# projects

application_id: 7462269
project_number: 5R01HL074219-05
project_title: Integrin Signaling In Vascular Cells
administering_ic: NHLBI
award_notice_date: 2008-06-18
application_type: 5
activity_code: R01
ic: HL
serial_number: 074219
program_official: SRINIVAS, POTHUR R
project_start_date: 2004-08-01
project_end_date: 2010-06-30
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertension atherosclerosis and restenosis. SMC function is controlled by complex regulatory mechanisms which are governed in part by interactions with the extracellular matrix. Integrins the predominant receptors for the extracellular matrix activate adhesion-dependent signaling pathways and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. The objective of this application is to understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. We observed that wild-type mice treated with an antibody-inhibitor of beta3-integrins but not beta3-integrin-deficient (beta3-/-) mice were protected from the development of intimal hyperplasia and have found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for our in vivo observations. Based on our preliminary data we hypothesize that integrin alphaVbeta3- dependent intracellular signaling positively and negatively regulates SMC growth and migration thorough distinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize genetic pharmacologic and RNA interference techniques to target integrin alphaVbeta3 in well-characterized cellular and animal models of SMC function. First we will identify alphaVbeta3-dependent pathways in stimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch to regulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s) responsible for GTPase regulation. Second based on our preliminary data we have identified a role for alphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPK pathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMC quiescence. Third we will delineate the contribution of alphaVbeta3 to physiologic responses in cultured vessels and well-established mouse models of arterial injury. These results will provide specific insights into the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implications for understanding alphaVbeta3 integrin function in angiogenesis osteoporosis and other disorders.

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


application_id: 7461980
project_number: 1R01EY017594-01A2
project_title: The Role of CaMKII in Cell Death and Survival Responses of Retinal Ganglion Cells
administering_ic: NEI
award_notice_date: 2008-05-21
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: EY
serial_number: 017594
suffix: A2
program_official: GREENWELL, THOMAS
project_start_date: 2008-06-01
project_end_date: 2012-05-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Acute;Affect;Agonist;Animal Model;Blindness;Brain-Derived Neurotrophic Factor;Calcium/calmodulin-dependent protein kinase;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Condition;Data;Development;Diabetic Retinopathy;Disease;Equilibrium;Event;Eye diseases;Ganglion Cell Layer;Gene Targeting;Genes;Genes Regulator;Glaucoma;Glutamate Receptor;Glutamates;Goals;In Vitro;Injection of therapeutic agent;Injections Intraperitoneal;Ischemia;Knowledge;Laboratories;Link;Localized;Mediating;Methods;Modeling;Nuclear;Optic Neuropathy Anterior Ischemic;Pathway interactions;Patients;Peptides;Phosphotransferases;Physiological reperfusion;Play;Process;Protein Isoforms;RNA Interference;RNA Splicing;Rattus;Reperfusion Therapy;Research;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Testing;Therapeutic Intervention;Time;Transcript;Transcription Genetic;Transduction Gene;Visual impairment;autocrine;calmodulin-dependent protein kinase II;caspase;caspase-3;inhibitor/antagonist;insight;neuroprotection;paracrine;prospective;public health medicine (field);response;retinal ischemia;retinal neuron;transcription factor


application_id: 7461917
project_number: 2R01GM066152-05A2
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2008-05-01
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: GM
serial_number: 066152
suffix: A2
program_official: FABIAN, MILES
project_start_date: 2002-05-01
project_end_date: 2012-03-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Antibodies;Binding Sites;Biochemical;Biological;Biological Assay;Biological Process;Biology;Cell Line Transformed;Cells;Chemical Structure;Dependence;Development;Dimethylallyltranstransferase;Discrimination (Psychology);Drug Design;Enzymes;Event;Exhibits;Farnesyl Transferase Inhibitor;Funding;Future;Goals;Growth;Immunoprecipitation;Lead;Lipids;Malignant Neoplasms;Methods;Modification;Molecular Target;Monoclonal Antibodies;Mutagenesis Site-Directed;Numbers;Oncogenes;Pathway interactions;Peptides;Play;Preparation;Process;Protein Isoprenylation;Protein Processing Post-Translational;Proteins;Proteomics;Reagent;Research;Role;Screening procedure;Signal Transduction;Sites Active;Specificity;Substrate Specificity;Techniques;Testing;Therapeutic Intervention;Toxic effect;analog;cancer therapy;cellular targeting;chemical synthesis;clinical effect;cytotoxicity;design;enzyme substrate;geranylgeranyl diphosphate;in vivo;inhibitor/antagonist;innovation;isoprenoid;lipophilicity;novel;prenyl;prenylation;programs;protein farnesyltransferase;protein function;protein geranylgeranyltransferase;public health medicine (field);tool;tumor progression


application_id: 7461258
project_number: 1R01AA016166-01A2
project_title: Developmental Transitions and Risk for Alcohol Use
administering_ic: NIAAA
award_notice_date: 2008-03-05
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AA
serial_number: 016166
suffix: A2
program_official: SHIRLEY, MARIELA
project_start_date: 2008-03-10
project_end_date: 2013-02-28
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 2092801
contact_pi: SMITH, GREGORY 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_terms:
Address;Adolescence;Adolescent;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Behavior;Binge Eating;Child;Development;Developmental Process;Distress;Elevation;Emotions;Environment;Esthesia;Event;Expectancy;Frequencies (time pattern);Growth;Impulsivity;Individual;Individual Differences;Intercept;Intervention;Investigation;Learning;Left;Light;Longitudinal Studies;Measures;Mental Depression;Modeling;Moods;National Institute on Alcohol Abuse and Alcoholism;Personality;Persons;Play;Process;Psychological reinforcement;Rate;Recording of previous events;Research;Risk;Risk Behaviors;Role;Schools;Shapes;Smoking;Testing;Time;Variant;base;behavior change;drinking;early onset;experience;girls;prospective;psychologic;psychosocial;public health medicine (field);purge;theories;trait;underage drinking


application_id: 7461072
project_number: 1R01HL089588-01A1
project_title: Function and Regulation of SR-A in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2008-03-28
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 089588
suffix: A1
program_official: FLEG, JEROME L
project_start_date: 2008-04-01
project_end_date: 2008-09-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 7875399
contact_pi: POST, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Despite recent advances in lipid lowering therapy atherosclerosis remains a leading cause of cardiovascular disease. SR-A which is primarily expressed by macrophages promotes both ligand internalization and cell adhesion. The ability of SR-A to mediate different macrophage functions suggests that it may have multiple roles in the pathogenesis of atherosclerosis. Understanding the role of SR-A in atherosclerosis requires the ability to independently study SR-A-mediated ligand internalization and macrophage adhesion. Therefore identifying the structural features and cellular mechanisms that regulate SR- A function may help in understanding the role of this receptor in atherosclerosis. Our preliminary results indicate that SR-A-mediated cell adhesion and ligand internalization involve distinct cytoplasmic domains and activation of different intracellular signaling pathways. Moreover our data suggest that the physiologic role of SR-A may depend in part upon the level of SR-A expression and the relative abundance of immobilized and soluble SR-A ligand. Thus the hypothesis of this proposal is that SR-A binding to modified matrix proteins localizes SR-A with intracellular signaling proteins involved in macrophage adhesion and promotes macrophage accumulation in atherosclerotic plaques. The creation of receptor constructs that mediate cell adhesion but not ligand internalization or mediate ligand internalization but not cell adhesion provides us with unique reagents that allow us to test this hypothesis. Our first aim is to define the structural domains that couple SR-A to ligand internalization and cell adhesion. These studies will define the structural features required for SR-A-mediated cell adhesion and ligand internalization via endocytosis or phagocytosis. Our second aim is to determine the relationship between SR-A localization and function. Studies proposed in this aim will use biochemical and cell biological approaches to examine a previously undefined role for SR-A localization in lipid rafts in distinguishing SR-A-mediated functions. Our final aim is to determine the importance of SR-A-mediated ligand internalization and macrophage adhesion in atherogenesis. These studies take advantage of a bone marrow transfer approach to express unique SR-A constructs that mediate only cell adhesion or ligand internalization to determine the relative contribution of these functions in atherosclerosis. Overall completion of the proposed studies will further our understanding regarding the role of SR-A in regulating macrophage function and atherogenesis. With this understanding it may be possible to design therapeutic approaches that target specific macrophage functions to reduce atherosclerosis and enhance the benefit of lipid lowering. PUBLIC HEALTH RELEVANCE: Despite recent advances in lipid lowering therapy atherosclerosis remains a leading cause of cardiovascular disease. Class A scavenger receptors (SR-A) are particularly interesting therapeutic targets as they mediate multiple activities that may differentially affect macrophage participation in the development of atherosclerosis. A better understanding of the role of SR-A in regulating specific macrophage functions may identify new therapeutic approaches that will reduce atherosclerosis and will enhance the benefit of lipid lowering.

project_terms:
Actins;Adhesions;Affect;Arterial Fatty Streak;Atherosclerosis;Bacteria;Binding (Molecular Function);Biochemical;Biological;Bone Marrow;Cardiovascular Diseases;Cell Adhesion;Cells;Cholesterol;Complex;Cytoplasmic Tail;Data;Development;Disease;Disease Progression;Elements;Endocytosis;Focal Adhesions;Goals;Lesion;Ligands;Lipids;Lipoproteins;Localized;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Mediating;Membrane Microdomains;Mus;Mutation;Pathogenesis;Phagocytosis;Physiological;Proteins;Reagent;Regulation;Relative (related person);Research;Role;SR-A proteins;Signal Pathway;Signal Transduction;Signaling Proteins Intracellular;Testing;Therapeutic;Thinking function;Transgenic Organisms;Work;acetyl-LDL;atherogenesis;base;design;innovation;interest;macrophage;monocyte;novel therapeutics;public health medicine (field);receptor;receptor expression;research study;therapeutic target;uptake


application_id: 7460742
project_number: 5R01DA018822-03
project_title: Gated Carbon Nanotube Membrane Transdermal Drug Delivery
administering_ic: NIDA
award_notice_date: 2008-07-02
application_type: 5
activity_code: R01
ic: DA
serial_number: 018822
program_official: AIGNER, THOMAS G
project_start_date: 2006-09-30
project_end_date: 2011-06-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 7929219
contact_pi: HINDS, BRUCE JACKSON
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Affinity;Alkanes;Alkanesulfonates;Binding (Molecular Function);Caliber;Carbon;Cavia;Characteristics;Charge;Cigarette;Clonidine;Compatible;Development;Devices;Dose;Drug Delivery Systems;Drug Kinetics;Electronics;Family suidae;Fentanyl;Film;Human;In Vitro;Incidence;Invasive;Iontophoresis;Ligands;Longitudinal Studies;Marketing;Membrane;Methods;Molecular;Nanotubes;Nanotubes Carbon;Nicotine;Object Attachment;Opiates;Patient-Controlled Analgesia;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Polymers;Polystyrenes;Production;Protocols Treatment;Rate;Reaction Time;Research Personnel;Role;Safety;Security;Skin;Smoker;Solutions;Solvents;Strengths Ionic;Sus scrofa;System;Therapeutic;Transdermal substance administration;Withdrawal;aqueous;base;biomaterial compatibility;carboxylate;chronic pain;cost;craving;dosage;improved;in vivo;irritation;programs;prototype;size;skin irritation;smoking cessation;success;voltage


application_id: 7460665
project_number: 5T32ES011564-05
project_title: UofL Environmental Health Sciences Training Program
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2008-06-25
opportunity_number: PAR-00-038
application_type: 5
activity_code: T32
ic: ES
serial_number: 011564
program_official: SHREFFLER, CAROL A
project_start_date: 2004-07-01
project_end_date: 2009-06-30
study_section: Environmental Health Sciences Review Committee[EHS]
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
project_abstract:
DESCRIPTION (provided by applicant):   This proposal describes an environmental health sciences predoctoral training program at the  University of Louisville.  It is a dynamic partnership between the Departments of Biochemistry &  Molecular Biology and Pharmacology & Toxicology both of which have long-standing successful graduate programs. The training program benefits from their combined faculty research and programmatic strengths. The state-of-the art training program is enhanced through active participation and interaction with six interdisciplinary research centers: 1) Center for Environmental and Occupational Health Sciences 2) Center for Genetics and Molecular Medicine and 3) Institute for Public Health Research 4) Birth Defects Center 5) James Graham Brown Cancer Center and 6) Institute for Bioethics Health Policy and Law.  Trainees rotate through faculty laboratories to receive interdisciplinary research training and to select dissertation research projects focusing in four areas of environmental health science research: 1) environmental genomics 2) basic mechanisms of environmental insult 3) reproductive health and 4) environmental cardiology.  A core curriculum provides an interdisciplinary academic foundation in biochemistry and molecular biology pharmacology and toxicology cell biology genetics epidemiology biostatistics research methods and bioethics.  Initially student recruitment and funding for predoctoral trainees is provided by the University of Louisville School of Medicine Integrated Programs in the Biomedical Sciences recruitment gateway. Funds are requested to support two predoctoral trainees/year beginning in their second year. The training program will begin with four trainees and increase to eight trainees as the program matures.  Several interdisciplinary program projects and core facilities also strengthen student training. The University of Louisville has increased its commitment to health science research and infrastructure graduate education and minority recruitment making this training program particularly timely.


application_id: 7460645
project_number: 5T32DA016176-05
project_title: Training in Drug Abuse Related Research.
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2008-06-27
application_type: 5
activity_code: T32
ic: DA
serial_number: 016176
program_official: AVILA, ALBERT
project_start_date: 2004-07-01
project_end_date: 2009-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The goal of this training program is to prepare promising graduate students and postdoctoral fellows for successful careers in drug abuse research. We will provide broad-based training in modern concepts of drug abuse research with a special emphasis on: (i) cellular and molecular studies of receptors involved in the response to drugs (ii) development of ligands which interact with these receptors as potential pharmacotherapies for drug abuse and (iii) cellular and molecular aspects of neuroAIDS. The unifying focus of the training faculty is our interest in understanding basic mechanisms related to drug abuse at the molecular level. This training program provides the formal framework for faculty in several different departments who share common and overlapping interests in neuroscience and molecular mechanisms. The emphasis of the training faculty complement each other with a focus on building upon long-term strengths in the drug abuse field with existing expertise in molecular aspects of receptor interaction and response neuroplasticity and disease (neuroAIDS aging and neurotrama) and the development of targeted therapeutic agents. Thus the program will provide a fundamental understanding of how drugs of abuse affect cell function at the macromolecular level and how this addictive transformation affects health. Trainees will learn from faculty who utilize a broad spectrum of state-of-the-art methodological approaches to probe critical questions in drug abuse research. The national need for training new investigators in drug abuse research is clear and the introduction of modern methodologies is crucial for future advances in this area. Only if we better understand the basic mechanisms that regulate drug abuse and apply this knowledge will we make progress in solving the problems of drug abuse. A unique aspect of this program is the interaction of its trainees with those from a training program in the psychological and behavioral aspects of drug abuse. Thus our trainees will have a broad based knowledge of both molecular cellular psychological and behavioral drug abuse research. Our ability to attract and train graduate students and postdoctoral fellows to meet the challenges in the area of drug abuse will be greatly enhanced by this training grant.


application_id: 7459910
project_number: 5U13GM058252-10
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2008-06-27
application_type: 5
activity_code: U13
ic: GM
serial_number: 058252
program_official: ECKSTRAND, IRENE A
project_start_date: 1998-09-01
project_end_date: 2009-09-04
study_section: Minority Programs Review Subcommittee B[MPRC-B]
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant):  The overall objective of this application is to continue our challenge to empower faculty at institutions with high minority enrollment to develop and submit competitive research proposals. Building on our past experience the competing renewal has three facets which will take place concurrently: 1) up-dating current modules (14) and the development testing and evaluation of two new internet course modules; 2) recruitment and training of participants through 5 workshops at remote sites and subsequent participation in the web-based course; 3) continuing evaluation of the training modules for the purpose of technological and content versions. Significant changes from the original program include moving the pre-course conference off-site to maximize the number of faculty participating from contiguous institutions and the introduction of machine language technology to aid in the editing and packaging of participants' grant writing efforts. At the conclusion of the initiative each participant should be both motivated and empowered to submit a competitive proposal. Thus our continuing partnership with NIGMS should improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and strengthen minority institution's overall research environment.

