
project_title: Angiotensin: A Link Between Obesity and Hypertension
administering_ic: NHLBI
award_notice_date: 2007-05-25
opportunity_number: RFA-HL-02-016
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: BAROUCH, WINIFRED
project_start_date: 2003-06-03
project_end_date: 2009-06-30
study_section: ZHL1-CSR-S(F1)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The proposed studies are in response to RFA-HL-02-016 and will address the working hypothesis that a moderately high fat diet (MHF) stimulates the adipose renin-angiotensin system contributing to obesity-related elevations in blood pressure.  Preliminary data demonstrates that rats fed a MHF diet segregate into obesity prone (OP) versus obesity-resistant (OR) populations.  In OP rats blood pressure was increased coincident with activation of the systemic and adipose renin-angiotensin system.  The first hypothesis is that a MHF diet activates the adipose renin-angiotensin system resulting in an increase in circulating angiotensin peptides and blood pressure.  Time-dependent regulation of adipose versus non-adipose components of the renin-angiotensin system will be examined in control OR and OP rats and compared to the time course for elevations in blood pressure.  The contribution of various circulating angiotensin peptides to blood pressure elevations in control OR and OP rats will be determined.  The second hypothesis is that adipocytes from OP rats exhibit a redistribution of free cholesterol from the plasma membrane to intracellular triglyceride pools thereby increasing the activity of sterol regulatory binding protein-2 and stimulating angiotensinogen (Ao) mRNA expression.  This would provide an adipocyte-specific mechanism for regulation of Ao gene expression in response to the MHF diet.  The intracellular localization of free cholesterol in adipocytes prepared from control OR and OP rats will be determined and compared to the level of Ao mRNA expression.  The effect of depletion of intracellular free cholesterol pools on adipocyte Ao mRNA expression will be determined.  The third hypothesis is that elevations in circulating angiotensin peptides increase blood pressure in OP rats by stimulating sympathetic drive.  The responsiveness of the baroreceptor reflex and the blood pressure response to ganglionic blockade will be determined in control OR and OP rats.  A second approach will determine the effect of neonatal sympathectomy on blood pressure elevations in diet-induced obesity. In hypothesis 4 a novel animal model will be developed to determine the effect of targeted deficiency of Ao in adipose tissue on blood pressure regulation in diet-induced obesity.  The goals of this research are to definitively determine the role of adipose-derived angiotensins and the systemic renin-angiotensin system in blood pressure elevations in diet-induced obesity.

project_terms:
Address;Adipocytes;Adipose tissue;Adult;Angiotensin II;Angiotensinogen;Angiotensins;Animal Model;Baroreflex;Binding Proteins;Blood Pressure;Body mass index;Brown Fat;Cardiovascular system;Cell membrane;Characteristics;Chemicals;Cholesterol;Complication;Cyclodextrins;Data;Development;Diet;Elevation;Exhibits;Fatty acid glycerol esters;Figs - dietary;Gene Expression;Goals;Human;Hypertension;Kidney;Laboratories;Link;Liver;Modeling;Mus;Neonatal;Obesity;Obesity Related Hypertension;Peptides;Population;Production;Proteins;RNA Messenger;Rattus;Regulation;Renin;Renin-Angiotensin System;Research;Resistance;Rodent;Role;Sterols;Sympathectomy;Sympathetic Nervous System;Time;Triglycerides;Work;blood pressure regulation;feeding;mRNA Expression;novel;response


application_id: 7237907
project_number: 5R01NS046267-04
project_title: Tat NADPH oxidase and HIV-dementia
administering_ic: NINDS
award_notice_date: 2007-04-20
application_type: 5
activity_code: R01
ic: NS
serial_number: 046267
program_official: WONG, MAY
project_start_date: 2004-07-15
project_end_date: 2007-12-24
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-05-01
project_abstract:
DESCRIPTION (provided by applicant): HIV dementia (HIVD) is a central nervous system complication of HIV viral infection that appears in as much as one fourth of AIDS patients. As HIV infection in the brain is relatively restricted an unresolved issue in HIV research is how the low viral load in the brain causes such pronounced neuronal dysfunction. An intriguing possibility is that the deleterious effects of HIV infection in the brain are mediated by viral proteins and a viral protein that has been repeatedly implicated in the pathogenesis of HIVD is the regulatory protein Tat. While it is not yet clear how Tat could cause the many manifestations of HIVD recent data from our laboratory show that Tat is able to specifically increase NADPH oxidase-associated superoxide release and subsequent redox-based  inflammatory signaling in glial cells thereby driving toxic brain inflammation. Based on this data we propose that Tat perturbs brain function by increasing both blood brain barrier breech and neuronal injury and that these distinct pathways are mediated by a single mechanism: Tat-mediated induction of NADPH oxidase. To test this hypothesis we have designed in vitro and in vivo studies making use of 2 novel mouse models of Tat-neurotoxicity to model HIVD. Specific aim 1 will test the hypothesis that Tat is able to significantly induce oxidative burst activity and  redox-based signaling in astrocytes and microglial cells both in vitro and in vivo. Specific aim 2 will test the hypothesis that by directly triggering oxidative burst activity Tat causes the release of  matrix metalloproteinases and thus disrupts blood brain barrier integrity in mouse models of HIVD.  Specific aim 3 will build upon these studies by testing the hypothesis that by increasing oxidative burst activity and redox signaling Tat causes the release of neurotoxic inflammatory mediators (free radicals excitotoxins and cytokines) culminating in neuronal injury and behavioral abnormalities in  mice. Completion of these studies will result in a thorough understanding of the mechanisms of Tat-mediated neurotoxicity and could highlight a novel target for therapeutic intervention in HIVD.