project_terms:
Advisory Committees;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Computer software;Databases;Development;Educational workshop;Enrollment;Environment;Evaluation;Faculty;Feedback;Funding;Future;Goals;Grant;Grant Review Process;Grants Applications;Institution;Internet;Language;Learning;Learning Machine;Mentors;Minority;National Institute of General Medical Sciences;Numbers;Online Systems;Participant;Peer Review;Purpose;Reports Progress;Research;Research Personnel;Research Project Grants;Research Proposals;Rest;Role;Scientist;Services;Site;Study Section;System;Technology;Time;Training;Training Programs;Underrepresented Minority;United States National Institutes of Health;Universities;Work;Writing;base;evaluation/testing;experience;follow-up;impression;improved;member;novel strategies;programs;skills;symposium;training project


application_id: 7459588
project_number: 5R01CA125152-02
project_title: Breast Cancer Chemoprevention Potential of Common Spices
administering_ic: NCI
award_notice_date: 2008-05-23
application_type: 5
activity_code: R01
ic: CA
serial_number: 125152
program_official: MILNER, JOHN A
project_start_date: 2007-07-01
project_end_date: 2012-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_terms:
17p;American Cancer Society;Anise Seed;Antioxidants;Apiaceae;Attention;Binding (Molecular Function);Biological Assay;Biological Markers;Blotting Western;Breast Cancer Model;Breast Cancer Prevention;Caraway;Cell Proliferation;Chemoprevention;Chemopreventive Agent;Coriander (Spice);Cumin (spice);Cytochrome P450;DNA Adduction;DNA Adducts;DNA Damage;Data;Development;Dill;Disease;Dose;Early Diagnosis;Enzymes;Estradiol;Estrogen Metabolism;Estrogen Receptors;Estrogen Replacement Therapy;Estrogens;Family;Female;Fennel - dietary;Free Radicals;Future;Gene Mutation;Goals;Hormones;Housing;Human;Immunohistochemistry;Implant;In Vitro;Intervention;Laboratories;Lead;Lesion;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary Tumorigenesis;Measures;Mediating;Modeling;Molecular;Mortality Vital Statistics;Nutritionist;Oxidation-Reduction;PCNA gene;Pathology;Phytochemical;Plants;Polymerase Chain Reaction;Rats Inbred ACI;Rattus;Risk;Route;Silastic;Site;Spices;Standards of Weights and Measures;Subgroup;System;Testing;Time;Tissues;United States;Woman;Work;base;carcinogenicity;disorder prevention;improved;in vivo;indexing;multidisciplinary;oxidative DNA damage;prevent;subcutaneous;trend;tumor


application_id: 7459248
project_number: 3U01CA114622-04S3A1
project_title: InterACTS: An Interdisciplinary Approach to Colorectal Cancer Screening
administering_ic: NCI
award_notice_date: 2008-07-08
opportunity_number: RFA-CA-07-501
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S3A1
program_official: CANTO, MARIA TERESA
project_start_date: 2005-05-06
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZCA1 RPRB-G (J1)]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Although death from colorectal cancer (CRC) is largely preventable it remains the second-leading cause of cancer-related deaths in the United States. Incidence and mortality can be reduced by screening; however less than 50% of eligible adults are adherent to screening guidelines. Rates of adherence are even smaller In Appalachia. West Virginia's rates of CRC screening with sigmoidoscopy or colonoscopy (2004) were lower (46.6%) than the US average (53.4%). The goal of this pilot study is to design and test the feasibility of an intervention directed by community pharmacists to increase patient knowledge and improve patient readiness to seek CRC screening especially in medically underserved communities. The intervention will utilize community-based pharmacists to educate and counsel patients 50 years old and older at average risk about CRC screening. The limited availability of primary care clinicians especially in rural Appalachia encourages testing unique interdisciplinary approaches to patient education and outreach. Community pharmacists are viewed as members of the primary care team in clinics and communities throughout Appalachia. The primary outcome of the intervention is to move patients along the stages of change continuum as measured by: patient knowledge of CRC risk and the accepted screening modalities; patient intention to discussion screening with their primary care provider; patient intention to obtain CRC screening and other indicators of stage progression. This pilot study is consistent with Phase II of the National Cancer Institute Community Networks Program because it encompasses key principles of community-based participatory research: it builds on the existing strengths and resources within rural communities in particular the skills and expertise of community pharmacists and the trust that exists between pharmacists and their patients; and involves community pharmacists members of the Appalachia Community Cancer Network and lay community members in its development and implementation. The interdisciplinary research team is well positioned to conduct this research because of its links with pharmacists and community organizations and its expertise in cancer prevention and control interventions. The results of this study are expected to inform an R03 or R21 application which could lead to a randomized controlled trial (R01) testing the efficacy of an interdisciplinary approach involving non-physician primary care providers to increase CRC screening.

project_terms:
Adherence (attribute);Adult;Advisory Committees;Age-Years;Aged 80 and over;Appalachian Region;Appendix;Attitude;Behavior;Behavioral Sciences;Build-it;Cancer Control;Cancer Etiology;Cancer Patient;Cessation of life;Chronic Disease;Clinic;Colonoscopy;Colorectal Cancer;Communities;Community Networks;Consult;Counseling;Development;Disease;Drops;Education and Outreach;Education Continuing;Evaluation;Funding;Goals;Guidelines;Incidence;Intention;Intervention;Knowledge;Lead;Life;Link;Malignant Neoplasms;Measures;Mentors;Modality;Mortality Vital Statistics;National Cancer Institute;Outcome;Patient Education;Patients;Personal Satisfaction;Pharmacists;Pharmacy facility;Phase;Physician's Role;Physicians;Pilot Projects;Play;Population;Positioning Attribute;Primary Care Physician;Primary Health Care;Provider;Purpose;Randomized Controlled Trials;Rate;Readiness;Recommendation;Recruitment Activity;Research;Research Personnel;Research Training;Resources;Risk;Role;Rural;Rural Community;Schedule;Schools Pharmacy;Screening for Colorectal Cancer;Screening for cancer;Screening procedure;Services;Sigmoidoscopy;Smoke;Solutions;Staging;Study Interdisciplinary;Surveys;Testing;Theory Planning;Time;Training;Trust;United States;Universities;West Virginia;Work;base;cancer prevention;cancer risk;community based participatory research;community organizations;cost;design;experience;improved;innovation;interdisciplinary approach;medically underserved;member;programs;response;skills;therapy design;tool;uptake;willingness


application_id: 7459239
project_number: 3U01CA114622-04S2A1
project_title: Overcoming Barriers to Colorectal Cancer Screening in Appalachia: A Pilot Study
administering_ic: NCI
award_notice_date: 2008-07-03
opportunity_number: RFA-CA-07-501
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S2A1
program_official: CANTO, MARIA TERESA
project_start_date: 2005-05-06
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZCA1 RPRB-G (J1)]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Purpose: The overall goal of this study is to develop methods and gather preliminary data for a future R01 study that will test the efficacy of fecal immunochemical test (FIT) screening and telephone barriers counseling in rural Appalachia.   
Design: A prospective clinic-based participatory design will be used to determine acceptability of a provider-recommended take-home FIT kit and screening adherence with and without follow-up telephone barriers counseling. The telephone barriers counseling is based upon the Cognitive-Social Health Information Processing (C-SHIP) theoretical model.   
Methods: A purposive sample of patients age 50 and older at average CRC risk and currently non- adherent for CRC screening (n=300) attending a regularly-scheduled office visit in two rural Appalachian primary care clinics will be recruited and complete the baseline questionnaire in the clinic waiting room. During the patient's exam/consultation the provider will recommend CRC screening and offer a take-home FIT screening kit and educational brochure on CRC with a request for the completed test to be mailed to a central lab for processing within one week. Non-compliers will receive a single telephone barriers counseling session to address barriers reported at baseline and during the counseling session. Those who remain non- adherent following barriers counseling will receive a second brief telephone assessment to determine reasons for non-compliance and encourage completion of screening.   
Analysis: Primary outcomes are patient acceptability of the intervention and screening adherence rates with and without barriers counseling. Secondary outcomes are CRC-related knowledge and barriers to screening assessed at baseline and 3-months follow-up. Screening outcomes will be evaluated by examining percentages of completed screening following provider recommendation of screening and following barriers counseling compared to those in the literature. A process evaluation will assess overall feasibility of the intervention.   
Dissemination: Findings will be disseminated through the participating clinics and their local cancer coalitions scientific meetings and a manuscript submitted to a peer-reviewed journal. Findings will also be used as a foundation for the development of future studies and applications for extramural research support.   
Contributions: This research will provide an important contribution to the understanding of patient barriers to CRC screening the primary care physician's role in increasing CRC screening and the discovery of effective cancer control methods that ultimately may help reduce the cancer burden in Appalachia.

project_terms:
Address;Adherence (attribute);Advisory Committees;Affective;Age;American;Appalachian Region;Area;Behavior;Behavioral;Behavioral Research;Behavioral Sciences;Breast;Cancer Burden;Cancer Control;Cancer Control Research;Cancer Information Service;Case Manager;Clinic;Clinical;Cognitive;Colorado;Communication;Communities;Comprehensive Cancer Center;Computer Assisted;Computer information processing;Consultations;Controlled Clinical Trials Randomized;Core Facility;Counseling;County;Data;Delaware;Development;Doctor of Philosophy;Educational Materials;Educational aspects;Effectiveness;Epidemiology;Evaluation;Extramural Activities;First Degree Relative;Foundations;Fox Chase Cancer Center;Future;Goals;Health;Health Communication;Health Education Community;Health Personnel;Health Sciences;Home environment;Incidence;Institutes;Intervention;Journals;Kentucky;Knowledge;Licensing;Literature;Localized Malignant Neoplasm;Mails;Malignant Neoplasms;Manuscripts;Medical center;Medicine;Mentors;Methods;Mortality Vital Statistics;New Jersey;Office Visits;Office of the Director;Ohio;Outcome;Outreach Community;Pamphlets;Participant;Patients;Peer Review;Pennsylvania;Personal Satisfaction;Physician Assistants;Physician's Role;Pilot Projects;Population;Population Sciences;Prevention Research;Preventive;Primary Care Physician;Primary Health Care;Principal Investigator;Process;Provider;Psychologist;Purpose;Quality of life;Questionnaires;Randomized Controlled Trials;Rate;Recommendation;Recruitment Activity;Reporting;Research;Research Design;Research Personnel;Research Support;Risk;Rural;Rural Population;Sampling;Schedule;Screening for Colorectal Cancer;Screening for cancer;Screening procedure;Services;Societies;Survivors;Telephone;Testing;Theoretical model;Tobacco;Underserved Population;Universities;Week;anticancer research;base;cancer health disparity;cancer prevention;cancer risk;career;college;community based participatory research;design;experience;follow-up;health belief;implementation research;innovation;member;oncology;professor;programs;prospective;public health medicine (field);social;survivorship


application_id: 7459019
project_number: 5R25RR023304-03
project_title: "TRY-IT" Translating Research to Youth through Information Technology
administering_ic: NCRR
award_notice_date: 2008-06-30
opportunity_number: PAR-06-080
application_type: 5
activity_code: R25
ic: RR
serial_number: 023304
program_official: BECK, LAWRENCE A
project_start_date: 2006-09-15
project_end_date: 2011-06-30
study_section: ZRR1-SEPA-9(01)
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Academy;Address;Age;Award;Awareness;Behavioral Sciences;Biomedical Research;Biomedical Technology;Clinical Research;Clinical Trials;Commit;Communities;County;Development;Disadvantaged;Drug abuse;Educational Curriculum;Educational aspects;Educational workshop;Exhibits;Family;Future;Gambling;Gender;Goals;Graduate Education;Hand;Health;Human;Human Biology;Imagery;Information Technology;Institutes;Institution;Instruction;Kentucky;Knowledge;Learning;Life Style;Mentors;Minority;Modeling;Museums;National Center for Research Resources;Numbers;Parents;Participant;Pharmaceutical Preparations;Phase;Play;Professional counselor;Research;Research Personnel;Role;Rural;Schools;Science;Science Enrichment;Scientist;Students;Teachers School;Technology;Testing;Translating;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;Youth;alcohol research;boys;career;design;experience;girls;interest;literacy;novel;novel strategies;programs;research study;rural area;science education;skills;success;teacher


application_id: 7458658
project_number: 5R01AG024950-05
project_title: Aging stem cells and their microenvironment
administering_ic: NIA
award_notice_date: 2008-07-29
opportunity_number: RFA-AG-04-008
application_type: 5
activity_code: R01
ic: AG
serial_number: 024950
program_official: WILLIAMS, JOHN
project_start_date: 2004-09-30
project_end_date: 2010-07-31
study_section: ZAG1-ZIJ-7(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): Most if not all of the body's organ systems show the effects of aging. It is now increasingly apparent that homeostatic maintenance of organ function owes to cellular renewal derived ultimately from stem cells. Therefore aging stem cells may critically impact maintenance of normal organ function. Adult stem cells in all organs studied rely on micro environmental cues from supporting stroma to modulate if not direct stem cell replication differentiation and quiescence. This proposal investigates the effect of aging on both stem cells and the microenvironment. Using hematopoietic stem cells as a model we test the hypothesis that the number of stem cells available in bone marrow affects that organ's capacity to supply blood and immune cells during aging. Quantitative trait loci (QTL) affecting natural variation in stem cell numbers in mice have been mapped and congenic strains have been generated in which independent effects of the loci can be studied. Efforts underway to identify the genes responsible for the QTL will identify molecular pathways important in regulating stem cell numbers and the effect of aging on them. Effects of age on the stem cell microenvironment will focus on two essential functions. The first is to capture stem cells from the circulating blood. Stem cells are in a natural state of flux between the marrow and blood with evidence that this pathway is bidirectional. Homing of stem cells to the marrow is the first critical step in stem cell transplantation in the treatment of hematologic and non-hematologic malignancies. As more and older patient's become candidates for transplant the effects of age on homing are largely unexplored. Lastly clinical science has found ways to dramatically alter the flux of stem cells from the marrow microenvironment into the blood in a process called mobilization. Despite its widespread use in harvesting stem cells for transplantation the basic mechanisms are not only incompletely understood the effects of aging are uncharted. We will use mouse models to test the hypothesis and the flux of stem cells both to and from the marrow is altered in aging.

project_terms:
Accounting;Address;Adult;Affect;Age;Aging;Animals;Blood;Blood Circulation;Bone Marrow;Bone and Bones;Candidate Disease Gene;Cell Count;Cells;Censuses;Characteristics;Clinical;Clinical Sciences;Collection;Condition;Congenic Strain;Coupled;Cues;Data;Equilibrium;GTP-Binding Proteins;General Anesthesia;Genes;Genetic;Goals;Harvest;Hematopoiesis;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Immune;Intervention;Invasive;Leukapheresis;Literature;Location;Longevity;Maintenance;Maps;Marrow;Mice Inbred Strains;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Non-Hematologic Malignancy;Numbers;Organ;Pathway interactions;Patients;Play;Population;Population Sizes;Procedures;Process;Property;Protocols Treatment;Quantitative Trait Loci;Reporting;Role;Seeds;Signal Transduction;Solid;Stem cell transplant;Stem cells;Stress;Stromal Cells;Testing;Tissues;Transplantation;Variant;Vascular blood supply;adult stem cell;age effect;body system;clinically relevant;cohort;migration;mouse model;older patient;research study;self-renewal;stem;trafficking;trait


application_id: 7458656
project_number: 5R01DE015565-05
project_title: REGULATION OF NODAL SIGNALING IN HOLOPROSENCEPHALY
administering_ic: NIDCR
award_notice_date: 2008-06-02
application_type: 5
activity_code: R01
ic: DE
serial_number: 015565
program_official: SCHOLNICK, STEVEN
project_start_date: 2004-07-01
project_end_date: 2011-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Holoprosencephaly represents a common birth defect (1:16000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline) which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors Smad2 and 4 and FoxH1 (FAST). Importantly members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto Null allele and recently we generated a Cripto hypomorphic allele Cripto3-loxP by genetic manipulation. Approximately 50 percent of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-( signaling by blocking Smad2 function. Interestingly mutations in human TGIF gene are associated with holoprosencephaly suggesting its function in axial midline formation presumably through regulating Nodal/Smad2 signaling pathway. Based on these results we will pursue the following Specific Aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

project_terms:
Activins;Alleles;Anterior;Biological Assay;Biological Models;Brain;CFC1 gene;Cells;Cleft Lip;Congenital Abnormality;Cultured Cells;Defect;Development;Dorsal;Ectoderm;Embryo;Embryonic Development;Endoderm;Extracellular Protein;Eye;Family;Figs - dietary;Floor;Gene Targeting;Genes;Genes Homeobox;Genetic;Head;Holoprosencephaly;Homeodomain Proteins;Human;IL10 gene;Ice;In Vitro;Incisor;Investigation;Lead;Left;Live Birth;Mediating;Mesoderm;Mice Mutant Strains;Midbrain structure;Molecular;Morphology;Mus;Mutation;Nodal;Nuclear Protein;Nuclear Proteins;Pattern;Phenotype;Play;Process;Prosencephalon;Proteins;Range;Regulation;Reporting;Research;Role;Series;Signal Pathway;Signal Transduction;Stillbirth;Structure of notochord;Symptoms;System;Tissues;Transforming Growth Factor beta;Zebrafish;base;craniofacial;density;genetic manipulation;improved;in vivo;insight;interest;malformation;member;precursor cell;receptor;relating to nervous system


application_id: 7458650
project_number: 5R01AG027297-03
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2008-06-20
application_type: 5
activity_code: R01
ic: AG
serial_number: 027297
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2006-09-01
project_end_date: 2011-06-30
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating and irreversible neurological disease that progressively alters personality and behavior and destroys cognitive function. With an annual price tag exceeding 100 billion dollars AD is also one of the nation's most costly diseases. In recent years anti-inflammatory agents have emerged as promising compounds for delaying the onset of AD symptoms. Yet our understanding of the mechanisms underlying neuro-immune/inflammatory (im/inf) signaling in the brain remains incomplete. The Ca2+/calmodulin dependent protein phosphatase calcineurin plays a critical role in im/inf signaling cascades in lymphocytes and other cell types but has received little consideration for a similar role in nervous tissue. In the past year we found that calcineurin activation in neuron-glia co-cultures was sufficient for recapitulating several components of the im/inf response found consistently with aging and AD including astrocyte activation and the induction of numerous im/inf-related gene cascades. We also observed a marked and selective upregulation of calcineurin in activated astrocytes surrounding amyloid deposits in AD model mice. The long-term goal of this project is to therefore test the hypothesis that calcineurin is a critical component for the activation of im/inf signaling processes associated with AD. The first two aims will test whether activation of calcineurin and/or the calcineurin-dependent transcription factor NFAT is necessary for im/inf signaling in astrocytes. Biologically relevant inflammatory mediators will be delivered to astrocyte- specific cultures in the presence or absence of potent calcineurin and NFAT inhibitors. The induction of im/inf markers will be assessed with Western blots RT-PCR and cytokine arrays. Potential Ca2+ sources for calcineurin activation in astrocytes will also be examined along with the possibility that calcineurin amplifies its own activity by up-regulating these Ca2+ sources. Aim three will use cell fractionation immunoprecipitation Western blot phosphatase activity assays immunohistochemistry and in situ hybridization to qualitatively and quantitatively assess changes in calcineurin signaling in AD brain specimens and/or in a rodent model of AD. Completion of these studies will greatly increase our knowledge of the role of calcineurin in neuroinflammation and AD and may lead to the development of novel treatment strategies for this disease and other degenerative conditions where neuroinflammation is prominent.