project_terms:
AIDS Dementia Complex;Acquired Immunodeficiency Syndrome;Animal Model;Astrocytes;Automobile Driving;Behavioral;Blood - brain barrier anatomy;Brain;Brain Injuries;Cells;Complication;Cystine;Data;Encephalitis;Excitatory Neurotoxins;Free Radicals;Future;Gelatinase A;Gelatinase B;Glutamates;HIV;HIV Infections;In Vitro;Inflammatory;Laboratories;Lead;MAPK14 gene;MAPK8 gene;Matrilysin;Matrix Metalloproteinases;Mediating;Mediator of activation protein;Microglia;Modeling;Mus;NADPH Oxidase;Neuraxis;Neuroglia;Neuronal Dysfunction;Neuronal Injury;Neurons;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathway interactions;Patients;Production;Property;Reactive Oxygen Species;Research;Respiratory Burst;Role;Signal Pathway;Signal Transduction;Superoxides;Synapses;TNF gene;Testing;Therapeutic Intervention;Urticaria;Viral Load result;Viral Proteins;Virus Diseases;antiporter;base;cytokine;design;genetic regulatory protein;in vivo;mouse model;neurotoxic;neurotoxicity;novel;research study


application_id: 7237824
project_number: 5R01MH069991-04
project_title: Modular Abnormalities of Brain Organization in Autism
administering_ic: NIMH
award_notice_date: 2007-05-17
application_type: 5
activity_code: R01
ic: MH
serial_number: 069991
program_official: MEINECKE, DOUGLAS L
project_start_date: 2004-07-01
project_end_date: 2008-05-31
study_section: Special Emphasis Panel[ZRG1-DBD(01)Q]
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-01
project_abstract:
DESCRIPTION (provided by applicant): All subcortical arrangements are primarily nuclear in type. The cortex was the first part of the brain to evolve a radial and laminar arrangement of cells. The resultant modular arrangement is based on the cell minicolumn: a self-contained ecosystem of connectivity linking afferent efferent and interneuronal connections. Our preliminary study of the fundamental processing unit of the cortex the minicolumn indicates that the modular neocortical organization in the brains of autistic individuals differs from that of controls. More specifically a study of 3 neocortical sites in 9 autistic brains and an equal number of normal controls has shown significant differences in the horizontal spacing that separates minicolumns. It also revealed differences in their internal structure: less neuropil space in the periphery of the minicolumn and increased mean cell spacing. Similar abnormalities have now been reported in Asperger's syndrome but appear absent in Down syndrome (a control group added for mental retardation). This study will examine differences in minicolumnar morphometry between 24 autistic brains and 24 controls matched for age and sex from both the Autism Tissue Program and the Yakovlev-Haleem Collection (Armed Forces Institute of Pathology). The patients provide a new cohort not previously examined by the investigator. Ten Down syndrome brains will provide a second control group. Sampled cortical regions include Brodmann's areas 4 9 10 17 21 22 30 33 and 39 which represent sensory motor association and limbic cortex obtained from 4 different brain lobes. The study will utilize quantified computer imaging and stereology in both Nissl and myelin-stained material. The parameters tested include the width of minicolumns the amount of neuropil space within them the mean cell density within each minicolumn individual lamina depth cell size and type (pyramidal versus non pyramidal) and the distribution of cell types among different lamina. The study will employ inter-myelinated bundle measurements as a way of corroborating our minicolumnar width parameters. We will compare the results within multiple regions of the cortex as well as for lateralization. Finally we will correlate our minicolunmar parameters with different dimensions on the ADI. This study aims at better understanding the neuroanatomical basis of autism. If validated positive results from our studies will yield a great understanding of autism. For example many alleged animal models of autism lack the human neuroanatomic information to justify their utility. Candidate gene studies could also be refined if neuroanatomic development in autism was better understood. Treatment modalities especially neuropharmaceutical agents will prove more specific as their targets are better understood.

project_terms:
Acceleration;Accounting;Affect;Age;Amygdaloid structure;Animal Model;Anterior;Area;Area striata structure;Asperger Syndrome;Autistic Disorder;Autopsy;Axon;Behavior;Bilateral;Blindness;Brain;Brain Part;Brain region;Brodmann's area;Candidate Disease Gene;Case Study;Cell Count;Cell Size;Cells;Cerebral cortex;Cerebrum;Chromosome Pairing;Clinical;Code;Cognitive;Cognitive deficits;Collection;Communication;Communication Personal;Computer information processing;Concept Formation;Control Groups;Count;Data;Deafness;Density Cell;Depth;Development;Diagnosis;Diagnostic;Diamond;Dimensions;Disease;Down Syndrome;Ecosystem;Evolution;Exhibits;Eye;Facial Expression;Fiber;Functional Imaging;Functional disorder;Gene Abnormality;Gray unit of radiation dose;Growth;Hand;Human;Image;Image Analysis;Impairment;Individual;Institutes;Interview;Language;Learning;Left;Link;Literature;Lobe;Magnetic Resonance Imaging Functional;Measurement;Measures;Mental Retardation;Methods;Mind;Minor;Modality;Morphology;Motor;Motor Cortex;Myelin;Neocortex;Neurons;Neuropil;Nonverbal Communication;Nuclear;Numbers;Paper;Parietal Lobe;Pathology;Patients;Pattern;Persons;Planet Mars;Principal Investigator;Process;Pyramidal Cells;Radial;Range;Rate;Relative (related person);Reporting;Research;Research Personnel;Saccades;Sample Size;Sampling;Scanning;Scheme;Score;Seizures;Sensory;Severities;Site;Sound Localization;Staining method;Stains;Structure;Surface;Symptoms;Synapses;Temporal Lobe;Testing;Thick;Tissues;Tomography Emission-Computed Single-Photon;Trees;Upper arm;Variant;Weight;Width;Writing;association cortex;autistic Children;base;brain volume;cell body (neuron);cell type;cohort;computerized;concept;density;design;digital imaging;frontal lobe;gaze;indexing;interest;mind control;morphometry;neocortical;postnatal;programs;sensory cortex;sex;size;social;speech processing;stroke;theories;white matter