project_terms:
APP gene;Address;Adenoviruses;Age;Age-Months;Aging;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease model;Amygdaloid structure;Amyloid;Amyloidosis;Animal Model;Animals;Anti-Inflammatory Agents;Antibodies;Astrocytes;Behavior;Behavioral;Biological;Biological Assay;Biological Markers;Blotting Western;Brain;Brain Injuries;Calcineurin;Calmodulin;Catalytic Domain;Cell Fractionation;Cell membrane;Cells;Cerebellum;Chimeric Proteins;Clinical Data;Coculture Techniques;Cognitive;Condition;Coupled;Cytosol;Degenerative Disorder;Deposition;Development;Disease;Elevation;Gene Expression;Genes;Genotype;Glial Fibrillary Acidic Protein;Goals;Hippocampus (Brain);Human;Immune;Immunohistochemistry;Immunoprecipitation;Impaired cognition;In Situ Hybridization;Inferior;Inflammatory;Inflammatory Response;Kentucky;Knowledge;Lead;Link;Luciferases;Lymphocyte;Measures;Mediator of activation protein;Membrane Proteins;Microscopy;Modeling;Molecular;Mus;Mutation;NF-AT;NFAT Pathway;Nerve Degeneration;Nerve Tissue;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Nuclear;Nuclear Translocation;Parietal Lobe;Pathologic;Patients;Pattern;Personality;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Price;Process;Property;Protein Isoforms;Protein Overexpression;Protein phosphatase;Rattus;Recruitment Activity;Reporter;Reporting;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Rodent Model;Role;Senile Plaques;Signal Pathway;Signal Transduction;Signaling Molecule;Source;Specimen;Staging;Staining method;Stains;Subcellular Fractions;Swimming;Symptoms;System;T-Lymphocyte;Techniques;Testing;Tissues;Universities;Up-Regulation (Physiology);Ursidae Family;Voltage-Clamp Technics;Work;age related;aged;aging brain;amyloid pathology;behavior measurement;brain tissue;cell type;cognitive function;computerized data processing;cytokine;human tissue;inhibitor/antagonist;insight;interest;mouse model;nervous system disorder;neuroinflammation;neuropsychological;normal aging;novel;nuclear factors of activated T-cells;presenilin-1;programs;protein expression;research study;tau Proteins;time use;transcription factor;voltage


application_id: 7457880
project_number: 5R01AG013418-12
project_title: Neural Mechanisms Resetting the Aged Circadian Pacemaker
administering_ic: NIA
award_notice_date: 2008-08-08
application_type: 5
activity_code: R01
ic: AG
serial_number: 013418
program_official: SUNEJA, SANOJ
project_start_date: 1996-07-17
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-D(03)M]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Aging leads to deficits in many functionsincluding circadian timekeeping which has been the focus of our on-going research. Circadian rhythm disruption is associated with increased risk of cardiovascular disease and cancer as well as impaired memory. Our previous studies revealed age-related changes in serotonergic regulation of the suprachiasmatic nucleus (SON) the site of the master circadian pacemaker and the dorsal raphe nucleus (DRN) which also regulates circadian rhythms. We expanded our studies to include the hippocampus which regulates memory and observed aging changes in serotonergic regulation of this structure as well. In the SCN aging increases serotonin transporter sites and decreases VIP mRNA expression. VIP is a key peptide involved in circadian rhythm generation phase resetting and transmission of circadian output. We propose to investigate if the increase in transporter sites causes the age-related decrease in VIP mRNA since serotonin depletion attenuates VIP mRNA levels. Our previous studies also showed that aging decreases 5-HT7 receptors in the DRN and hippocampus. The age-related loss of 5-HT7 receptors in the DRN attenuates phase shifts to serotonergic drugs. We propose to investigate the neural pathways mediating DRN 5-HT7 receptor induction of phase shifts by exploring the role of the GABAergic and glutamatergic neurotransmission which are modulated by DRN 5-HT7 receptors in vitro. Finally the age-related loss of 5-HT7 receptors in the hippocampal CA1 may be related to age-related memory loss because genetic deletion of 5-HT7 receptors induces memory deficits. Exciting new studies of hippocampal neurons in vitro show that activation of 5-HT7 receptors stimulates neurite extensions critical process for synaptic connectivity. Decreased dendritic length is associated with memory impairments during aging and neurodegenerative diseases. Therefore we propose to further investigate the intriguing but relatively little explored effect of 5-HT7 receptor stimulation of neurite length. The specific aims are to investigate: 1) the role of age-related changes in serotonin transporter sites in regulating SCN VIP and GRP expression 2) the mechanisms by which 5-HT7 receptors in the dorsal raphe which are decreased with aging mediate nonphotic circadian phase shifts and 3) the effect of 5-HT7 receptors on neurite length in the hippocampus SCN and DRN and whether this effect decreases during aging.

project_terms:
Affect;Age;Aging;Agonist;Attenuated;Autoradiography;Brain region;Circadian Rhythms;Disruption;Dorsal;Environment;Exhibits;Funding;Gastrin releasing peptide;Generations;Genetic;Glutamates;Hamsters;Hippocampus (Brain);Human;Impaired cognition;In Vitro;Length;Lesion;Longevity;Maintenance;Malignant Neoplasms;Mediating;Memory;Memory Loss;Memory impairment;Metabolic Diseases;Microinjections;Mus;Nerve Degeneration;Neural Pathways;Neurites;Neurodegenerative Disorders;Neurons;Neuropeptides;Organ;Output;Pedunculopontine Tegmental Nucleus;Peptides;Peripheral;Phase;Process;Prosencephalon;RNA Messenger;Rattus;Receptor Activation;Research;Research Personnel;Role;Serotonin;Serotonin Agents;Signal Transduction;Site;Sleep;Strikes Employee;Structure;Structure of suprachiasmatic nucleus;Synapses;System;Time;Vasoactive Intestinal Peptide;Work;age related;aged;attenuation;base;cardiovascular disorder risk;cardiovascular risk factor;chemotherapy;circadian pacemaker;dorsal raphe nucleus;extracellular;gamma-Aminobutyric Acid;in vivo;mRNA Expression;nerve supply;neuromechanism;neuropeptide Y;neurotransmission;novel;programs;raphe nuclei;receptor;relating to nervous system;serotonergic regulation;serotonin 7 receptor;serotonin transporter;transmission process


application_id: 7457789
project_number: 5R01AG024040-03
project_title: Genetic and Environmental Risk Factors for PSP
administering_ic: NIA
award_notice_date: 2008-06-04
opportunity_number: PAS-03-092
application_type: 5
activity_code: R01
ic: AG
serial_number: 024040
program_official: MILLER, MARILYN
project_start_date: 2006-07-15
project_end_date: 2011-06-30
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 2452926
contact_pi: LITVAN, IRENE
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Progressive supranuclear palsy (PSP) is a sporadic tauopathy with unknown cause. The H1 tau haplotype is implicated in its etiology; however it is also present in 60% of normal controls. This coupled with late symptom onset indicates that genetics alone does not cause PSP. Support for the environmental factor hypothesis stems from animal models and the observed association between PSP and exposure to mitochondrial complex I inhibitors (i.e. acetogenins) which are neurotoxic to dopaminergic neurons. Impaired metabolism in PSP mitochondria and oxidative injury in affected brain areas also support this hypothesis. Hence genes and environment may both play a role either alone or through their interactions. This application will determine: 1) if there is an association between PSP and the HI/HI genotype specific HI sub-haplotypes alpha-synuclein polymorphisms or parkin gene deficits or if there are gene-gene interactions; 2) if there is an association between PSP occupational and/or environmental chemical exposures functionally or structurally similar to rotenone/acetogenins; and 3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP this case-control multicenter study involves 500 PSP cases 500 age/gender matched primary controls and 500 secondary controls for genetic confirmation. Previous case-control studies have been inconclusive because of limitations in size scope or structure. This is the first adequately powered series of PSP cases with matched controls that has the necessary infrastructure to address our hypotheses and explore gene-environmental interactions. As a result it will help resolve controversies concerning the cause(s) of PSP and will stimulate new avenues of pathogenesis research and prophylactic therapies. Understanding the etiology of PSP may also help explain the causes of other tauopathies such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists epidemiologists geneticists biostatisticians industrial hygienist and toxicologist is well suited to unravel the complex etiology of PSP. The use of the NINDS cell repository for genetic banking will also allow DNA sample sharing with other investigators.

project_terms:
Address;Affect;Age;Alzheimer's Disease;Animal Model;Area;Brain;Carbon Disulfide;Carbon Monoxide;Case-Control Studies;Cells;Chemicals;Chronic;Class;Clinical;Collaborations;Complex;Coupled;DNA;Deltastab;Development;Diagnosis;Disease;Enrollment;Environment;Environmental Exposure;Environmental Risk Factor;Epidemiologist;Etiology;Exposure to;Family;First Degree Relative;Future;Gender;Gene Mutation;Genes;Genetic;Genotype;Goals;Haplotypes;Herbicides;Hypertension;Injury;Intervention;Knowledge;Lead;Manganese;Metabolism;Methodology;Mitochondria;Movement Disorders;Multicenter Studies;Mutation;Neurodegenerative Disorders;Occupational;Organic solvent product;Paralysed;Parkin gene;Pathogenesis;Patients;Pattern;Personal Satisfaction;Pesticides;Play;Polymorphism Genetic;Promotor (Genetics);Purpose;Questionnaires;Range;Recording of previous events;Research;Research Infrastructure;Research Personnel;Resources;Risk;Risk Factors;Role;Rotenone;Sampling;Secondary Parkinson Disease;Series;Severity of illness;Site;Specialist;Structure;Suggestion;Supranuclear Palsy Progressive;Symptoms;Tauopathies;Testing;Tetrahydroisoquinolines;Transition Elements;Traumatic Brain Injury;Variant;Variation (Genetics);Work;acetogenin;alpha synuclein;base;carbamate insecticide;case control;design;dopaminergic neuron;environmental chemical exposure;gene interaction;genetic risk factor;inhibitor/antagonist;leucine-rich repeat kinase 2;multidisciplinary;neurotoxic;parkin gene/protein;programs;prophylactic;repository;size;sodium arsenite;stem;synuclein;tau Proteins;tau-1


application_id: 7457725
project_number: 5R01AG025159-03
project_title: Imaging Brain Function/Structure in Presymptomatic FTD
administering_ic: NIA
award_notice_date: 2008-06-06
application_type: 5
activity_code: R01
ic: AG
serial_number: 025159
program_official: HSIAO, JOHN
project_start_date: 2006-09-15
project_end_date: 2011-06-30
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) represents only 10-20% of all dementias but remains important clinically because of its earlier age of onset compared to Alzheimer's disease (AD) and its characteristic attack on core human qualities e.g..compassion insight and verbal communication. Treatment of FTD as in AD is more likely to succeed when applied in the early stages of the underlying pathology than in later stages when symptoms appear and worsen. Detection of brain pathology is needed prior to these symptoms in order to develop and evaluate such treatments. We propose to use functional and structural magnetic resonance imaging (MRI) to detect brain network functional alterations and subtle changes in cortical density in the frontal and anterior temporal lobes in persons without dementia symptoms but who are destined to develop FTD. The high likelihood of developing FTD is well-defined in identified subjects with mutations in the valosin-containing protein (VCP) gene on chromosome 9 associated with FTD Paget's disease of bone and inclusion-body myopathy. These persons will be tested to insure the absence of symptoms and typical cognitive impairments in FTD. Mutation carriers will be compared to non-carrier members of the same families. The first specific aim is to perform functional MRI studies to measure frontal and parietal activation during standard working memory and letter fluency tasks typically performed poorly in persons with early symptoms of FTD. We will also perform a control confrontation naming task shown in preliminary studies to activate regions of the posterior temporal and occipital regions equally in VCP mutation carriers and in non-carriers. These data will be analyzed using advanced analytical and statisitical techniques discriminant analysis and hierarchical clustering to identify carriers most likely to develop future dementia. The second specific aim is to compare regional cortical density measured from three-dimensional structural images between VCP mutation carriers and non-carriers. We will combine the functional and structural measures with cognitive test results to refine our predictive model for dementia. These fundamental studies are expected to demonstrate brain network functional alterations and regionally decreased cortical density in rigorously-defined presymptomatic FTD.

project_terms:
3-Dimensional;Adult;Affect;Age;Age of Onset;Alzheimer's Disease;Anterior;Area;Back;Behavioral;Behavioral Symptoms;Bone Diseases;Brain;Brain Diseases;Brain Pathology;Brain imaging;Brodmann's area;Central Nervous System Diseases;Cessation of life;Characteristics;Chromosomes Human Pair 17;Chromosomes Human Pair 9;Clinical;Cluster Analysis;Cognitive;Communication;Compassion;Cortex of frontal lobe;Data;Data Set;Dementia;Depression screen;Detection;Discriminant Analysis;Disease;Educational aspects;Equipment and supply inventories;Family;Frequencies (time pattern);Frontotemporal Dementia;Future;Gender;Genes;Genetic;Genetic Risk;High Risk Woman;Human;Image;Impaired cognition;Inclusion Bodies;Individual;Inferior;Internet;Laboratories;Language;Lead;Left;Letters;Link;Literature;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Maps;Markers Surrogate;Measures;Memory Short-Term;Mental Depression;Methods;Muscle;Mutation;Myopathy;Names;Numbers;Osteitis Deformans;Parietal;Pathology;Pathway interactions;Pattern;Performance;Personal Satisfaction;Persons;Phenotype;Population;Preventive;Process;Purpose;Qualifying;Relative (related person);Research;Research Personnel;Resolution;Respiratory Failure;Risk;Science of Anatomy;Site;Staging;Standards of Weights and Measures;Stimulus;Structure;Symptoms;Techniques;Temporal Lobe;Test Result;Testing;Time;Tissues;Visual;Woman;Work;base;brain tissue;density;disorder risk;executive function;follow-up;frontal lobe;gray matter;improved;insight;member;middle age;morphometry;mutation carrier;neurocognitive test;performance tests;predictive modeling;programs;response;tau Proteins;treatment trial;valosin-containing protein;white matter


application_id: 7457419
project_number: 3R01GM047915-13S1
project_title: Modified Photoproteins as Labels and Molecular Switches
administering_ic: NIGMS
award_notice_date: 2007-07-02
application_type: 3
activity_code: R01
ic: GM
serial_number: 047915
suffix: S1
program_official: EDMONDS, CHARLES G
project_start_date: 1995-01-01
project_end_date: 2009-01-14
study_section: Special Emphasis Panel[ZRG1-BECM(01)S]
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Bioluminescent photoproteins afford high sensitivity of detection and have been employed as labels inbioanalysis. We propose to further expand the applications of these photoproteins by modifying them toposses unique bioluminescence properties. One of the goals of this work is to alter the electronic and H-bonding network within the chromophore-binding pocket of these photoproteins in order to shift theiremission wavelengths. This will be achieved by incorporation of non-natural amino acids into the aequorinstructure and by performing site-directed mutagenesis. The resulting proteins will be characterized in termsof their activity and structure-function relationship. We also propose to mimic the natural phenomenon thatoccurs in the jellyfish Aequorea Victoria where transfer of energy from aequorin to GFP results in theemission of green light. For that we propose to prepare protein-based "artificial jellyfish" by attaching afluorophore to unique sites on aequorin close tot he coelenterazine binding poceket. This will allow transferof energy from aequorin to the fluorophore thus shifting the wavelength of emission of the protein."Molecular switches" that can be "turned on" in the presence of a target analyte will be prepared byconstructing hybrid proteins between aequorin variants and a binding protein for a specific analyte. Thehybrid proteins will be constructed by inserting the gene of the binding protein into the gene of aequorin.The conformational changes that occur in the binding protein upon ligand binding will bring the two parts ofaequorin together allowing for the emission of bioluminescence. In addition "molecular switches" will beconstructed by preparing fusion proteins of a dissected aequorin and genes that code for a pair ofpoplypeptides that can form a leucine zipper. The leucine zipper allows for aequorin to re-assembly andbioluminescence emission. When target DNA is present the leucine zipper is pulled apart aequorin isdisassembled with the subseque loss of light. Applications of the above modified photoproteins inbioanalysis will be demonstrated by developing highly sensitive assays for panels of analytes that areimportant in disease diagnosis. Furthermore these assays based on aequorin variants with differentemission wavelengths will be incorporated into a microcentrifugal microfluidic platform which should result inmultiplex analysis with applications in point-of-care diagnostics and HTPS.