application_id: 7237187
project_number: 5R01AI057808-05
project_title: Role of RANTES in Pneumococcal Immunopathogenesis
administering_ic: NIAID
award_notice_date: 2007-08-28
application_type: 5
activity_code: R01
ic: AI
serial_number: 057808
program_official: KHAMBATY, FARUKH M
project_start_date: 2004-08-01
project_end_date: 2010-05-31
study_section: Bacteriology and Mycology Subcommittee 2[BM-2]
contact_pi_person_id: 1860389
contact_pi: LILLARD, JAMES W
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-01
project_abstract:
DESCRIPTION (provided by applicant): Streptococcus pneumoniae infections are becoming increasingly difficult to manage due to the inability of susceptible individuals to mount appropriate anti -polysaccharide and to a lesser degree -surface protein antibody responses as well as increasing antibiotic resistance. Hence new prophylactic interventions and understanding of pneumococcal immunopathogenesis are greatly needed. This proposal stems from and focuses on our recent findings that RANTES (regulated on activation normal T cell expressed and secreted) significantly yet differentially enhances mucosal and systemic immunity. We present preliminary data that RANTES mRNA mucosal expression is elevated during the primary inflammatory/adaptive recognition response to pneumococcal carriage which suggests that RANTES is essential for protective mucosal immunity to S. pneumoniae infections. RANTES MIP-1alpha and CCR5 polymorphisms resulting in diminished expression are also associated with increased susceptibility to- and progression of- other mucosal pathogens in man. In this regard our preliminary results show that RANTES blockade leads to the transition of pneumococcal carriage to lethal pneumonia in a mouse model of carriage using S. pneumoniae strain EF3030. These findings provide the rationale to support the hypothesis that RANTES is essential for the induction of protective mucosal and systemic adaptive immunity against S. pneumoniae.  We have emphasized in vivo approaches using mouse models of pneumococcal -carriage and -pneumonia to test this hypothesis. Aim One will assess the recognition phase host immune response to EF3030 challenge in normal RANTES- or T cell- blocked mice. Aim Two will characterize the adaptive (activation/effector phase) mucosal and systemic immune responses to the phosphorylcholine determinant of C-polysaccharide (PC) and pneumococcal surface adhesin A (PsaA) during pneumococcal disease in control Ab-treated or RANTES-inhibited mice. Aim Three will ascertain the role of RANTES in protection against carriage and/or pneumonia induced by wild type mutant surface protein (e.g. psaA-) and rough EF3030 strains. This study will provide important and new information regarding the cellular and molecular mechanisms that RANTES uses to induce protective immunity against pneumococci.

project_terms:
6H8H-34-dihydropyrimido(45-c)(12)oxazin-7-one;Address;Adhesins Bacterial;Antibodies;Antibody Formation;Antigens;CCR5 gene;CD4 Positive T Lymphocytes;CD8B1 gene;Computer software;Control Groups;Data;Development;Enzyme-Linked Immunosorbent Assay;Flow Cytometry;Hepatitis B e Antigens;Image;Immune response;Immunity;Immunity Cellular;Immunity Mucosal;Immunization;Immunoglobulin A;Individual;Infection;Infectious Agent;Inflammatory;Interleukin-10;Intervention;Kinetics;Leukocytes;Life;Ligands;Macrophage Inflammatory Protein-1;Macrophage Inflammatory Proteins;Mediating;Medical Surveillance;Membrane Proteins;Molecular;Mus;Nose;Numbers;Organ;Pathogenesis;Phase;Phosphorylcholine;Play;Pneumococcal Infections;Pneumonia;Polymorphism Genetic;Polysaccharides;Predisposition;Production;RNA Messenger;Research;Resistance Antibiotic;Role;Series;Serum;Small Inducible Cytokine A3;Spleen;Streptococcus pneumoniae;Surface;System;T-Lymphocyte;Testing;Time;Tissues;Virulence Factors;capsule (pharmacologic);cytokine;day;enzyme linked immunospot assay;in vivo;mRNA Expression;man;mouse model;mutant;pathogen;polysaccharide C-substance (Streptococcus);programs;prophylactic;research study;response;stem


application_id: 7236740
project_number: 5R01DE015254-05
project_title: Pattern Recognition of P. gingivalis Virulence Factors
administering_ic: NIDCR
award_notice_date: 2007-05-29
application_type: 5
activity_code: R01
ic: DE
serial_number: 015254
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-07-01
project_end_date: 2008-07-31
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: 2007-07-01
project_abstract:
DESCRIPTION: Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) form functional receptor complexes that recognize pathogen-associated molecular patterns (PAMPs). Activation of the TLR signaling pathway by PAMPs leads to induction of immune and inflammatory responses. Porphyromonas gingivalis is an important pathogen in human periodontitis. A major cell surface component of this oral pathogen is the fimbriae which function as an adhesin. Strikingly fimbriae activate transcription factor NF-KappaB and induce production of proinflammatory cytokines through interactions with several PRRs. Understanding the molecular basis of how the host recognizes and responds to P. gingivalis fimbriae is essential for developing molecular approaches to control periodontal inflammation. Therefore the objective of this grant is to elucidate the proinflammatory interactions of fimbriae with PRRs. The application proposes that fimbriae function as a PAMP and interact in a regulated mode and through discrete epitopes with different binding PRRs resulting in the activation of proinflammatory TLR signaling. Fimbrial epitopes involved in cellular binding and/or activation will be identified using fimbrial peptides and mutant fimbriae. Importantly epitopes involved in binding but not activation may find application as antagonists of fimbria-induced inflammation. Experiments in our laboratory have shown that TLR2 and TLR4 mediate fimbria-induced signaling but initial recognition of fimbriae is mediated by a cooperation between CD14 and CD11 b/CD18 which thus appear to serve as TLR co-receptors. It is posited that fimbriae initially bind to CD14 and the fimbriae/CD14 complex induces TLR2-mediated "inside-out" signaling that leads to activation of the ligand-binding capacity of CD11b/CD18. PRR-fimbriae interactions will be examined in human monocytes and mouse macrophages derived from normal and PRR-deficient mice. Elucidation of the mechanisms whereby PRRs recognize and respond to fimbriae and identification of fimbrial antagonists may facilitate the design of novel approaches to therapeutic intervention in both periodontitis and atherosclerosis where P. gingivalis has also been implicated.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Adhesins Bacterial;Adopted;Affinity;Amino Acids;Antigens CD11;Atherosclerosis;Binding (Molecular Function);Biological Assay;CD14 gene;Cell model;Cell surface;Chronic;Complex;Data;Development;Disease;Epitopes;Fimbria of hippocampus;Genes;Grant;Human;ITGAM gene;Immune;Immunity Natural;Infection;Inflammation;Inflammatory;Inflammatory Response;Laboratories;Length;Ligand Binding;Ligands;Maps;Mediating;Molecular;Molecular Conformation;Monoclonal Antibodies;Mus;NF-kappa B;Parents;Pattern;Pattern Recognition;Pattern recognition receptor;Peptides;Periodontitis;Pilum;Porphyromonas gingivalis;Production;Receptor Activation;Receptor Signaling;Recruitment Activity;Research Personnel;Role;Signal Pathway;Signal Transduction;TLR2 gene;TLR4 gene;Therapeutic Intervention;Thinking function;Toll-like receptors;Transducers;Virulence Factors;activating transcription factor;base;cytokine;design;fimbrillin;inhibitor/antagonist;macrophage;monocyte;mutant;novel strategies;oral pathogen;pathogen;programs;receptor;receptor function;research study;response


application_id: 7236632
project_number: 5R01CA095609-04
project_title: Transcriptional Control of Breast Cancer Through PPARg
administering_ic: NCI
award_notice_date: 2007-04-13
application_type: 5
activity_code: R01
ic: CA
serial_number: 095609
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2004-08-05
project_end_date: 2009-05-31
study_section: Biochemical Endocrinology Study Section[BCE]
contact_pi_person_id: 8288294
contact_pi: KILGORE, MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-06-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of these studies is to develop therapeutic strategies to treat or prevent breast cancer. Since our demonstration that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed and functionally active in breast cancer cells a rapidly growing body of evidence has accumulated indicating that PPARgamma plays a central role in many types of cancer including breast cancer. Ligands include the antidiabetic thiazolidinediones prostaglandin J2 fatty acids and others. Treating breast cancer cells with PPARgamma ligands have alternatively been reported to induce cell cycle withdrawal apoptosis or mediate the expression of genes leading to a more differentiated less malignant state. Other ligands including fatty acids have been reported to mediate the expression of genes that alter the malignancy and metastatic potential of breast cancer cells. The mechanism underlying these divergent actions has not been established. We have recently reported that the expression of ERalpha inhibits PPARgamma transactivation. Thus we will test the hypothesis that selective transactivation of PPARgamma by different ligands mediates gene expression profiles that favor either differentiation or proliferation depending on the specific ligand used and the functional status of the ER in the same cells. Therefore in Specific Aim 1 we will test the hypothesis that different PPARgamma ligands induce conformational changes that result in selective regulation of gene expression profiles and physiological responses in normal epithelia and in breast cancer cells. In Specific Aim 2 we will examine the necessity of PPARgamma in mediating the gene expression profiles involved in proliferation differentiation and apoptosis. In Specific Aim 3 we will examine the mechanism whereby the estrogen receptor alters the transactivation of PPARgamma and examine the physiological consequences of this interaction. This represents a novel approach to understanding the role PPARy plays in breast cancer and its selective modulation could point to novel mechanisms of action and to therapeutic targets.


application_id: 7235611
project_number: 5R01EY015422-04
project_title: Novel Mouse Models of Age-Related Macular Degeneration
administering_ic: NEI
award_notice_date: 2007-05-03
opportunity_number: PA-00-009
application_type: 5
activity_code: R01
ic: EY
serial_number: 015422
program_official: SHEN, GRACE L
project_start_date: 2004-06-01
project_end_date: 2010-05-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Introduction: Age-related macular degeneration (AMD) is the leading cause of elderly blindness in the U.S. Absence of good animal models has limited mechanistic understanding and thwarted development of therapies. We observed that mice genetically deficient either in the macrophage chemokine CCL2 or its cognate receptor CCR2 develop the pathological hallmarks of AMD in an age-dependent fashion.    Preliminary Data: (1) CCL2-/- and CCR2-/- mice develop lipofuscin drusen geographic atrophy and choroidal neovascularization (CNV) as they age. (2) Complement C5 and IgG are deposited in the retinal pigmented epithelium (RPE) and choroid of both knockout strains as they age as in patients with AMD. (3) These findings are not present in age-matched wild-type mice. (4) Macrophages infiltrate into the choroid of aged wild-type mice but not knockouts in large numbers. (5) C5a and IgG upregulate RPE secretion of CCL2. (6) C5a and IgG upregulate RPE and choroidal endothelial cell secretion of vascular endothelial growth factor (VEGF) consistent with CNV development. (7) Macrophages are immobilized by and adhere to C5a & IgG.    Hypotheses: (1) The accumulation of drusen and lipofuscin associated with senescence in CCL2-/- or CCR2- /- mice is due to impaired clearance by scavenger macrophages whose recruitment is impaired in the absence of CCL2 or its receptor CCR2 and ultimately leads to geographic atrophy and CNV. (2) Rescue of CCL2 or CCR2 function can prevent or regress AMD-like pathology in knockout mice.    Specific Aims: (1) To quantify the development of AMD-like features in CCL2-/- or CCR2-/- mice by ophthalmoscopy angiography and histopathology compared to age-matched wild-type mice. (2) To demonstrate that protein deposits found in the RPE and choroid of senescent CCL2-/- or CCR2-/- mice stimulate CCL2 and VEGF production and that macrophages adhere to and degrade these protein deposits. (3) To demonstrate that rescue of CCL2 or CCR2 function inhibits or regresses AMD-like pathology in elderly CCL2-/- or CCR2-/- mice.    Significance: These studies will provide mechanistic insights into and more effective treatments for AMD.

project_terms:
Adherence (attribute);Age;Age related macular degeneration;Age-Months;Amyloid;Amyloid beta-Protein;Angiography;Animal Model;Atrophic;Binding Proteins;Blindness;Blotting Western;Bone Marrow;CCL2 gene;Cell secretion;Cells;Choroid;Choroidal Neovascularization;Code;Complement 5a;Complement component C5;Data;Deposition;Development;Disease regression;Drusen;Elderly;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Eye;Frozen Sections;Glass;Histopathology;Human;Immunoglobulin G;Immunohistochemistry;In Situ;In Vitro;Knock-out;Lipofuscin;Mice Knockout;Mus;Numbers;Ophthalmoscopy;Pathology;Patients;Photography;Production;Proteins;Research Personnel;Serum;Slide;Spottings;Stem cells;Structure of retinal pigment epithelium;Testing;Transplantation;Vascular Endothelial Growth Factors;Vitronectin;Wild Type Mouse;adeno-associated viral vector;age related;aged;chemokine;complement C3 precursor;insight;macrophage;monocyte chemoattractant protein 1 receptor;mouse model;novel;prevent;programs;protein degradation;response;senescence;subretinal injection;therapy development