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


application_id: 7456612
project_number: 5R01HL081525-04
project_title: MAPK/PKR Modulation of Diaphragm Weakness
administering_ic: NHLBI
award_notice_date: 2008-06-05
application_type: 5
activity_code: R01
ic: HL
serial_number: 081525
program_official: SMITH, ROBERT A
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-K(07)M]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): The respiratory muscles of critically ill patients requiring mechanical ventilation are profoundly weak and infections are a major factor contributing to the development of this debility. The cellular mechanisms by which systemic infection induces respiratory muscle weakness however are poorly understood. In other tissues the effects of infection are mediated by a variety of signaling pathways but virtually nothing is known about the signaling pathways activated in respiratory skeletal muscle in response to infection. The purpose of the experiments in this proposal is to examine this issue. These experiments will test our central hypothesis: p38 JNK and PKR kinase pathways interact to regulate diaphragm muscle death receptor activation death receptor active caspase 8 formation and caspase mediated reductions in diaphragm force generation. Aim I studies will test the hypothesis that p38 and JNK modulate inflammation induced skeletal muscle caspase 8 activation and contractile dysfunction. Studies will be done using mice given endotoxin and C2C12 muscle cells exposed to cytokines. We will examine the time course of activation of p38 and JNK and will also determine if chemical or genetic inhibition of p38 and/or JNK prevents inflammation induced caspase 8 formation and diaphragm weakness. We will also determine if NADPH oxidase mediated superoxide generation causes skeletal muscle p38 and JNK activation in response to inflammation. Aim II studies will test the hypothesis that PKR also contributes to inflammation induced skeletal muscle caspase 8 activation and weakness. We will examine the time course of skeletal muscle PKR activation and will determine if chemical or genetic inhibition of PKR prevents inflammation induced skeletal muscle caspase 8 formation and weakness. We will also determine if PACT/RAX activation is responsible for activating PKR in skeletal muscle following inflammatory stimuli. Aim III studies will test the hypothesis that inflammation induces specific changes in skeletal muscle death receptor complex (DISC) characteristics that are linked to activation of the p38 JNK and PKR signaling pathways. We will both characterize the effects of inflammation on DISC formation localization and autocatalytic activity and determine if these alterations can be blocked by inhibition of p38 JNK and/or PKR signaling pathways.

project_terms:
Animal Model;Animals;Biological Assay;Blotting Western;Cartilage;Cell physiology;Cells;Cessation of life;Characteristics;Chemicals;Complex;Contractile Proteins;Critical Illness;Development;Diaphragm (Anatomy);Dominant-Negative Mutation;Endotoxins;Environmental air flow;Functional disorder;Generations;Genetic;Hand;Hyperglycemia;In Vitro;Individual;Infection;Inflammation;Inflammatory;Knock-out;Limb structure;Link;MAP Kinase Activation Pathway;MAP Kinase Gene;MAPK14 gene;MAPK8 gene;Measures;Mechanical ventilation;Mediating;Mitogen-Activated Protein Kinases;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;NADP;NADPH Oxidase;Pathway interactions;Patients;Phosphotransferases;Play;Proteolysis;Proteomics;Protocols documentation;Purpose;Receptor Activation;Research;Research Personnel;Respiratory Failure;Respiratory Muscles;Role;Secondary to;Sepsis;Signal Pathway;Skeletal muscle structure;Skeletal system;Stimulus;Stress;Superoxides;Systemic infection;Techniques;Testing;Time;Tissues;Weaning;Work;caspase;caspase-3;caspase-8;caspase-9;cell injury;cell type;chemical genetics;cytokine;design;eIF-2 Kinase;inhibitor/antagonist;macrophage;p38 MAPK Signaling Pathway;prevent;programs;receptor;research study;respiratory;response


application_id: 7456496
project_number: 5R21DA019526-02
project_title: Prenatal cocaine effects on sexual motivation
administering_ic: NIDA
award_notice_date: 2008-03-12
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: DA
serial_number: 019526
program_official: VOLMAN, SUSAN
project_start_date: 2007-07-01
project_end_date: 2010-03-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7876913
contact_pi: AKINS, CHANA K.
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 broad long-term objective of the current application is to develop a novel approach to studying the effects of prenatal drugs of abuse on later drug reward and sexual motivation. The novel approach involves utilizing an avian animal model that is precocial fast-maturing allows for control of dose timing of drug exposure and avoidance of potentially confounding maternal and/or littermate factors associated with the use of rodents. The specific aims of the current application are to 1) validate the embryonic model by investigating embryotoxic effects of prenatal cocaine 2) investigate prenatal effects of cocaine on cocaine- induced locomotor activity and cocaine place preference in adult male and female quail and 3) test prenatal cocaine effects on sexual motivation in sexually mature males. The potential influence of gestational cocaine exposure in altering rewarding properties of psychostimulants is a considerable health concern since there may be an increased liability for addiction to these drugs as a result of prenatal exposure. In addition gestational cocaine may affect other motivational systems such as the sexual behavior system. Increased liability for cocaine addiction may also be linked to risky sexual behavior such as a higher frequency of sexual activity sex with multiple partners and unprotected sex. These behaviors have been linked to to the transmission of HIV and hepatitis C. The findings that result from this research may contribute information about how prenatal cocaine exposure alters responding to drugs in adulthood and how it may enhance sexual motivation. The methodology includes injecting viable eggs with cocaine during various embryonic stages and then assessing hatchability and motility (movement inside the egg); behavioral tests on the activating effects and rewarding properties of cocaine adult birds; and tests of sexual motivation using a social proximity test.

project_terms:
Acute;Adult;Affect;Animal Model;Behavior;Behavioral;Biological;Biological Process;Birds;Brain;Chick Embryo;Cocaine;Condition;Coturnix japonica;Data;Dependences Cocaine;Development;Developmental Delay Disorders;Dose;Drug Exposure;Drug abuse;Embryo;Exposure to;Female;Fetal Cocaine Exposure;Frequencies (time pattern);Goals;HIV;Health;Hepatitis C;Human;Injection of therapeutic agent;Link;Literature;Maternal Behavior;Methodology;Modeling;Motivation;Motor Activity;Movement;Outcome;Partners Multiple;Personal Satisfaction;Pharmaceutical Preparations;Property;Purpose;Quail;Rate;Research;Reserpine;Rewards;Rodent;Rodent Model;Route;Sex Behavior;Sex Characteristics;Site;Staging;Structure of zygote;System;Testing;Time;Toxic effect;Unsafe Sex;addiction;behavior test;behavioral sensitization;cell motility;day;drug of abuse;drug reward;egg;hatching;high risk sexual behavior;male;neurobehavioral;novel strategies;placental transfer;preference;prenatal;prenatal exposure;psychostimulant;research study;reward processing;sex;social;transmission process


application_id: 7456423
project_number: 5R03AR052904-04
project_title: Lck activity in autoimmune TSAD-deficient mice
administering_ic: NIAMS
award_notice_date: 2008-06-20
opportunity_number: PAR-04-002
application_type: 5
activity_code: R03
ic: AR
serial_number: 052904
program_official: MANCINI, MARIE
project_start_date: 2006-07-01
project_end_date: 2010-06-30
study_section: ZAR1-EHB-H(O1)
contact_pi_person_id: 7732443
contact_pi: MARTI, FRANCESC
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):  Lymphocyte specific kinase (Lck) is one of the first signaling molecules to be activated downstream of the T cell antigen Receptor (TCR). As a member of the Src-family of Tyrosine Kinases (TK) Lck shares their structural features with a unique NH2-terminal region followed by Src-homoly (SH) domains SH3 and SH2 and a COOH-terminal TK domain. The SH domains allow Lck to directly bind not only with other protein complexes but also display intramolecular interactions that stabilize the conformation and modulate the Lck enzymatic function. The exquisite fine-tuned regulation of Lck activity underscores the importance of this protein in T cell activation. In this context Lck is critical for thymocyte development lnterleukin-2 (IL-2) production and homeostatic proliferation of T cells. Indeed aberrant Lck activity has been associated with a broad spectrum of T cell-derived pathologies including autoimmune diseases (AD). Our laboratory has been dissecting the molecular mechanisms underlying the spontaneous systemic AD of mice that are deficient in the expression of the T cell Specific Adapter (TSAd) protein. We have shown that TCR-induced production of IL-2 is impaired in primary T cells from TSAd-/- mice which may account for the development of the AD in these mice. Furthermore we have recently demonstrated that TCR/CD28-induced activation of Lck is defective in TSAd-/- T lymphocytes. We postulate that the impaired Lck activity is the primary cause of the development of the autoimmune disease in TSAd-/- mice. In this regard we propose to explore the mechanism by which TSAd regulates Lck activity and understand the consequences of aberrant Lck regulation in TSAd-/- T cells. Specifically in Aim 1 we will test the hypothesis that TSAd binds directly to Lck and we will reveal the structural and functional features of this interaction. In Aim 2 we will unravel the signaling events differentially modulated in TSAd-/- T lymphocytes as a result of the reduced Lck activity. It is anticipated that these studies will lead a new line of research focused on novel means by which Lck is regulated with the ultimate goal to define alternative therapeutic approaches to the treatment of AD.

project_terms:
Accounting;Acetylation;Antigens;Autoantigens;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Binding (Molecular Function);Biochemical;CD3 Antigens;Cell Death;Cell membrane;Cells;Cellularity;Cessation of life;Clonal Expansion;Complex;Cytoplasmic Tail;Cytosol;Development;Disruption;Equilibrium;Event;Exhibits;Family member;Generations;Genes;Goals;Growth;Human;Immune response;Interleukin 2 Receptor;Interleukin-2;Laboratories;Lead;Leukocytes;Lymphocyte;Lymphocyte Specific Protein Tyrosine Kinase p56(lck);Lymphoid Cell;Modeling;Modification;Molecular;Molecular Conformation;Mus;N-terminal;Numbers;Pathology;Peripheral;Phosphotransferases;Play;Production;Proteins;Receptor Signaling;Receptors Antigen;Recruitment Activity;Regulation;Research;Role;SH3 Domains;Self Tolerance;Signal Pathway;Signal Transduction;Signaling Molecule;T-Cell Activation;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Thymocyte Development;Thymus Gland;Tyrosine Kinase Domain;ZAP-70 Gene;ZAP-70 Kinase;adapter protein;immunological synapse;in vivo;member;myristoylation;novel;palmitoylation;pathogen;response;src-Family Kinases;thymocyte


application_id: 7456400
project_number: 5R03DC007983-03
project_title: Molecular mechanisms of aging in the intrinsic laryngeal muscles
administering_ic: NIDCD
award_notice_date: 2008-06-18
opportunity_number: PAR-04-062
application_type: 5
activity_code: R03
ic: DC
serial_number: 007983
program_official: SHEKIM, LANA O
project_start_date: 2006-08-15
project_end_date: 2010-06-30
study_section: ZDC1-SRB-Y(52)
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): As individuals age muscle weakness and neuromuscular disorders have the potential to diminish the quality of life increase health care costs and lead to institutionalization. The larynx is part of a complex motor system that serves dually as the vibratory source of phonation and as a valve that separates and protects the airway from the digestive tract. In the elderly age-related changes in the intrinsic laryngeal muscles may compromise voice quality thus impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal dysfunction may also cause dysphagia and increase the risk of aspiration which may translate to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age; however the biology of these small muscles remains largely unexplored. This project in response to the NIDCD Small Grant (R03) Program will achieve two objectives: (1) it will determine how age alters neuromuscular junction organization and function in the intrinsic laryngeal muscles; (2) it will provide a mechanism to further the professional development of the PI leading to scientific independence. The studies will test the central hypothesis that aging disrupts the organization and stability of the neuromuscular junction in the intrinsic laryngeal muscles. Using the Fischer 344-Brown Norway F1 hybrid rat model of aging the studies will examine to what extent aging alters NMJ organization in the posterior cricoarytenoid (PCA vocal fold abductor) and thyroarytenoid (TA vocal fold adductor) muscles. Three Specific Aims will be accomplished. Specific Aim 1 will test whether age changes NMJ ultrastructure and the expression of acetylcholine receptor subunits in the intrinsic laryngeal muscles. Specific Aim 2 will evaluate if aging represses cellular signaling pathways that initiate and sustain NMJ organization in the intrinsic laryngeal muscles. Specific Aim 3 will assess to what extent age alters the acetylcholine vesicle release system in the presynaptic terminals of the intrinsic laryngeal NMJs. This project will generate novel data on how age disrupts NMJ organization in the intrinsic laryngeal muscles and will provide the bases for interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles. In addition the anticipated results will be of relevance to diseases not associated with aging but that affect NMJ structure and function such as myasthenia gravis and the Lambert- Eaton myasthenic syndrome.

project_terms:
Acetylcholine;Achievement;Affect;Age;Aging;Architecture;Biochemical;Biological;Biology;Calcium Channel;Calcium Channels L-Type;Cell physiology;Cells;Cholinergic Receptors;Complex;Data;Deglutition Disorders;Development;Disease;Elderly;Ensure;Functional disorder;Gastrointestinal tract structure;Glycoproteins;Goals;Grant;Health Care Costs;Hybrids;Individual;Institutionalization;Intervention;Lambert-Eaton Myasthenic Syndrome;Laryngeal muscle structure;Larynx;Lead;Localized;Maintenance;Mentorship;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Motor;Muscle;Muscle Weakness;Myasthenia Gravis;Neuromuscular Diseases;Neuromuscular Junction;Norway;Numbers;Phenotype;Phonation;Presynaptic Terminals;Principal Investigator;Quality of life;Rattus;Risk;Scientist;Signal Pathway;Signal Transduction;Source;Structure;System;Testing;Translating;Utrophin;Vesicle;Vocal cord structure;Voice Quality;age effect;age related;base;neuromuscular transmission;novel;prevent;programs;research study;response;size;stoichiometry;synaptotagmin;syntaxin;vesicle-associated membrane protein


application_id: 7455151
project_number: 5K02DE018412-02
project_title: Role of TFII-I in Craniofacial Development
administering_ic: NIDCR
award_notice_date: 2008-06-12
opportunity_number: PA-06-527
application_type: 5
activity_code: K02
ic: DE
serial_number: 018412
program_official: HARDWICK, KEVIN S
project_start_date: 2007-07-01
project_end_date: 2008-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 6065455
contact_pi: BAYARSAIHAN, DASHZEVEG
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): This Independent Scientist Award (K02) application is based on the applicant's recently funded NIH R01 award from NIDCR (DE 017205) for the years of 2006-2010. The parental R01 award entitled "Role of TFII-I in Craniofacial Development" addresses the function of the TFII-I transcription factor in orofacial development. The proposed research presented in the "Research Plan" section of this K02 application does not have significant changes compared with the studies proposed in the original R01 application except that some progress made since then is incorporated in the preliminary data section of this application. The research approaches and experimental design proposed in the original R01 application are largely based on the applicant's scientific training and expertise in mouse genetics and molecular biology. The applicant fully realizes the importance of multi-discipline in conducting competitive and high quality research which is essential for a successful scientific career. Therefore the applicant plans to acquire additional expertise and learn new systems to promote the original proposal to a higher level and extent the principal investigator's scientific expertise in functional screening protein biochemistry and proteomics and systems biology. The details and rationale are described in the following section of the candidate's "career developmental plan".