application_id: 7233896
project_number: 3R41AA014555-01S2
project_title: Application of plant genomics to alcoholic brain damage
administering_ic: NIAAA
award_notice_date: 2006-05-25
opportunity_number: RFA-AA-03-005
application_type: 3
activity_code: R41
ic: AA
serial_number: 014555
suffix: S2
program_official: FERTIG, JOANNE
project_start_date: 2004-06-15
project_end_date: 2008-05-31
study_section: ZAA1
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
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Alcoholic liver damage (ALD) is among the ten most common causes of death in the USA. The liver may be uniquely sensitive because it metabolizes ethanol at a high rate. This generates acetaldehyde intracellularly damaging cell components directly and/or inducing apoptotic cell death. Although some plant natural products are protective it would be of value to discover agents with greater efficacy against ALD. Here a novel biotechnology based on selection of mutant plant cells for resistance to alcohol followed by high throughput pharmacological screening (HTPS) of extracts from surviving cells is applied to this problem. The mutant population will be generated by activation tagging mutagensis and extracts from the resulting alcohol-resistant clonal cultures screened for protection of hepatocyte cultures against ethanol-induced damage. However because plant cells in culture metabolize ethanol to a very limited extent we propose first to produce transgenic plant lines (N tabacum) over-expressing the activated gene for plant or mammalian ADH. Cell cultures derived from these plants will be evaluated for similarities to mammalian liver cells in metabolism of ethanol to acetaldehyde. Phase 1 is the creation of these ADH-expressing (ADHE) lines. In subsequent phases hepatoprotective compounds from resitant clonal extracts will be tentatively identified by GC/MS.  Regardless of whether novel compounds are discovered the ADHE plant lines and the ethanol resistant clonal cultures are patentable and represent a valuable resource for development of alcohol-related medications in the future.

project_terms:
Agrobacterium tumefaciens;alcoholism /alcohol abuse;antioxidants;biotechnology;biotherapeutic agent;brain injury;drug screening /evaluation;ethanol;fluorescence microscopy;gas chromatography mass spectrometry;gene expression;genetically modified plants;high throughput technology;molecular cloning;molecular probes;neural degeneration;neuropharmacology;neuroprotectants;neurotoxicology;oxidation;oxidative stress;plant extracts;plant genetics;protoplast /spheroplast;tissue /cell culture


application_id: 7233804
project_number: 1R01DK077624-01
project_title: B-cells in pups of mild and severe STZ diabetic mothers; andtioxidant protection
administering_ic: NIDDK
award_notice_date: 2006-09-21
opportunity_number: RFA-DK-05-014
application_type: 1
activity_code: R01
ic: DK
serial_number: 077624
program_official: CASTLE, ARTHUR
project_start_date: 2006-09-15
project_end_date: 2007-07-31
study_section: Special Emphasis Panel[ZDK1 GRB-N (O1)]
contact_pi_person_id: 8340262
contact_pi: LIU, YE Q
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): Maternal diabetes (MD) increases risk for obesity and type 2 diabetes mellitus (T2DM) in adulthood. Our long-term goal is to understand offspring pancreatic B-cell damage by MD and the adaptive mechanisms of the offspring B-cell to insulin resistance and what goes wrong in this adaptation during the pathogenesis of T2DM. Specifically we are interested in the role of free radical oxygen species (ROS) during pregnancy that may be critical for damaging offspring B-cell adaptation. The insulin secreting B-cell is one of the most sensitive cells in the body to ROS damage and the levels of anti-ROS enzymes such as catalase superoxide dismutase (SOD) are the lowest and are not up-regulated by hyperglycemia. Most of the support for the antioxidant hypothesis derives from treatment of diabetic rats with antioxidant vitamins E and C. However there is only a little evidence that comes from basic research on B-cell. In addition most works were done on streptozotocin (STZ)-induced severe diabetic models that produce low birth weight offspring and more significant outcomes than that in mildly hyperglycemic models. In human hyperglycemia in most diabetic women is under control before and during pregnancy thus hyperglycemia is not severe and the offspring birth weight of most diabetic mothers is high (macrosomic); therefore STZ-induced severe MD is not like human MD. We have observed that severe MD induced aberrations in pancreatic islet. To test the ROS hypothesis and significance of offspring birth weight and the significance of severity of MD we will apply our expertise in islet function to determine if insulin secretion is preserved by transgenic antioxidant proteins in the offspring of mild and severe diabetic mothers. We have produced fourteen lines of transgenic mice that overexpress catalase manganese SOD (MnSOD) and metallothionein (MT) in B-cells and we have tested that these transgenes have no deleterious effect on FVB mouse B-cell structure or function. We have showed that catalase MnSOD and MT overexpression protects islets against STZ or ROS and found a high level of protection against diabetes. They provide an ideal model to test the hypothesis that ROS contribute to B-cell damage. We will produce two kinds of offspring from STZ-induced mild and severe diabetic mothers and comparatively examine whether antioxidant treatment and these antioxidant transgenes in fetal B-cells can prevent or delay the development of T2DM in adulthood.

project_terms:
antioxidants;catalase;disease /disorder model;free radical oxygen;gene expression;genetically modified animals;glucose clamp technique;glucose tolerance test;insulin;insulin sensitivity /resistance;laboratory mouse;metallothionein;noninsulin dependent diabetes mellitus;obesity;oxidation;pancreatic islets;pregnancy;streptozotocin;superoxide dismutase


application_id: 7233778
project_number: 1R01DK077632-01
project_title: Protective Effects of Stearic Acid on Gestational and Acquired Diabetes Mellitus
administering_ic: NIDDK
award_notice_date: 2006-09-21
opportunity_number: RFA-DK-05-014
application_type: 1
activity_code: R01
ic: DK
serial_number: 077632
program_official: CASTLE, ARTHUR
project_start_date: 2006-09-15
project_end_date: 2010-09-14
study_section: Special Emphasis Panel[ZDK1 GRB-N (O1)]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: GRAF, GREGORY A
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
CD antigens;adipose tissue;angiotensins;diabetes mellitus therapy;disease /disorder model;fatty acids;gestational diabetes mellitus;glucose tolerance test;laboratory mouse;membrane transport proteins;nonhuman therapy evaluation;oxidation;pathogenic diet;phenotype;pregnancy;protein localization;protein structure function;stearates;tissue /cell culture