project_terms:
Accounting;Address;Affect;Alleles;Animals;Apoptosis;Award;Binding Sites;Branchial arch structure;Cell Lineage;Cell Proliferation;Cells;Cephalic;Class;Condition;Congenital Abnormality;Data;Defect;Depth;Development;Discipline;Disease;Embryo;Exons;Experimental Designs;Face;Funding;Gene Expression;Gene Targeting;Genes;Genetic;Goals;Histones;Human;Independent Scientist Award;Knowledge;Learning;Mandible;Mice Knockout;Molecular;Molecular Biology;Molecular Genetics;Morphogenesis;Mus;Neural Crest;Neural Crest Cell;Outcome;Pathogenesis;Pathway interactions;Play;Primordium;Principal Investigator;Protein Biochemistry;Proteins;Proteomics;Recombination Genetic;Regulation;Regulatory Pathway;Regulatory Sequences Nucleic Acid;Research;Role;Screening procedure;Signal Pathway;Signal Transduction;Signaling Pathway Gene;Site;Structure;System;Systems Biology;Tissues;Training;Transcription Genetic;United States National Institutes of Health;base;career;chromatin immunoprecipitation;craniofacial;insight;member;migration;mutant;orofacial;programs;relating to nervous system;transcription factor


application_id: 7454329
project_number: 5R01MH078228-03
project_title: Neuroimaging Studies of Depression in Parkinson's Disease
administering_ic: NIMH
award_notice_date: 2008-06-26
opportunity_number: RFA-MH-06-003
application_type: 5
activity_code: R01
ic: MH
serial_number: 078228
program_official: MEINECKE, DOUGLAS L
project_start_date: 2006-07-01
project_end_date: 2010-06-30
study_section: ZMH1-ERB-H(03)
contact_pi_person_id: 8273960
contact_pi: BLONDER, LEE XENAKIS
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Depression is a common and potentially serious complication of Parkinson's disease (PD). Studies show that approximately 40 percent of PD patients are depressed. There is evidence that these patients have deficits in verbal fluency set shifting confrontation naming and memory relative to non-depressed PD patients. Despite the widespread toll on emotional health posed by PD few studies have undertaken a comprehensive examination of the neural underpinnings of Parkinsonian depression. In this project we will compare depressed versus non-depressed Parkinson patients to a sample of demographically-matched healthy controls using neuropsychological assessment and magnetic resonance imaging (MRI). Our primary hypothesis is that depression in PD is linked to structural and functional abnormality in dorsal and ventral striatum amygdala orbitofrontal cortex medial frontal cortex and anterior cingulate. Based on this we predict that in comparisons with non-depressed PD patients PD patients with depression will show 1.) significant reductions in the volume of the caudate nucleus orbitofrontal cortex medial frontal cortex anterior cingulate and amygdala; and 2.) reduced activation on cognitive and emotional tasks known to engage these regions. Our secondary hypothesis is that anti-parkinsonian medications particularly D2/D3 receptor agonists will result in elevation in mood and increased activation in these brain regions among depressed PD patients during the performance of cognitive and emotional tasks. To delineate the neural substrates of Parkinsonian depression each patient and control will undergo neuropsychological testing and structural and functional MRI. We will compare regional brain volume in structures associated with depression and patterns of functional MRI activation during working memory and facial affect processing tasks. Neuropsychological testing and fMRI will be performed "on" and "off dopaminergic pharmacotherapy in PD patients and at two similar time points in the unmedicated control group. The research proposed herein will contribute to our understanding of the neural pathways that underlie depression in PD the relationship of dysphoria to cerebral activation during cognitive and affective processing and the effects of dopaminergic pharmacotherapy on brain response in prefrontal and limbic regions.

project_terms:
Affect;Affective;Agonist;Amygdaloid structure;Anterior;Brain;Brain region;Caudate nucleus structure;Cerebrum;Cognitive;Complication;Control Groups;Depressed mood;Dopamine Agonists;Dorsal;Elevation;Emotional;Face;Health;Human;Individual;Link;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Medial;Memory;Memory Short-Term;Mental Depression;Moods;Names;Neural Pathways;Neuropsychological Tests;Parkinson Disease;Parkinsonian Disorders;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacotherapy;Prefrontal Cortex;Prevalence;Process;Quality of life;Rate;Regulation;Relative (related person);Research;Sampling;Striatum Ventral;Structure;Structure of putamen;Time;Variant;base;brain volume;disturbance in affect;dysphoria;frontal lobe;neuroimaging;neuromechanism;neuropsychological;receptor;relating to nervous system;research study;response;reward processing


application_id: 7454183
project_number: 5R01CA106281-04
project_title: The CXCR4-SDF-1 Axis in Metastatic Rhabdomyosarcoma
administering_ic: NCI
award_notice_date: 2008-06-03
application_type: 5
activity_code: R01
ic: CA
serial_number: 106281
program_official: TRICOLI, JAMES
project_start_date: 2005-09-20
project_end_date: 2010-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Rhabdomyosarcoma (RMS) is the most common sarcoma in children and very often infiltrates the bone marrow (BM).  Our recently published data show that stromal derived factor-1 (SDF-1) which is secreted within the BM microenvironment may play a crucial role in directing to the BM the RMS cells that express the receptor for SDF-1 CXCR4.  To investigate the mechanisms operating in the metastasis of RMS and develop a new therapeutic approach to blocking the SDF-1-CXCR4 axis in RMS we propose three aims.  Aim #1. To elucidate the molecular mechanisms of CXCR4 priming.  Since we observed that scatter factor (SF) increases/primes the chemotactic response of CXCR4+ RMS cells to an SDF-1 gradient we will focus on molecular mechanisms of crosstalk between the SDF-1-CXCR4 and SF-c-Met axes in RMS metastasis.  We will investigate which SDF-1-mediated steps in metastasis are influenced by SF and based on our preliminary data we will test the hypothesis that SF by increasing inclusion of CXCR4 into membrane lipid rafts modulates the responsiveness of RMS cells to SDF-1 gradient.  Aim #2. To determine whether PAX genes regulate the expression of CXCR4.  Since in RMS cell lines the expression of CXCR4 correlates with alveolar RMS and expression of the PAX3-FKHR and PAX7-FKHR genes we will investigate whether PAX genes directly regulate CXCR4 expression in RMS cells.  We will test whether CXCR4 expression in cells isolated from RMS patients also correlates with the alveolar type of RMS and with PAX3- and PAX7-FKHR fusion and/or overexpression of PAX-3 and PAX-7 wild-type genes.  Aim # 3. To assess therapeutic strategies to block the metastatic behavior of RMS cells by targeting the SDF-1-CXCR4 axis.  We noticed that radio-/chemotherapy induces SDF-1 secretion in various organs and creates a "metastasis-permissive" environment.  Thus we hypothesize that the SDF-1-CXCR4 axis may play a role in the spread of tumor cells that have escaped therapy.  To control the spontaneous and radio-/chemotherapy-induced metastatic behavior of RMS cells in vivo we will employ the newly synthesized small-molecular inhibitor of the CXCR4 receptor (TE14013) in a human RMS xenotransplant-immunodeficient mouse model.  This work will be of relevance for designing strategies to block the SDF-1-CXCR4 axis to treat CXCR4-positive cancers.

project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;Acute leukemia;Adhesions;Affect;Alveolar;Amides;Amphotericin B;Antibiotics;Appendix;Autologous Bone Marrow Transplantation;Behavior;Binding Sites;Blast Cell;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cell Line;Cells;Chemicals;Chemotaxis;Child;Data;Dose;Drug usage;Environment;Fibroblasts;Filipin;Genes;Growth;Guidelines;Hepatocyte Growth Factor;Human;Immunodeficient Mouse;In Vitro;Ligands;Malignant Neoplasms;Marrow;Mediating;Membrane Lipids;Membrane Microdomains;Modeling;Modification;Molecular;Neoplasm Metastasis;Numbers;Nystatin;Organ;Osteoblasts;PAX3 gene;Patients;Peptides;Personal Satisfaction;Play;Polyenes;Prognostic Factor;Prognostic Marker;Promotor (Genetics);Protein Overexpression;Publishing;Radio;Rhabdomyosarcoma;Rhabdomyosarcoma Alveolar;Rhabdomyosarcoma Embryonal;Role;T140 peptide;Testing;Therapeutic;Work;Xiphosura;angiogenesis;base;chemokine;chemokine receptor;chemotherapy;design;experience;fusion gene;immunodeficient mouse model;in vivo;inhibitor/antagonist;insight;migration;neoplastic cell;novel therapeutics;pneumococcal purpura-producing principle;programs;receptor;response;sarcoma;tumor


application_id: 7454159
project_number: 5R01DE017205-03
project_title: ROLE OF TFII-I IN CRANIOFACIAL DEVELOPMENT
administering_ic: NIDCR
award_notice_date: 2008-05-16
application_type: 5
activity_code: R01
ic: DE
serial_number: 017205
program_official: SCHOLNICK, STEVEN
project_start_date: 2006-07-01
project_end_date: 2008-12-31
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 6065455
contact_pi: BAYARSAIHAN, DASHZEVEG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): Craniofacial related birth defects account for 1/3rd of all congenital anomalies. Defects in neural crest cells (NCC) cause most of these disorders; however the signaling pathways involved in craniofacial morphogenesis are poorly understood. Therefore knowledge of the molecular mechanisms of neural crest development is necessary to understand human craniofacial disorders. Our long-term goal is to identify the regulatory pathways that instruct NCC morphogenesis. The objective of this application is to determine the molecular and genetic role of the TFII-I transcription factor in craniofacial development. Deletion of the Gtf2i allele which encodes this protein causes craniofacial defects in mice. TFII-I regulates the transcription of target genes via interactions with histone deacetylases and Smad2 and is expressed in neural crest-derived tissues. We hypothesize that 1 of the roles of TFII-I is to control signaling cascades critical for neural crest morphogenesis. We therefore propose an in depth analysis of Gtf2i to understand its role during neural crest development. First molecular and cellular changes underlying craniofacial defects will be analyzed in mutant embryos. Second a set of downstream target genes regulated by TFII-I in cranial NCC will be identified using microarray and chromatin immunoprecipitation analysis. Third the Gtf2i allele will be abrogated in the NCC lineage with the conditional Cre/LoxP recombination system. The outcome of the proposed research will allow us to identify the TFII-l-dependent genes and signaling pathways involved in the morphogenesis of neural crest-derived structures. These studies will provide a better understanding of craniofacial genetic pathways and pathogenesis of human birth defects.

project_terms:
Accounting;Affect;Alleles;Animals;Apoptosis;Binding Sites;Branchial arch structure;Cell Lineage;Cell Proliferation;Cells;Cephalic;Class;Condition;Congenital Abnormality;Data;Defect;Depth;Development;Disease;Embryo;Exons;Face;Gene Expression;Gene Targeting;Genes;Genetic;Goals;Histones;Human;Knock-out;Knowledge;Mandible;Methodology;Mice Knockout;Molecular;Molecular Genetics;Morphogenesis;Mus;Neural Crest;Neural Crest Cell;Outcome;Pathogenesis;Pathway interactions;Pattern;Play;Primordium;Promotor (Genetics);Proteins;Recombination Genetic;Regulation;Regulatory Pathway;Regulatory Sequences Nucleic Acid;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Signaling Pathway Gene;Site;Structure;Surface Ectoderm;System;Time;Tissues;Transcription Genetic;chromatin immunoprecipitation;craniofacial;insight;member;migration;mutant;programs;transcription factor


application_id: 7454126
project_number: 5R01DC008168-02
project_title: Perceptual processing of indirect sound
administering_ic: NIDCD
award_notice_date: 2008-05-23
application_type: 5
activity_code: R01
ic: DC
serial_number: 008168
program_official: KING, KELLY ANNE
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1908853
contact_pi: ZAHORIK, PAVEL A
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Acoustics;Address;Affect;Algorithms;Arts;Auditory;Auditory system;Brain;Brain Stem;Cochlear Implants;Communication;Communication impairment;Complex;Condition;Dependence;Ear structure;Environment;Event;Exposure to;Goals;Hearing;Hearing Aids;Human;Individual;Knowledge;Lead;Mediating;Motion;Pattern;Performance;Positioning Attribute;Process;Property;Recording of previous events;Research;Research Personnel;Research Support;Role;Self-Help Devices;Sound - physical agent;Sound Localization;Source;Speech;Speech Intelligibility;Stimulus;Surface;Techniques;Testing;Time;Travel;Work;auditory stimulus;base;computerized data processing;concept;design;environmental adaptation;experience;hearing impairment;improved;interest;loss of function;precedence effect;programs;public health medicine (field);research study;simulation;size;virtual


application_id: 7452495
project_number: 5R01DC006698-05
project_title: NEURAL MODULATION OF CENTRAL TASTE PROCESSING
administering_ic: NIDCD
award_notice_date: 2008-05-09
opportunity_number: PA-03-115
application_type: 5
activity_code: R01
ic: DC
serial_number: 006698
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT F
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Food intake is not only regulated by homeostatic processes as is evidenced by eating beyond homeostatic needs if presented with highly palatable food. The palatability of taste i.e. hedonic tone is unquestionably a key factor in guiding food intake. A positive hedonic tone stimulates feeding and is one of many dietary factors associated with excess energy intake and in the long term may lead to obesity diabetes and hypertension. The object of this project is to understand how neural activity in the cortex and limbic system control taste processing in subcortical gustatory nuclei. The long-term objective is to elucidate how the brain assigns hedonic value to taste stimuli that reinforce or weaken their consumption. There must be neural circuitry by which gustatory hedonic value can be modified. For example an unpleasant experience with food-learned taste aversion-can result in the rejection of a previously accepted taste while a mineral imbalance--Na+ appetite-can transform a normally rejected Na+ solution into a highly preferred one. In normal animals changes in the motivational qualities of taste stimuli are coincident with selective alterations in the responses of brainstem taste cells. Although the isolated brainstem contains the sensory and motor apparatus necessary to produce feeding behavior ventral forebrain mechanisms are necessary for motivational states to modify these behaviors. One interpretation is that feedback from rostral structures normally modulates the afferent neural activity that conveys the hedonic value of a taste stimulus. Using electrophysiological neuroanatomical neurochemical and lesion analysis this project will test hypotheses about the centrifugal control of taste processing in the brainstem. Specific experiments examine (1) differences between the influence of forebrain activity on NST and PBN taste neurons (2) the route through which descending cortical and limbic projections modulate PBN taste neurons and (3) the neurochemicals released in the PBN by activation of cortical and limbic system nuclei.

project_terms:
Amygdaloid structure;Animals;Behavior;Brain;Brain Stem;Cell Nucleus;Cells;Chemicals;Chromatography High Pressure Liquid;Chronic;Consumption;Corticotropin-Releasing Hormone;Desire for food;Diabetes Mellitus;Dietary Factors;Dopamine;Eating;Electric Stimulation;Energy Intake;Feedback;Feeding behaviors;Food;Glutamates;Hypertension;Hypothalamic structure;Lateral;Lead;Learning;Lesion;Limbic System;Liquid substance;Measures;Medial;Mediating;Microdialysis;Minerals;Motor;Neurons;Neuropeptides;Neurotensin;Neurotransmitters;Norepinephrine;Nucleus solitarius;Obesity;Oral;Process;Prosencephalon;Radioimmunoassay;Rattus;Research Personnel;Route;Science of neurochemistry;Sensory;Serotonin;Solutions;Somatostatin;Specificity;Stimulus;Structure;Substance P;Taste Perception;Testing;experience;feeding;hedonic;immunoreactivity;neural circuit;parabrachial nucleus;programs;relating to nervous system;research study;response


application_id: 7451482
project_number: 3R01CA108696-04S1
project_title: An Appalchian Cervical Cancer Prevention Project
administering_ic: NCI
award_notice_date: 2007-06-29
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: 2009-06-30
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:
Despite its nearly preventable status13000 new cases of invasive cervical cancer are diagnosed each yearwith 4600 deaths. While nationally women have experienced a 75% reduction in cervical cancer mortality inthe past 5 decades rural Appalachian women continue to sustain low rates of Pap testing anddisproportionately high cervical cancer rates. To reduce this cervical cancer burden experienced by middleaged and older Appalachian women we propose to undertake a community participatory tailored faith-based intervention entitled "Faith Moves Mountains." While extensive literature has established theassociation between rural culture and religiosity aside from programs involving African-American churchessurprisingly few scientifically-based interventions have located disease prevention activities within thetrusted sustainable rural religious institutions of rural Appalachia. To address this missed opportunity thisproject will develop a random stratified sample of 50 congregations with 600 participants to: (1) Examine thefactors (both barriers and assets) that influence the use of Pap tests; (2) Administer a faith-based lay healthadvisor 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 aimscorrespond to 3 phases a developmental ethnographically-oriented phase; a community-participatoryintervention phase; and a qualitative and quantitaitve evaluation phase. With a multidisciplinary team ofsocial scientists community leaders physicians and cancer control experts the results from the proposedproject will enable researchers and communities to better address the barriers that prevent rural women fromreceiving Pap tests and recommended follow-up care; draw on local community assets to promote the use ofPap 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;Evaluation;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;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: 7449850
project_number: 1K01CA133138-01
project_title: Promoting Mammography in African American Women Visiting the Emergency Department
administering_ic: NCI
award_notice_date: 2008-06-12
opportunity_number: PAR-06-220
application_type: 1
activity_code: K01
ic: CA
serial_number: 133138
program_official: OJEIFO, JOHN O
project_start_date: 2008-06-12
project_end_date: 2013-05-31
study_section: Education Study Section (G)[NCI-G (J1)]
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accident and Emergency department;Address;African;African American;American;Breast Cancer Early Detection;Cancer Control;Cancer Etiology;Cancer Intervention;Caring;Cessation of life;Class;Communication;Controlled Clinical Trials Randomized;Development;Discipline of Nursing;Educational Materials;Evaluation;Foundations;Goals;Guidelines;Health Insurance;Healthcare;Intervention;Knowledge;Low income;Malignant neoplasm of breast;Mammography;Medical;Mentored Research Scientist Development Award;Mentors;Methodology;Methodology Research;Methods;Modeling;Movement;Phase;Pilot Projects;Qualitative Research;Randomized Controlled Trials;Rate;Readability;Research;Research Personnel;Research Project Grants;Sampling;Schedule;Scientist;Screening procedure;Second Primary Cancers;Services;Source;Staging;Structure;Testing;Training;Visit;Woman;Women's Group;Work;aged;cancer prevention;concept;design;experience;health belief;health disparity;peer;public health medicine (field);research study;skills;theories


application_id: 7449558
project_number: 5R01GM079516-02
project_title: Structural and Functional Studies of the SMC5-6 Complex
administering_ic: NIGMS
award_notice_date: 2008-07-18
application_type: 5
activity_code: R01
ic: GM
serial_number: 079516
program_official: PREUSCH, PETER
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 8139941
contact_pi: YE, HONG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
ATP phosphohydrolase;C-terminal;Cells;Characteristics;Chromosome Condensation;Chromosome Structures;Chromosomes;Complex;DNA;DNA Binding;DNA Repair;DNA biosynthesis;DNA Ribosomal;Eukaryota;Eukaryotic Cell;Fingers;Head;Helix (Snails);Helix of ear;Heterodimerization;In Vitro;Investigation;Length;Ligase;Link;Localized;Maintenance;Maps;Mediating;Meiosis;Mitosis;Molecular;Molecular Conformation;Mutation;N-terminal;Phenotype;Prokaryotic Cells;Proteins;Recombinant DNA;Recombinants;Research Personnel;Resolution;Saccharomyces cerevisiae;Series;Sister Chromatid;Site;Structure;Upper arm;Yeast Fission;Yeasts;base;cohesin;condensin;ds-DNA;homologous recombination;in vivo;member;programs;telomere;ubiquitin-protein ligase


application_id: 7449530
project_number: 5R01AG020941-06
project_title: Changes in myogenic progenitor potential with age
administering_ic: NIA
award_notice_date: 2008-06-24
opportunity_number: RFA-AG-06-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 020941
program_official: WILLIAMS, JOHN
project_start_date: 2002-06-01
project_end_date: 2011-06-30
study_section: ZAG1-ZIJ-2(M1)
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   This project will explore a novel mechanism potentially contributing both to muscle atrophy and increased muscle lipid with age. Our work shows that in the mouse the progenitors present in muscle that are primarily responsible for postnatal muscle growth repair and maintenance activate an adipocyte-like gene program with age. The balance between myogenic and adipogenic potential appears to be regulated by Wnt signaling. In fact the constellation of Wnt ligands present and the signaling pathways activated appear to crosstalk to control muscle size and lipid content. Thus Wnt signaling may provide the mechanistic link whereby exercise influences both muscle properties. We hypothesize that Wnt signaling is altered in myogenic progenitors as a function of age contributing to impaired muscle function through loss of muscle mass and increased intramyocellular lipid following injury. In addition intermyocellular lipid increases with age and we will assess the cellular properties of myofibroblasts to test the hypothesis that changes in their potential through altered Wnt signaling may contribute to lipid accumulation surrounding myofibers. In Aim 1 we will identify the signaling pathways that account for the distinct function of WntlOb in repressing adipogenic gene expression compared to other Wnts that promote myogenic differentiation and hypertrophy and determine the role of changes in Wnt signaling in altering myogenic progenitor potential with age. Myofibroblasts will be characterized in vitro in Aim 2 to determine if adipogenic potential increases with age potentially contributing to intermyocellular lipid. Co-culture of myogenic progenitors and myofibroblasts from different aged mice will determine if age affects their interaction. In Aim 3 myogenic progenitors will be "exercised" in vitro with a Flexcell stretcher to attempt to alter adipogenic potential. Lipid accumulation and myotube size will be quantified to determine if the effects of exercise differ with age through altered signaling. Preliminary data in human myogenic progenitors suggest that age also increases their adipogenic potential and focused analyses will be translated into humans. In Aim 4 myogenic progenitors and myofibroblasts will be isolated from older compared to younger humans to characterize myogenic and adipogenic differentiation potential that will be correlated with age muscle adiposity size and strength. The effects of an exercise regimen on muscle properties in vivo will be assessed in relation to changes in myogenic progenitor potential in vitro. We will examine the underlying mechanisms involved and whether response differs with age. The long term goal of this research is to characterize changes in cell fate with age and determine their contribution to impaired muscle function in the elderly. Using this information rational new strategies for frailty prevention can be designed and tested.

project_terms:
Accounting;Adipocytes;Affect;Age;Aging;Area;Cells;Coculture Techniques;Collaborations;Data;Elderly;Equilibrium;Exercise;Gene Expression;Genes;Goals;Growth;Human;Hypertrophy;In Vitro;Injury;Intervention Studies;Knock-out;Ligands;Link;Lipids;Maintenance;Mus;Muscle;Muscle Fibers;Muscle function;Muscular Atrophy;Myoblasts;Myofibroblast;Obesity;Prevention;Property;Protocols Treatment;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Testing;Transgenic Organisms;Translating;Work;aged;design;frailty;in vitro Model;in vivo;novel;postnatal;progenitor;programs;repaired;response;size


application_id: 7449398
project_number: 1R21AI078111-01
project_title: Leptospira interrogans Len adhesins
administering_ic: NIAID
award_notice_date: 2008-06-19
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: AI
serial_number: 078111
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2008-06-19
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-A (90)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Leptospirosis caused by the spirochete Leptospira interrogans and close relatives of that genus is a significant zoonotic disease affecting humans throughout the United Sates and many other parts of the world. These bacteria infect humans and other animals by penetrating mucous membranes or conjunctiva or through breaks in the skin. Bacteria then disseminate throughout the host via the bloodstream followed by invasion of other tissues. Leptospirosis in humans can lead to a range of debilitating symptoms and not infrequently death. Understanding the mechanisms by which leptospires are able to initiate and establish infection can direct development of improved diagnostics and preventative/treatment therapies.   
  
Infectious leptospires are very resistant to their hosts' alternative pathway of complement-mediated killing. Our studies found that L. interrogans can bind the host complement regulator factor H to its outer surface a strategy adopted by many other pathogens to avoid killing by host complement. During infection L. interrogans invades and colonizes kidneys and other host organs apparently facilitated by the spirochete's abilities to interact with host extracellular matrix (ECM) components. We discovered that L. interrogans carries six separate but similar genes each of which encodes a protein that can bind factor H and/or ECM proteins. All six leptospiral proteins share predicted structural and some functional similarities with mammalian endostatin and have been designated LenA LenB LenC LenD LenE and LenF (Len = Leptospiral ENdostatin-like protein). We hypothesize that Len proteins enable L. interrogans to both resist killing by host complement and to interact with host ECM. As a corollary to our central hypothesis we predict that all infectious leptospires produce one or more Len proteins to facilitate mammalian infection and that infected humans and other animals produce antibodies against those Len proteins. To test our hypothesis we will (1) perform functional characterization of interactions between Len proteins and their host ligands and (2) evaluate the practicality of using Len proteins for serological diagnosis of leptospirosis patients.   
  
PUBLIC HEALTH RELEVANCE: The causative agents of leptospirosis Leptospira interrogans and closely-related members of that genus are highly invasive pathogens that can establish persistent infections of immunocompetent individuals. The aim of this project is to characterize a family of six leptospiral proteins we found to interact with human immune system regulators and extracellular matrix components and may therefore play important roles in human leptospirosis.

project_terms:
Adhesins Bacterial;Adopted;Affect;Amino Acids;Animals;Antibodies;Arts;Bacteria;Binding (Molecular Function);Blood Circulation;Cessation of life;Clinic;Complement;Complement Factor H;Complement Pathway Alternative;Data;Development;Diagnosis;Diagnostic;Disease;Endostatins;Evaluation;Extracellular Matrix;Extracellular Matrix Proteins;Family;Fibronectins;Genes;Genetic;Human;Immune response;Immune system;Immunocompetent;In Situ;In Vitro;Individual;Infection;Invaded;Invasive;Kidney;Killings;Laboratories;Laminin;Lead;Leptospira;Leptospira interrogans;Leptospirosis;Ligand Binding;Ligands;Mediating;Methods;Mucous Membrane;Mutagenesis Site-Directed;Mutate;Order Spirochaetales;Organ;Patients;Play;Procedures;Property;Proteins;Purpose;Range;Recombinants;Relative (related person);Resistance;Role;Sampling;Serodiagnoses;Serological;Serum;Skin;Surface;Symptoms;Testing;Tissues;Travel;Zoonoses;conjunctiva;improved;member;pathogen;protein function;public health medicine (field);tool


application_id: 7448594
project_number: 5R01ES014849-03
project_title: AHR-Protac a novel aryl hydrocarbon receptor antagonist
administering_ic: NIEHS
award_notice_date: 2008-06-23
application_type: 5
activity_code: R01
ic: ES
serial_number: 014849
program_official: COLLINS, JENNIFER B
project_start_date: 2006-08-15
project_end_date: 2011-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): The broad long term goals of this proposal are to use a novel class of antagonists of the aryl hydrocarbon receptor (AHR) AHR-Protacs developed herein as 1) a research tool to delineate the mechanisms by which activation of the AHR pathway by environmental agents leads to carcinogenesis in the human population and identify roles of the AHR in other disease processes and 2) a therapeutic agent to treat cancers diabetes and cardiovascular diseases. Exposures to environmental factors such as benzo[a]pyrene and 2378 tetrachlorodibenzo-p-dioxin (TCDD) are thought to play important roles in the development of human cancers. While these agents are known to exert many of their carcinogenic actions via activation of the AHR the mechanisms by which the AHR elicits the key events are unknown. Further it has not yet been established whether targeting the AHR would be an effective chemopreventive approach. Finally emerging evidence implicates a role for the AHR in not only cancer but also diabetes and cardiovascular diseases. The immediate goals of the current proposal are to optimize and characterize novel AHR antagonists some of which have already been developed in our laboratories as appropriate AHR antagonists. Specific Aims: (1) Synthesis of optimum AHR Protacs. (2) Determine that the optimum AHR Protac molecule(s) inhibits AHR signaling in cultured cells with high efficacy. (3) Determine whether the optimum AHR Protac(s) inhibits the ability of TCDD to alter cell cycle apoptosis and senescence. (4) Determine whether the optimum AHR Protac(s) alters the AHR pathway with high specificity. The work proposed herein will develop a novel research tool that can be used to identify how inappropriate activation of the AHR by environmental carcinogens leads to human cancers and to understand the role of the AHR in normal biological processes. In addition this work will set the stage for the development of drugs that target the AHR and may be clinically useful not only as agents that may prevent cancers but may also be effective in the treatment of diabetes and cardiovascular diseases.

project_terms:
Address;Affinity Labels;Agonist;Apigenin;Apoptosis;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Biological;Biological Factors;Biological Process;Biotin;Carcinogens Environmental;Cardiovascular Diseases;Cell Cycle;Cells;Chemopreventive Agent;Chromatography Affinity;Class;Coupled;Cultured Cells;DNA Binding;Development;Diabetes Mellitus;Dioxins;Disease;Drug Delivery Systems;Environmental Pollution;Environmental Risk Factor;Event;Exhibits;Exposure to;G1 Arrest;Goals;Human;Human Development;Initiators Tumor;Kaempferols;Laboratories;Ligands;Malignant Neoplasms;Numbers;Pathway interactions;Pharmaceutical Preparations;Play;Population;Process;Promoters Tumor;Protac;Proteins;RNA Small Interfering;Receptor Signaling;Recruitment Activity;Reporter;Research;Role;Signal Pathway;Specificity;Staging;Technology;Therapeutic Agents;Thinking function;Transcription Genetic;Work;affinity labeling;base;carcinogenesis;design;environmental agent;kaempferol;novel;novel strategies;prevent;receptor;receptor expression;research study;senescence;small molecule;stem;tool


application_id: 7448586
project_number: 5R01NS039041-10
project_title: Neurogeneic Amplification of Pancreatitis Pain
administering_ic: NINDS
award_notice_date: 2008-03-26
application_type: 5
activity_code: R01
ic: NS
serial_number: 039041
program_official: PORTER, LINDA L
project_start_date: 2000-04-01
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-5(04)M]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN N.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): Many patients with pancreatitis or pancreatic cancer complain of abdominal pain that is resistant even to morphine. Our previous studies have determined that pain in patients with cancer involving the pelvic visceral organs is relieved by a neurosurgical lesion limited to the midline of the dorsal column of the spinal cord. We determined that sensory input from the pancreas is primarily transmitted to higher brain sensory processing centers as a midline component of the postsynaptic dorsal column pathway using anatomical electrophysiological and behavioral methods. In our laboratory recently we have developed a model of persistent visceral pain in Lewis inbred rats that resembles human pancreatitis in blood values and histology. The purpose of the proposed project is to study the neuronal pathway by which pain signals from the pancreas reach higher brain centers and how sensitization of this pathway can lead to persistent pain states. A multidisciplinary approach is used including behavioral electrophysiological and functional magnetic resonance imaging (fMRI) methods. The following hypothesis and specific aims were devised to improve our understanding of chronic visceral pain processing toward the long term goal of improved therapy: HYPOTHESIS: Nociceptive information arising from the inflamed pancreas is relayed in the spinal cord transmitted through medially ascending pathways to higher centers and produces central sensitization in medially located brain structures. Specific Aim 1 is to determine the nociceptive pathways activated in persistent pancreatitis. Specific Aim 2 is to reduce activation in the visceral nociceptive pathways maintaining central sensitization in a persistent pancreatitis model in Lewis inbred rats. The long-term outcome expected is that information about the visceral nociceptive pathway will contribute to future identification of therapeutic targets for these devastatingly painful conditions involving the pancreas.

project_terms:
Abdominal Pain;Animals;Behavioral;Block Sympathetic Nerve;Blood;Blood Volume;Brain;Cell Nucleus;Cells;Central cord canal structure;Central gray substance of midbrain;Characteristics;Chest;Chronic;Clinical;Clinical Treatment;Communities;Condition;Dorsal;End Point;Endothelin;Follow-Up Studies;Future;Goals;Histology;Human;Laboratories;Lead;Lesion;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Malignant Neoplasms;Malignant neoplasm of pancreas;Medial;Medical;Methods;Modeling;Morphine;Neurons;Nociception;Numbers;Operative Surgical Procedures;Organ;Outcome;Pain;Pan Genus;Pancreas;Pancreatitis;Pathway interactions;Patients;Pelvic Cancer;Pelvis;Persistent pain;Physiological;Play;Pontine structure;Process;Psyche structure;Purpose;Rats Inbred Lew;Rattus;Refractory;Reporting;Research Personnel;Resistance;Role;Route;Sensory;Sensory Process;Signal Transduction;Spinal;Spinal Cord;Structure;Syndrome;System;Thalamic structure;Visceral;Visceral Afferents;Visceral pain;cancer pain;central sensitization;clinically relevant;day;dorsal column;improved;insight;interdisciplinary approach;novel;postsynaptic;programs;raphe nuclei;research study;response;therapeutic target;transmission process


application_id: 7448483
project_number: 5R01CA105266-04
project_title: Ethnicity Breast Cancer Recurrence and Long-Term QOL
administering_ic: NCI
award_notice_date: 2008-07-22
application_type: 5
activity_code: R01
ic: CA
serial_number: 105266
program_official: AZIZ, NOREEN M
project_start_date: 2005-09-09
project_end_date: 2011-05-31
study_section: Epidemiology of Cancer Study Section[EPIC]
contact_pi_person_id: 6652159
contact_pi: BAUMGARTNER, KATHY B
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-22
project_abstract:
DESCRIPTION (provided by applicant): This application proposes a follow-up study of the New Mexico Women's Health Study (NMWHS: 1992-1996) a statewide population-based case-control breast cancer study for survival recurrence and quality of life (QOL) approximately 14 years (y) post-diagnosis. The NMWHS included 1556 Hispanic (H) and non-Hispanic white (NHW) women. Women newly diagnosed with in situ or invasive breast carcinoma ascertained through the New Mexico Tumor Registry (NMTR) were eligible based on the following criteria: age 30-74y diagnosis year 1992- 1994; and New Mexico (NM) resident at diagnosis. All H cases were included and a 33% random sample of NHW cases was identified for inclusion. The sampling fraction for NHW cases was chosen to give a similar distribution to the H cases based on age and geographic distribution of H cases ascertained during an earlier 3-y period. Of the eligible cases participation rates were 68% (n=332) for H cases; and 77% (n=380) for NHW cases. Controls were recruited using a modified version of the Waksberg random digit-dialing method and were frequency-matched by ethnicity age-group and health planning district. Of the eligible controls participation rates were 76% (n=388) for H cases and 86% (n=456) for NHW cases. Mean age at diagnosis for cases was 54y compared to 53y for controls. In an initial review of a 10% (n=156) random sample of NMWHS participants only 9% of 142 classified as 'alive' were not located (deceased=14). Of the 'alive' group 82% were located within NM. Based on these results we estimate that there will be 670 subjects to be followed for survival 430 for recurrence (517 if deceased are included) and 969 for QOL assuming a 75% participation rate. An additional random 12.9% sample showed 93% still in NM. Recurrence will be ascertained through self-report and verified through medical records. New primaries will be ascertained through linkage with the NMTR. Mortality will be confirmed using the National Death Index. QOL measures will be based on a standardized questionnaire used in a previous breast cancer cohort study and conducted via telephone. The proposed follow-up study will provide a unique opportunity to evaluate factors influencing survival and recurrence in long-term breast cancer survivors and QOL compared to population-based controls. Most important the study will allow the comparison of H vs. NHW women for these outcomes and the interaction of ethnicity with other prognostic factors in an aging cohort. There are few studies of QOL in older long-term breast cancer survivors and no large studies that we are aware of that have compared QOL in cases with population-based controls. There are scant data comparing H with NHW women for these outcomes. The proposed study could have important implications for treatment of H vs. NHW women and long-term care of older breast cancer survivors.