application_id: 7233735
project_number: 1R21DK077643-01
project_title: Fetal Adiponectin Expression /Obesity of Gestational Diabetes Mellitus Offspring
administering_ic: NIDDK
award_notice_date: 2006-09-21
opportunity_number: RFA-DK-05-014
application_type: 1
activity_code: R21
ic: DK
serial_number: 077643
program_official: CASTLE, ARTHUR
project_start_date: 2006-09-15
project_end_date: 2008-09-14
study_section: Special Emphasis Panel[ZDK1 GRB-N (O1)]
contact_pi_person_id: 8333955
contact_pi: SHAO, JIANHUA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Over the last two decades the prevalence of obesity has increased to epidemic proportions in the general population of the US. Gestational diabetes mellitus (GDM) increases the neonate birth weight which closely associates with the development of adolescent and adult obesity. Therefore the intrauterine GDM environment predisposes a high risk of obesity in GDM offspring. Our long-term goal is to investigate the underlying mechanisms that increase birth weight and the susceptibility of obesity in GDM offspring. Adiponectin is an adipose-derived hormone and plays an important role in regulating glucose and lipid metabolism. Recent studies revealed that fetal and neonatal serum adiponectin concentrations are 4-7 fold higher than those in adults. Serum adiponectin levels positively correlate with gestational age and body weight which indicates that adiponectin may regulate fetal development and growth. Furthermore most recent studies demonstrated that the overexpression of adiponectin promotes obese phenotype in mice and adiponectin enhances adipocyte differentiation and lipid accumulation. Our preliminary studies demonstrated that newborn mice from mothers with GDM exhibit a high birth weight elevated adiponectin expression and serum adiponectin protein levels. High fat feeding also induces more weight gain in the GDM offspring. We hypothesize that the GDM intrauterine environment increases fetal adiponectin expression which predisposes high birth weight and susceptibility of obesity in GDM offspring. In Specific Aim 1 we will determine the effect of the GDM intrauterine environment on adiponectin gene expression from fetus to adult using a well established GDM mouse model (db/+). The relationship of maternal or fetal energy metabolism and fetal adiponectin gene expression will be evaluated. In Specific Aim 2 the role of adiponectin in GDM- induced high birth weight and subsequent development of obesity will be studied by cross-mating db/+ and adiponectin gene deficient mice. The results of this project will not only determine the role of adiponectin in GDM-associated high birth weight and the subsequent development of obesity but also provide very useful information regarding fetal adiponectin gene expression and the involvement of adiponectin in regulating fetal development and growth under normal gestational condition. These results will lead to a new strategy for obesity prevention.

project_terms:
adiponectin;animal birth weight;biological models;disease /disorder proneness /risk;embryo /fetus;gene environment interaction;gene expression;genetic regulation;genetically modified animals;gestational diabetes mellitus;growth /development;hormone regulation /control mechanism;laboratory mouse;mature animal;obesity;pathologic process;pregnancy


application_id: 7233697
project_number: 5U10NS053368-02
project_title: Neuroprotection Exploratory Trials in PD (NET-PD)
administering_ic: NINDS
award_notice_date: 2007-02-05
opportunity_number: RFA-NS-05-004
application_type: 5
activity_code: U10
ic: NS
serial_number: 053368
program_official: MOY, CLAUDIA S
project_start_date: 2006-05-17
project_end_date: 2010-11-30
study_section: ZNS1-SRB-K(30)
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Parkinson's disease (PD) is a slowly but relentlessly progressive neurodegenerative disorder resulting in a time-dependent worsening of clinical symptoms. Anti-PD drugs effectively ameliorate most of the major parkinsonian signs and symptoms in a majority of patients. However traditional drug therapies do not modify the progressive deterioration of motor function and functional disability worsens over time. Thus disease modifying drugs that can slow clinical progression enhance repair of damaged neurons restore or enhance function of residual parts of the dopamine (DA) system are much needed. Since disease progression is generally slow treatment with compounds that target multiple pathogenic mechanisms can be implemented over a relatively long period of time. The NET-PD multicenter trial is aimed at testing the efficacy of potential neuroprotective compounds in early stage PD patients. Compounds that are ascertained to be effective in the Futility studies will be tested in large double-blinded placebo control studies. The Neurodegeneration and Clinical Trial Groups of the NINDS are requesting applications for new centers to collaborate in clinical trials to test potential neuroprotective agents. We are proposing to become a NET-PD center. The Movement Disorders Center at University of Kentucky serves the greater Lexington area a primarily urban community and the largely rural 63-county area of central eastern and southeastern Kentucky. In addition we treat several PD patients (-25) who reside in West Virginia and Southern Ohio. We follow -600 PD patients and we diagnose on average 5 new PD patients per month. Therefore we expect to be able to enroll 1-2 early stage PD patients per month into the Pilot Trials.

project_terms:
Accounting;Affect;Age;Age of Onset;Anxiety;Area;Autonomic Dysfunction;Back;Basal Nucleus of Meynert;Bradykinesia;Chromosome Pairing;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Communities;Corpus striatum structure;County;Deterioration;Diagnosis;Disease;Disease Progression;Dopamine;Double-Blind Method;Enrollment;Environmental Risk Factor;Etiology;Functional disorder;Futility;Gait;Gait abnormality;Genetic;Impaired cognition;Incidence;Individual;Kentucky;Lead;Life Style;Mental Depression;Motor;Motor Manifestations;Movement Disorders;Multicenter Trials;Muscle Rigidity;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neuroprotective Agents;Numbers;Occupations;Ohio;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pigments;Productivity;Range;Request for Applications;Residual state;Rest Tremor;Rural;Signs and Symptoms;Smell Perception;Staging;Structure of locus ceruleus;Structure of putamen;Substantia nigra structure;Symptoms;Synapses;Testing;Thinking function;Time;Toxic Environmental Substances;Toxin;Universities;West Virginia;career;disability;dopamine system;executive function;functional disability;neuropathology;neuroprotection;nigrostriatal system;pars compacta;pilot trial;placebo controlled study;raphe nuclei;repaired


application_id: 7233301
project_number: 5F31AR050951-04
project_title: Use of Cellular Energy Delivery System in Wound Healing
administering_ic: NIAMS
award_notice_date: 2007-03-22
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: AR
serial_number: 050951
program_official: LAPHAM, CHERYL K
project_start_date: 2005-04-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-DIG-B(29)L]
contact_pi_person_id: 7141987
contact_pi: THOMAS, CANDICE M
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 long-term goals of Ms. Thomas' project are to understand how topically applied VitaSol (ATP encapsulated in fusogenic lipid vesicles) can accelerate the rates of wound closure and how VitaSol affect scar formation. A wound to the integument is an area of ischemia and a number of reviews have suggested that the major inhibition to wound healing is the lack of oxygen and nutrients to the wound border cells. vltaSol overcomes the problem of ischemia because ATP is delivered directly to the cells and thus the need for oxygen and nutrients to produce ATP is significantly reduced. Preliminary data in the PI's lab has shown a superior effect of VitaSol on wound closure rates (>70% increase in wound closure time). The specific aims the project are: 1) Identify the ATP consumption rate of epidermal and dermal skin in swine 2) Adjust the formulation of VitaSol in order to deliver ATP to the epidermal and dermal wound broader cells at rates that match or exceed the ATP consumption rate of the skin cells 3) Apply VitaSol to full-thickness and partial thickness wounds and measure the rates of wound closure and scare formation and 4) Determine the toxicity and morbidity of topically applied VitaSol to the skin and to the whole animal.


application_id: 7232559
project_number: 1R56AI067869-01
project_title: YopM and protective innate defenses against plague
project_terms: cytokine;genes
administering_ic: NIAID
award_notice_date: 2006-06-27
opportunity_number: PA-04-119
application_type: 1
activity_code: R56
ic: AI
serial_number: 067869
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague and a significant concern to public health and safety due to its potential abuse as a bioterrorist weapon. This proposal focuses on how the plague virulence protein YopM undermines host innate defenses early in plague. The studies of Aim 1 will establish a sequence and hierarchy for the roles of macrophages dendritic cells PMNs natural killer cells and CD8+ T cells in the innate host response to plague and determine how this response is modulated by YopM. Mice will be depleted of specific immune cell populations infected with Y. pestis KIMS or a YopM- mutant and assessed for their cellular histopathological and cytokine gene and protein expression as well as bacterial numbers in organs during the initial days of systemic plague. The experiments of Aim 2 will map the cytokine circuitry in the presence and absence of YopM by ablating and reconstituting mice for key cytokines of three major antimicrobial pathways and analyzing the outcome of infection by parent and YopM- mutant Y. pestis as in Aim 1. The studies of Aim 3 build upon the discovery of a plague-resistant inbred mouse strain that appears to by-pass the effects of YopM. The proposed studies will map the genes responsible for resistance by determining dominance and then conducting backcross and SSLP marker linkage analysis. In parallel the host responses that are altered in these mice will be analyzed by using the methods of Aims 1 and 2 to aid in identification of the responsible resistance gene(s) in these mice as well as to reveal how innate defenses can be altered to confer resistance to plague. The proposed studies will determine how YopM modulates the innate immune response to Y. pestis and in the process develop a systematic characterization of the innate immune response to plague. The project will enrich our understanding of both basic immunology and the pathogenesis of plague as well as provide the foundation for therapies to enhance resistance to plague in humans.


application_id: 7232415
project_number: 5K08NS050110-03
project_title: Alpha-synuclein mRNA is a putative microRNA target
administering_ic: NINDS
award_notice_date: 2006-06-05
application_type: 5
activity_code: K08
ic: NS
serial_number: 050110
program_official: MURPHY, DIANE
project_start_date: 2005-04-01
project_end_date: 2010-04-30
study_section: Neurological Sciences Training Initial Review Group[NST]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_terms:
alpha synuclein;antisense nucleic acid;bioinformatics;human tissue;intermolecular interaction;messenger RNA;microRNAs;nucleic acid purification;nucleic acid quantitation /detection;polysomes;ribonucleoproteins;tissue resource /registry


application_id: 7232265
project_number: 5R01HD052694-02
project_title: Endothelin-2 in Ovarian Follicle Rupture
administering_ic: NICHD
award_notice_date: 2007-03-31
application_type: 5
activity_code: R01
ic: HD
serial_number: 052694
program_official: TAYMANS, SUSAN
project_start_date: 2006-05-15
project_end_date: 2011-02-28
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-03-01
project_abstract:
DESCRIPTION (provided by applicant): The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in follicle rupture. The program of ovulation is activated by a surge of luteinizing hormone which initiates dramatic changes in molecular biochemical and physical aspects of the ovary eventually leading to rupture of follicles. However the factors involved in and the mechanism governing the process of follicle rupture are yet to be unveiled. Using a gene expression profiling approach we have identified EDN-2 a potent smooth muscle constrictor which is exclusively and transiently expressed in the granulosa cells of periovulatory follicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in the ovarian tissue while tezosentan an endothelin receptor antagonist released the contraction. These novel findings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture of the follicle. Supporting the hypothesis immunohistochemical analysis identified a well-organized smooth muscle layer in the theca externa of each follicle which forms a sponge-like smooth muscle network at the whole ovarian level. Furthermore we found that intraovarian injection of tezosentan prior to ovulation completely blocked follicle rupture. In this study we will elucidate the mechanism of EDN-2 action in follicle rupture. We will determine the target tissues of EDN-2 action the endothelin receptor subtype(s) that mediates EDN-2 action and the ovarian concentration of EDN-2. We will also determine the mechanism of endothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrictive molecules (VIPs PACAPs and prostaglandins). In addition the functional link of progesterone estrogen and prostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposal is in the identification of EDN-2 and the ovarian smooth muscle network as the key components of follicle rupture. The novelty of the proposed experiments is the interdisciplinary approaches (genome-wide gene expression profiling intraovarian injection and isometric tension measurement). The proposed studies are exceptionally important in order to further our understanding of the mechanism of follicle rupture. The proposed experiments will provide clinical direction in identifying the therapeutic target for the cure of annovulatory symptoms one of the leading causes of female infertility.