project_terms:
Acculturation;Address;Age;Age Group Unspecified;Aging;Alcohol consumption;Appendix;Behavioral;Breast Carcinoma;Cancer Control;Cancer Survivor;Cessation of life;Characteristics;Clinical;Cohort Studies;Comorbidity;Cultural Characteristics;Data;Diagnosis;Diagnostic Neoplasm Staging;Diet;Dietary intake;Digit structure;Dimensions;Educational aspects;Elderly woman;Employment;Equipment and supply inventories;Ethnicity aspects;Fatigue;Follow-Up Studies;Frequencies (time pattern);Geographic Distribution;Goals;Growth;Health Insurance;Health Planning;Hispanics;Hormone Receptor;In Situ;Invasive;Length;Life Style;Long-Term Care;Malignant neoplasm of breast;Mammography;Marital Status;Measures;Medical Records;Menopausal Status;Methods;Mortality Vital Statistics;New Mexico;Newly Diagnosed;Not Hispanic or Latino;Operative Surgical Procedures;Outcome;Participant;Patient Self-Report;Physical activity;Physical assessment;Physiological;Piper;Population;Prognostic Factor;Psyche structure;Quality of life;Questionnaires;Rate;Recruitment Activity;Recurrence;Registries;Risk Factors;Role;SF-36;Sampling;Screening procedure;Smoking;Status Socioeconomic;Survival Rate;Telephone;Time;Tumor stage;Universities;Weight;Woman;Women's Health;base;cancer recurrence;cancer therapy;case control;case-based;cohort;diagnosis quality;ethnic difference;improved;indexing;lymph nodes;size;social;tumor


application_id: 7447438
project_number: 5F31AA016265-03
project_title: Longitudinal & experimental analysis of positive urgency
administering_ic: NIAAA
award_notice_date: 2008-07-01
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: AA
serial_number: 016265
program_official: WHITE, AARON
project_start_date: 2006-07-01
project_end_date: 2009-06-30
study_section: ZAA1-HH(52)
contact_pi_person_id: 10403879
contact_pi: CYDERS, MELISSA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The goal of the proposed program of research is to further examine the role of positive urgency in college alcohol use and risky behavior. Positive urgency can be defined as the tendency to act rashly and maladaptively while in a very positive mood state; it may be an important predictor of college drinking and risk taking which tend to be celebratory in nature. In a recent series of studies I developed and validated self-report and interview measures of positive urgency: the measures related to drinking quantity/frequency problem drinking and certain kinds of risky behavior. With this award I propose to first test whether positive urgency measured at the beginning of the freshman year in college predicts problem drinking and drinking while in a positive mood over the course of that first year. Second I propose to conduct three laboratory experiments. Those experiments will show that (a) individuals high in positive urgency become more disinhibited when in a very positive mood than when not; (b) they become more disinhibited when in a positive mood than do individuals low in positive urgency; and (c) they drink more alcohol when in a very positive mood than do others.

project_terms:
Age;Alcohol abuse;Alcohol consumption;Alcohols;Automobile Driving;Award;Binge Eating;Cessation of life;Coitus;Drug usage;Equation;Esthesia;Expectancy;Exposure to;Fellowship;Frequencies (time pattern);Goals;Heavy Drinking;Impulsive Behavior;Impulsivity;Individual;Individual Differences;Injury;Interview;Investigation;Joints;Laboratories;Lead;Measures;Mediation;Melissa;Modeling;Names;Nature;Numbers;Ohio;Patient Self-Report;Play;Probability;Process;Questionnaires;Range;Rate;Reinforcements Positive;Research;Riots;Risk;Risk Behaviors;Risk Factors;Risk-Taking;Role;Sampling;Score;Series;Sports;Symptoms;Testing;Time;Violence;Walking;alcohol related problem;college;college drinking;day;drinking;drinking behavior;experience;experimental analysis;high risk drinking;improved;negative mood;positive mood;programs;prospective;research study;response;sex;theories;trait;university student;vandalism


application_id: 7447437
project_number: 5K02DE016845-04
project_title: Regulation of Nodal Signaling in Holoprosencephaly
administering_ic: NIDCR
award_notice_date: 2008-05-15
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DE
serial_number: 016845
program_official: HARDWICK, KEVIN S
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
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):  Holoprosencephaly represents a common birth defect (1:16000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline) which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors Smad2 and 4 and FoxH1(FAST). Importantly members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto null allele and recently we generated a Cripto hypomorphic allele Cripto3-loxP by genetic manipulation. Approximately 50% of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-beta signaling by blocking Smad2 function. Interestingly mutations in human TGIF gene are associated with holoprosencephaly suggesting its function in axial midline formation presumably through regulating Nodal/Smad2 signaling pathway. Based on these results we will pursue the following specific aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

project_terms:
Abnormal Cell;Activin Receptors Type I;Activins;Address;Affect;Alleles;Anterior;Anterior nares;Binding (Molecular Function);Biochemical Genetics;Biological Assay;Biological Models;Brain;Bypass;CFC1 gene;Categories;Cell Nucleus;Cells;Chickens;Child;Classification;Cleft Lip;Cloning Molecular;Complex;Congenital Abnormality;Cultured Cells;Cysteine;DNA Binding;Data;Defect;Development;Developmental Process;Disease;Disruption;Dorsal;EGF gene;EP300 gene;Ectoderm;Embryo;Embryonic Development;Endoderm;Event;Extracellular Protein;Eye;Face;Family;Family Leave;Family member;Figs - dietary;Floor;Forebrain Development;Gene Family;Gene Targeting;Genes;Genes Homeobox;Genetic;Genetic Programming;Head;Histones;Holoprosencephaly;Holoprosencephaly Alobar;Homeodomain Proteins;Human;In Vitro;Incisor;Individual;Invertebrates;Investigation;Laboratories;Lead;Left;Literature;Live Birth;Lobar Holoprosencephalies;Maintenance;Mediating;Mesoderm;Mice Mutant Strains;Microinjections;Midbrain structure;Modeling;Molecular;Molecular Genetics;Morphology;Mus;Mutation;N-terminal;Names;Nodal;Nose;Nuclear Protein;Nuclear Proteins;Organogenesis;Output;Pathway interactions;Patients;Pattern;Pattern Formation;Phenotype;Phosphorylation;Phylogenetic Analysis;Play;Positioning Attribute;Prevalence;Process;Property;Prosencephalon;Proteins;Pus;Rana (genus);Range;Receptor Signaling;Recruitment Activity;Regulation;Reporting;Repression;Research;Retinoids;Role;Semilobar Holoprosencephalies;Series;Side;Signal Pathway;Signal Transduction;Specific qualifier value;Stillbirth;Streaks Primitive;Structure;Structure of notochord;Symptoms;System;Testing;Tissues;Transcription Coactivator;Transcription Genetic;Transducers;Transforming Growth Factor beta;Vesicle;Visual Fields;Xenopus;Zebrafish;base;brain malformation;cofactor;craniofacial;density;developmental disease/disorder;fetal;genetic manipulation;homeodomain;improved;in vivo;insight;interest;loss of function;malformation;member;mutant;neural plate;precursor cell;programs;prospective;receptor;relating to nervous system;research study;transcription factor


application_id: 7446179
project_number: 5R01AI068119-03
project_title: Do Condoms Protect From Non-Viral Sexually Transmitted Infections?
administering_ic: NIAID
award_notice_date: 2008-06-11
application_type: 5
activity_code: R01
ic: AI
serial_number: 068119
program_official: DAVID, HAGIT S
project_start_date: 2006-06-15
project_end_date: 2011-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD 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
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): A recent federal report suggested that rigorous tests of condom effectiveness against sexually transmitted infections (STIs) are urgently needed. 1 To date published studies have not described tests of condom effectiveness. Further a search of the CRISP database revealed that studies of condom effectiveness have not yet been funded. The proposed study uses an innovative approach to testing condom effectiveness against penile-vaginal acquisition of a) Chlamydia b) trichomoniasis and c) any of three non-viral STIs (Chlamydia trichomoniasis and gonorrhea) (Aim 1). The negative sequelae of these infections are well documented. The infections also increase the odds of HIV acquisition and transmission. Because the protective value is highly likely to vary between men and women the study will also test for moderating effects of sex (gender) on condom effectiveness (Aim 2). Based on a substantial amount of research conducted by the PI of the proposed study it is also quite apparent that various forms of condom failure must be accounted for in tests of condom effectiveness. Therefore the study will quantify the loss of protective value attributable to these sources of failure (Aim 3). A final study aim is to determine the loss of protective value incurred as the frequency of condom use decreases from 100% (Aim 4). The sample will be 625 men and 625 women (> 15 years of age) attending one of two clinics for the evaluation and treatment of an STI. Participants will be followed over 6 months. After initially being tested (using DNA amplification) and treated (using single-dose directly observed therapy) for existing non-viral STIs participants will learn how to use a Personal Digital Assistant to keep an electronic coital diary over the subsequent 6 months. This innovative method of data collection helps assure optimal validity of the assessed behaviors. A brief education session will also be provided. This session will promote the correct and consistent use of condoms during the study period thereby helping to ensure that an adequate number of participants are classified as "100%" users in the analyses. A 3-month follow-up screening will detect early reinfections or new infections. A 6-month follow-up period will also include re-screening for the three STIs. The study is adequately powered (> 80%) to detect even modest effect sizes. Findings will be disseminated to inform public health policy and programs related to the use of condoms in the prevention of these common non-viral STIs.

project_terms:
Accounting;Address;Age-Years;American;Behavior;Bias Systematic;Chlamydia;Chlamydia trachomatis;Clinic;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Condition;Condoms Male;Condoms Unspecified;DNA amplification;Data Collection;Databases;Directly Observed Therapy;Dose;Educational aspects;Educational workshop;Effectiveness;Electronics;Ensure;Evaluation;Event;Facility Construction Funding Category;Failure (biologic function);Federal Government;Female;Frequencies (time pattern);Funding;Gender;Gonorrhea;HIV;Health Policy;Incidence;Infection;Investigation;Journals;Laboratories;Latex;Learning;Methods;Neisseria gonorrhoeae;Numbers;Outcome;Papillomavirus Human;Participant;Patient Self-Report;Personal Digital Assistant;Policies;Porosity;Prevention;Prevention program;Prophylactic treatment;Prospective Studies;Published Comment;Publishing;Relative (related person);Reporting;Research;Research Design;Research Personnel;Risk;Risk Reduction;Sampling;Screening procedure;Sexually Transmitted Diseases;Sound - physical agent;Source;Statistically Significant;Syphilis;Tail;Testing;Trichomonas Infections;Trichomonas vaginalis;United States Dept. of Health and Human Services;Vagina;Viral;Woman;base;cohort;design;diaries;follow-up;genital herpes;innovation;male;men;prevent;programs;prospective;public health medicine (field);sex;size;transmission process


application_id: 7446129
project_number: 5F31NS056574-02
project_title: Role of sPLA2 in Spinal Cord Injury and Demyelination
administering_ic: NINDS
award_notice_date: 2008-02-29
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: NS
serial_number: 056574
program_official: KLEITMAN, NAOMI
project_start_date: 2007-01-19
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-F01-N(20)L]
contact_pi_person_id: 8601658
contact_pi: TITSWORTH, WILLIAM L
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Demyelination is a pathological process associated with many CMS diseases including traumatic spinal cord Injury (SCI). The death of oligodendrocytes following SCI results in myelin loss and functional impairment. Given that total phospholipases A2 (PLA2) is upregulated following SCI SPLA2-IIA is expressed following SCI and causes central demyelination when injected. It is proposed that SPLA2-IIA released after SCI triggers oligodendrocyte cell death which leads to demyelination and loss of function. Therefore blocking sPLA2-IIA may represent a novel strategy to prevent demyelination associated with secondary SCI. To further address this issue injections of sPLA2 will be used to create a model of focal demyelination in the dorsolateral white matter targeting the cervical rubrospinal tract. This model will allow testing of therapeutic strategies against sPLA2-IIA-induced demyelination. This investigation will determine 1) whether SPLA2-IIA- induced focal demyelination results in oligodendrocyte cell death. 2) If so whether sPLA2 inhibitors can block the death of oligodendrocytes in vitro. 3) Finally whether inhibitors of sPLA2 can create histological and functional improvement in a clinically relevant contusion model of SCI.

project_terms:
Address;Affect;Apoptosis;Area;Astrocytes;Axon;Cell Death;Cells;Cervical;Cessation of life;Contusions;Data;Demyelinations;Development;Disease;Family;In Vitro;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Investigation;Lesion;Mechanics;Mediating;Mediator of activation protein;Microglia;Modeling;Motor Pathways;Multiple Trauma;Myelin;Neuroglia;Neurons;Oligodendroglia;Pathologic Processes;Pathway interactions;Phospholipase A2;Play;Quinacrine;Recovery of Function;Role;Spinal Cord;Spinal cord injury;Structure of rubrospinal tract;System;Testing;Therapeutic;Tissues;appendage;astrogliosis;clinically relevant;functional disability;functional improvement;functional outcomes;group X secretory phospholipase A(2);improved;inhibitor/antagonist;loss of function;novel strategies;phospholipase A2 inhibitor;prevent;white matter


application_id: 7446101
project_number: 5R03CA128028-02
project_title: A Pharmacogenetic approach to prostate cancer susceptibility
administering_ic: NCI
award_notice_date: 2008-05-12
opportunity_number: PAR-06-313
application_type: 5
activity_code: R03
ic: CA
serial_number: 128028
program_official: SRIVASTAVA, SUDHIR
project_start_date: 2007-06-12
project_end_date: 2009-05-31
study_section: ZCA1-SRRB-F(J1)
contact_pi_person_id: 8670251
contact_pi: KIDD, LA CREIS RENEE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
There is growing awareness cancer susceptibility may be attributed to multiple genetic variations and biological pathways rather than to single candidate genes. To date few studies model the complex interaction among polymorphic carcinogen activation clearance transport detoxification as well as DNA repair genes on the risk of prostate cancer development particularly within underserved populations. Objectives/Hypothesis: The primary goal of this project is to identify informative genetic markers to predict the risk of prostate cancer among men of African descent. Individuals possessing one or more putative rapid bioactivation genotypes as well as compromised detoxification transport and DNA repair genotypes are hypothesized to have a higher risk for developing prostate cancer relative to those possessing low-risk genotypes. This increased risk may be partially attributed to an altered capacity to metabolically activate extrude or detoxify hazardous compounds from cells and an inability to fully repair environmentally-induced DNA damage. Specific Aims: 1) Determine or verify the prevalence of single nucleotide polymorphisms (SNPs) in selected metabolic activation detoxification transport and DNA repair genes among men of African descent. 2) Evaluate the relationship between these polymorphic genes and prostate cancer risk. 3) Assess whether interaction among various genetic susceptibilities in selected metabolism metabolic clearance transport and DNA repair genes can be used to predict or detect the risk of developing prostate cancer. Study Design: Germ-line DNA collected from 918 men of African descent will be analyzed including 220 incident prostate cancer cases and 698 healthy controls. The occurrence of 28 putative high-impact markers will be analyzed using TaqMan allelic discrimination and polymerase chain reaction-restriction fragment length polymorphism strategies. In order to assess single-gene and combined effects on prostate cancer risk traditional statistical methods will be combined with sophisticated computational algorithms and hierarchical interaction graphs. Impact: The proposed study identifies and evaluates whether a complex array of genetic markers can detect prostate cancer susceptibility using a combination of traditional and innovative bioinformatic approaches. This comprehensive approach provides an opportunity to visualize verify and evaluate the predictive accuracy of gene-gene interactions as indicators of risk. Ultimately these study findings will help: 1) identify SNP signatures explaining disease progression and recurrence within high-risk populations; 2) clarify the role of multiple genes and biological pathways in prostate cancer detection; 3) predict patients benefiting from available chemoprevention and therapeutic regimens; and 4) reduce the mortality and morbidity of prostate cancer.