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


application_id: 7232152
project_number: 7R21AA015666-02
project_title: Alcohol Use & HIV: Developing Computerized Interventions
administering_ic: NIAAA
award_notice_date: 2006-05-24
opportunity_number: PA-03-107
application_type: 7
activity_code: R21
ic: AA
serial_number: 015666
program_official: BRYANT, KENDALL
project_start_date: 2006-05-24
project_end_date: 2007-05-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 1971511
contact_pi: CONIGLIARO, JOSEPH
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): Alcohol use and hazardous drinking have significant implications for the clinical management and health outcomes of HIV positive patients. Alcohol use in HIV positive patients is believed to be associated with increased morbidity and mortality more rapid disease progression poorer adherence to antiretroviral regimens and greater risk of viral resistance. Despite this risk HIV providers do not accurately identify alcohol use and hazardous drinking. The long-term objective of this developmental R21 proposal is to improve the detection and management of hazardous drinking in HIV clinical settings thereby reducing long term health and economic consequences. One (1) method to achieve this objective is through brief interventions (BIs). BIs are simple treatments that vary from brief advice to a short motivational interview and persuade drinkers to reduce their alcohol intake to low risk levels and consequently reduce medical complications and resource use. Computer technology offers a promising and understudied method of delivering Bis in the healthcare setting. This application will combine Bis with state-of-the-art computer technology to deliver patient-specific recommendations based on clinical guidelines. The specific aims of this developmental project are: 1) To adapt and test a computer alcohol screening and Bl prototype ("the prototype") using an iterative qualitative process of user testing focus groups and face-to-face interviews with providers and HIV positive patients; 2) To test the feasibility of implementing the prototype assess potential barriers to alcohol screening and intervention (e.g. complexity of medication regimen social issues etc.) and gather data on enrollment rates in two Department of Veterans Affairs HIV clinics; 3) To test whether the intervention is associated with a decrease in alcohol consumption 90 days post-BI in HIV positive patients who screen positive for hazardous drinking. This exploratory/developmental proposal will produce a field-tested intervention and dependable estimates for sample size recruitment rate and number of sites needed for a randomized clinical trial.

project_terms:
HIV infections;alcoholism /alcohol abuse therapy;behavior therapy;behavioral /social science research tag;clinical research;computer assisted medical decision making;counseling;diagnosis design /evaluation;human subject;patient care planning;patient oriented research;therapy design /development


application_id: 7232106
project_number: 5R21ES013821-03
project_title: Perinatal Breast Cancer Programming--Fat and estrogens
administering_ic: NIEHS
award_notice_date: 2007-05-14
opportunity_number: PAR-04-104
application_type: 5
activity_code: R21
ic: ES
serial_number: 013821
program_official: COLLINS, JENNIFER B
project_start_date: 2005-07-01
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1-EMNR-J(50)R]
contact_pi_person_id: 9250239
contact_pi: PISANO, M MICHELE
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this research is to investigate the fetal origins of breast cancer and the role of environmental factors during early development conception-weaning. 2 sources of estrogenic exposure relevant to man will be studied: a phytoestrogen preparation from soy mainly containing genistein and daidzein and the ubiquitous environmental xenoestrogen 4-nonylphenol. Our hypothesis states the maternal estrogenic environment has a strong influence on risk to mammary tumorigenesis in adult life. 2 corollaries are: (a) phytoestrogens (90 ppm genistein/daidzein) in conjunction with an isocaloric 20% fat-diet having high n-3/n-6 polyunsaturated fatty acid balance will significantly lower the risk of mammary tumors; and (b) xenoestrogen exposure (25 ppm 4-nonylphenol) in conjunction with a low dietary n-3/n-6 fatty acid balance will promote the risk. The hypothesis will be tested in a unique mouse model for breast cancer having mammary-specific expression of a conditional mutation in the tumor suppressor Trp53 allele (flox'd p53.R270H/WAP-Cre model). The "humanized" mutant allele is permanently activated in the mammary gland epithelium exclusively in females traversing their first pregnancy-lactation cycle. This expression predisposes females to mammary tumors (-70% incidence) between ages 25-52 weeks. The project has 2 concurrent Specific Aims. (1) To investigate the effects of gestational-neonatal exposure to phyto/xenoestrogens on mammary gland development and tumorigenesis in female offspring heterozygous for the conditional p53.R270H allele reared on diets of low and high n-3/n-6 fatty acid composition. (2) Using the powerful combination of gene expression profiling with laser capture microdissection enumerate the molecular abundance profiles of epithelial end-buds and subtending ducts as foci for pre-malignant changes in the naive (virgin) and initiated (parous) mammary gland of p53.R270H/WAP-Cre females. These studies will provide new biomarker leads based in genetic regulatory networks that correlate (or anti-correlate) with altered fetal programming and pre-malignancy together with the realization of how such networks might relate functionally to the prenatal environmental risk factors in breast cancer.

project_terms:
4-nonylphenol;Adult;Age;Alleles;Barker Hypothesis;Biological Markers;Conceptions;Condition;Congenital Abnormality;Development;Diabetes Mellitus;Diet;Diethylstilbestrol;Disease;Duct (organ) structure;Environment;Environment and Public Health;Environmental Risk Factor;Epithelial;Epithelium;Equilibrium;Estrogens;Event;Exposure to;Fatty Acids;Fatty Acids Polyunsaturated;Fatty acid glycerol esters;Female;Fetal Malnutrition;Fetus;Gene Expression Profiling;Genetic;Genistein;Goals;Health;Human;Incidence;Infertility;Institutes;International;Investigation;Life;Malignant Neoplasms;Malignant neoplasm of breast;Malignant neoplasm of cervix uteri;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Modeling;Molecular;Mutation;Netherlands;Perinatal;Phytoestrogens;Pregnancy;Premalignant;Preparation;Research;Research Personnel;Risk;Role;Source;System;TP53 gene;Testing;Toxicology;Tumor Suppressor Proteins;Universities;Weaning;Week;Woman;base;concept;daidzein;environmental chemical;fetal;fetal programming;laser capture microdissection;man;maternal cigarette smoking;mouse model;mutant;mutant mouse model;neonatal exposure;prenatal;programs;public health medicine (field);soy;tumor;tumorigenesis;xenoestrogen