project_terms:
ABCB1 gene;Address;African;Alleles;Asians;Awareness;Bioinformatics;Biological;Blood;Breast;CYP1A1 gene;CYP1A2 gene;Cancer Detection;Candidate Disease Gene;Carcinogens;Caucasians;Caucasoid Race;Cells;Chemoprevention;Code;Colorectal;Complex;Computational algorithm;Conflict (Psychology);DNA;DNA Adducts;DNA Damage;DNA Repair;DNA Repair Gene;Development;Discrimination (Psychology);Disease Progression;Drug Kinetics;ERCC2 gene;Gene Targeting;Genes;Genetic Markers;Genetic Predisposition to Disease;Genotype;Germ Lines;Glutathione S-Transferase;Goals;Graph;Haplotypes;Human;Individual;Joints;Logistics;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Metabolic Activation;Metabolic Biotransformation;Metabolic Detoxication Drug;Metabolism;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Multi-Drug Resistance;Mutation;Observational Study;Participant;Pathway interactions;Patients;Pharmacogenetics;Polymerase Chain Reaction;Polymorphism Genetic;Population;Predisposition;Prevalence;Prostate;Protocols Treatment;RNA Messenger;Recurrence;Regression Analysis;Regulatory Sequences Nucleic Acid;Relative (related person);Reporting;Research Design;Research Personnel;Restriction fragment length polymorphism;Risk;Role;Sample Size;Single Nucleotide Polymorphism;Statistical Methods;Stream;Study models;Therapeutic;Toxic effect;Transferase;Underserved Population;Uridine;Variation (Genetics);XPA gene;Xenobiotic Metabolism;Xenobiotics;cancer epidemiology;cancer risk;chemotherapeutic agent;design;drug efficacy;gene interaction;innovation;men;protein expression;protein structure function;repaired;response;urinary


application_id: 7446075
project_number: 5R01AG028925-03
project_title: INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION
administering_ic: NIA
award_notice_date: 2008-06-19
opportunity_number: PA-03-147
application_type: 5
activity_code: R01
ic: AG
serial_number: 028925
program_official: WILLIAMS, JOHN
project_start_date: 2006-09-15
project_end_date: 2011-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mechanisms controlling musculoskeletal recovery following disuse are poorly understood. However there is evidence that the restoration of lost tissue is impaired with aging. Precursor cell function in both muscle and bone is altered with advancing age which may contribute to the decreased recovery. The goal of this proposal is to investigate the role of tissue-specific precursor cells during the recovery from bone loss and muscle atrophy in response to hind-limb suspension (HS) in rats and to determine whether there are age- associated differences in this process. We hypothesize that changes in the function of tissue-specific precursor cells impair the restoration of musculoskeletal mass with advancing age. The strength of our approach is that both muscle and skeletal components will be studied in the same animals facilitating evaluation of the interaction between the two systems and the integration of common mechanisms. In Aim 1 we will investigate whether advancing age decreases the capacity to recover (by reambulation) the musculoskeletal atrophy induced by HS. The temporal correlation between loss of muscle and bone and their capacity for restoration will be investigated. Aim 2 addresses whether the underlying mechanisms of precursor cell function and apoptosis in bone and muscle are changed with aging and contribute to the impaired recovery from lost tissue in vivo. In Aim 3 bone marrow stem cells and myoblasts will be isolated and proliferation differentiation and apoptotic responses in vitro determined to investigate whether age- associated changes in these processes contribute to atrophy and impaired restoration of musculoskeletal mass. Our preliminary data suggest an age-dependent role for altered BMP signaling that may account for diminished restorative capacity in bone. Whether BMP is a common target underlying the mechanistic basis of bone and muscle regulation during aging and disuse will be determined. Finally in Aim 4 we will investigate in vitro and in vivo whether changes in the insulin-like growth factor (IGF)-1 pathway are involved in the impaired restoration of musculoskeletal mass with aging. Together these studies will provide important insight into the cellular mechanisms underlying the impaired ability of older animals to recover musculoskeletal integrity after disuse. Our proven integrative approach for studying muscle and bone will enable us to elucidate common mechanisms underlying the responsiveness of the musculoskeletal system during aging. Relevance to public health: Advancing age is associated with a loss of muscle as well as bone mass and it is unknown whether the musculoskeletal system in older individuals differs in its restorative capacity after periods of disuse. In this study we will identify common mechanisms underlying age-related changes in progenitor cell function. Identifying these common pathways influencing muscle and bone integrity could lead to putative targets for pharmacologic or therapeutic interventions.

project_terms:
Accounting;Address;Age;Aging;Animals;Apoptosis;Apoptotic;Atrophic;Bed rest;Bone Density;Bone Marrow;Bone Marrow Stem Cell;Bone and Bones;Cell Nucleus;Cell physiology;Cells;Condition;Daily;Data;Disease;Elderly;Evaluation;Event;Face;Goals;In Vitro;Individual;Insulin-Like Growth Factor I;Lead;Life;Limb structure;Longevity;Maintenance;Marrow;Mechanics;Molecular;Muscle;Muscle Fibers;Muscular Atrophy;Musculoskeletal;Musculoskeletal System;Myoblasts;NIH Program Announcements;Nuclear;Operative Surgical Procedures;Osteocytes;Pathway interactions;Process;Purpose;Rattus;Recovery;Regulation;Role;Signal Transduction;Skeletal muscle structure;Stem cells;Suspension substance;Suspensions;Systems Integration;Testing;Therapeutic Intervention;Time;Tissues;Workload;age related;base;bone loss;in vivo;insight;juvenile animal;paracrine;precursor cell;public health medicine (field);response;restoration;sarcopenia;satellite cell


application_id: 7446071
project_number: 5R01HL058686-08
project_title: Chemosensitivity of Tachykinin-containing Lung Afferents
administering_ic: NHLBI
award_notice_date: 2008-06-02
application_type: 5
activity_code: R01
ic: HL
serial_number: 058686
program_official: NOEL, PATRICIA
project_start_date: 1998-04-01
project_end_date: 2011-06-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Vagal bronchopulmonary C-fiber sensory nerves play an important role in regulating airway functions. Hypersensitivity of these afferents is believed to be involved in the manifestation of airway hyperresponsiveness associated with mucosal injury a prominent feature of asthma. During airway inflammatory reaction a number of low molecular weight highly cationic proteins are secreted by inflammatory cells such as eosinophils that infiltrate into the airways. It is well documented that the release of these proteins can induce mucosal injury and airway hyperresponsiveness. Our recent studies have established the first direct evidence demonstrating an intense and sustained effect of both human eosinophil granule-derived and synthetic cationic proteins on vagal bronchopulmonary C-fiber endings. However the mechanism underlying both the initial stimulatory and the sustained sensitizing effects of cationic proteins on these sensory nerves is poorly understood. Our central hypothesis is that the cationic charge carried by these proteins acts on the airway mucosa triggering the release of certain inflammatory mediators that in turn exert potent effects on the C-fiber terminals. The mast cells located in the airway mucosa probably play an important role in the interaction between cationic proteins and sensory endings. Sensitization of these afferents can then lead to airway hyperresponsiveness via both cholinergic reflex pathways and tachykininergic mechanisms. Single-fiber and whole-cell patch-clamp recording techniques will be employed to measure the activity of bronchopulmonary C fibers in anesthetized rats and in isolated neurons respectively. The results obtained from this study should provide critical information for gaining new insights into the mechanisms underlying the airway hyperresponsiveness induced by cationic proteins.

project_terms:
Asthma;C Fiber;Cells;Charge;Chemicals;Cholinergic Agents;Condition;Cytoplasmic Granules;Development;Exposure to;Fiber;Goals;Human;Hypersensitivity;Inflammation;Inflammatory;Injury;Laboratories;Lead;Lung;Measures;Mechanics;Mediating;Mediator of activation protein;Molecular Weight;Mucous Membrane;Neurons;Numbers;Pathway interactions;Personal Satisfaction;Play;Protein C;Proteins;Range;Rattus;Reaction;Reflex action;Relative (related person);Research Personnel;Research Project Grants;Role;Sensory;Tachykinin;Techniques;Testing;Work;aerosolized;afferent nerve;airway hyperresponsiveness;cholinergic;eosinophil;insight;mast cell;neutrophil;patch clamp;programs;response


application_id: 7446056
project_number: 5R37HL055757-14
project_title: OXYGEN RADICALS AND CARDIAC ADAPTATIONS TO ISCHEMIA
administering_ic: NHLBI
award_notice_date: 2008-06-23
application_type: 5
activity_code: R37
ic: HL
serial_number: 055757
program_official: LIANG, ISABELLA Y
project_start_date: 1995-05-01
project_end_date: 2010-06-30
study_section: NSS-H
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: 2008-07-01
project_abstract:
ecent evidence demonstrates that exercise induces delayed cardioprotection similar to that of ischemic preconditioning (PC) ia mechanisms that are presently unknown. Unlike ischemic or pharmacologic PC exercise PC is triggered by a physiologic itimulus and thus would appear to be a natural means for achieving cardioprotection. The overall objective of this proposal is.0 elucidate the molecular mechanisms .underlying the newly-discovered phenomenon of exercise PC. Our fundamentallypothesis is that exercise-induced release of NO (via eNOS) activates a signal transduction cascade that includes PKCeSrc/Lck and multiple transcription factors and culminates in the upregulation of iNOS which then mediates the protectioneither singularly or in conjunction with eNOS. A broad multidisciplinary approach will be used that will combine diverseechniques (integrative physiology protein chemistry mass spectrometry biochemistry cell biology molecular biology gene.argeting and transgenesis) and will integrate genetic information at the molecular level with biochemical information at thejrotein structure level and physiological information at the whole animal level. Unequivocal evidence for or against anDbligatory role of three specific kinases (PKCe Src.Lck) in exercise PC will be provided by the use of a novel dominantnegative PKCe transgenic mouse line and Src and Lck knockout mice this will enable us to achieve for the first time(inase-specific modulation of PKCe. Src.and Lck during exercise. The role of PKCs in initiating exercise PC will be onclusivelv established by determining the effects of specific transgenic inhibition of this isozyme. The kinase-specificactivity of all seven Src PTKs expressed in the mouse heart (Fyn Fgr Yes Src Lyn Lck and Blk) will be directly measuredat serial times after exercise PC. The role of Src PTKs in triggering versus mediating exercise PC'will be discerned bycomparing inhibition of these kinases on days 1 and 2 (during the exercise stimulus) versus day 3 (during coronary occlusion).Targeted disruption of the Src and Lck gene will be employed to conclusively establish the specific function of individualPTKs in the PC protection. The transcription factors responsible for exercise PC will be systematically interrogated by usingmice with targeted genetic ablation of each of the main factors known to bind to the iNOS gene (IRF-1 TNF-a STAT1 CREBAP-1 IL-2 and IL-6). The specific NOS isoforms responsible for initiating as well as mediating exercise PC will beconclusively identified by targeted gene disruption of eNOS iNOS and nNOS. The post-translational modulation ofiNOS 24 h after exercise will be elucidated by identifying the precise phosphorylation site(s) on iNOS with HPLC coupled-electrospray ionization mass spectrometry. Finally the role of Src PTKs in the post-translational modulation of iNOS will beestablished by measuring iNOS activity and tyrosine phosphorylation in the absence and presence of Src PTK inhibitors. Thisproposal should produce important new insights into the molecular mechanisms whereby the heart adapts not only to physicalstress but also to stress in general. Elucidation of the mechanism of exercise PC may have important therapeutic implications.

project_terms:
Ablation;Acute;Animals;Arginine;Atrial Natriuretic Factor;Binding (Molecular Function);Binding Sites;Biochemical;Biochemistry;Biological Assay;Blotting Western;CREB1 gene;Cardiac;Cellular biology;Chloride Ion;Chlorides;Chromatography High Pressure Liquid;Complex;Coronary Arteriosclerosis;Coupled;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Diethyldithiocarbamate;Disruption;Doctor of Medicine;Dominant-Negative Mutation;EGF gene;EMSA;Electrophoretic Mobility Shift Assay;Electrospray Ionization;Elements;Engineering;Epidermal Growth Factor;Event;Exercise;Exposure to;FOS gene;Family;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Techniques;Genetically Engineered Mouse;Glyceraldehyde-3-Phosphate Dehydrogenases;Heart;Heat shock proteins;Hypoxia-Responsive Elements;IRF1 gene;IRF2 gene;Immunoprecipitation;Individual;Interferon Regulatory Factor 2;Interferon Type II;Interferons;Interleukin-2;Interleukin-6;Investigation;Ischemia;Ischemic Preconditioning;Isoenzymes;Janus kinase;Laboratories;Lavendustin A;Left;Lymphocyte Specific Protein Tyrosine Kinase p56(lck);MAP Kinase Gene;Manganese Superoxide Dismutase;Measures;Mediating;Mediator of activation protein;Mice Knockout;Mice Transgenic;Mitogens;Modeling;Molecular;Molecular Biology;Molecular Genetics;Mus;Mutation;Myocardial Infarction;NOS1 protein human;NOS3 protein human;Nitrates;Nitric Oxide Synthase;Nitrites;Nitroglycerin;Nuclear;Numbers;Occlusions Coronary;Patients;Peroxonitrite;Phosphorylation Site;Phosphotransferases;Physiological;Physiological reperfusion;Physiology;Play;Positioning Attribute;Promotor (Genetics);Protein Chemistry;Protein Isoforms;Protein Kinase;Protein Kinase C;Protein Tyrosine Kinase;Proteins;Pyrazolones;Reactive Oxygen Species;Recruitment Activity;Reperfusion Injury;Reperfusion Therapy;Resistance;Response Elements;Role;S-nitro-N-acetylpenicillamine;STAT1 gene;Signal Pathway;Signal Transduction;Site;Spectrometry Mass Electrospray Ionization;Spectrum Analysis Mass;Stimulus;Stress;Structure;Techniques;Therapeutic;Thiopronine;Time;Transcription Factor AP-1;Transcription Genetic;Transducers;Transgenic Organisms;Tumor Necrosis Factor-alpha;Tyrosine;Tyrosine Kinase Inhibitor;Tyrosine Phosphorylation;Up-Regulation (Physiology);Ventricular;clinically relevant;day;diethylenetriamine;hypoxia inducible factor 1;inhibitor/antagonist;insight;interdisciplinary approach;interest;knockout gene;nitrate;novel;preconditioning;programs;protein kinase C epsilon;protein structure;protein-tyrosine kinase c-src;pyrazolone;transcription factor


application_id: 7442321
project_number: 5R01HL083320-03
project_title: Metabolic Mechanisms of Cardiac Injury and Protection
administering_ic: NHLBI
award_notice_date: 2008-06-18
application_type: 5
activity_code: R01
ic: HL
serial_number: 083320
program_official: LIANG, ISABELLA Y
project_start_date: 2006-07-15
project_end_date: 2011-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Acetylglucosamine;Acute;Acute myocardial infarction;Address;Affect;Attenuated;Cardiac;Cell Line;Cessation of life;Chronic;Cytoprotection;Data;Development;Disruption;Enzymes;Fostering;Functional disorder;Gene Transfer;Genetic;Goals;Heart Diseases;Heat-Shock Proteins 70;Hypoxia;In Vitro;Injury;Ischemia;Ischemic Preconditioning;Ischemic Preconditioning Myocardial;Knowledge;Link;Mediating;Mediator of activation protein;Metabolic;Metabolic Pathway;Mitochondria;Modality;Modification;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Myocytes Cardiac;Pathway interactions;Patients;Pharmacology;Physiological reperfusion;Preservation Biological;Process;Protein Processing Post-Translational;Pump;RNA Interference;Range;Reperfusion Injury;Reperfusion Therapy;Role;Serine;Severities;Signal Transduction;Structure;Threonine;Tissues;Transfer RNA;base;clinical application;design;glucose metabolism;improved;in vivo;information gathering;innovation;novel;preconditioning;protective effect


application_id: 7442308
project_number: 5R01HL065660-06
project_title: Role of the JAK-STAT Pathway in Ischemic Preconditioning
administering_ic: NHLBI
award_notice_date: 2008-06-20
application_type: 5
activity_code: R01
ic: HL
serial_number: 065660
program_official: SCHWARTZ, LISA
project_start_date: 2001-05-08
project_end_date: 2011-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1964532
contact_pi: XUAN, YU-TING
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this continuation of our ongoing project is to investigate the signaling and molecular mechanisms underlying the sustained infarct-sparing and anti-apoptotic effects observed during the late phase of ischemic preconditioning (PC). Although apoptosis has been shown to play a crucial role in cell death after ischemia/reperfusion injury it remains largely unknown whether late PC protects against cardiac apoptosis and what signaling/molecular mechanisms underlie these protective actions. Building upon our previous works we propose that brief episodes of mvocardial ischemia (ischemic PC protocol) protect against apoptotic cardiomyocyte death. Our fundamental hypothesis is that ischemic PC induces a sustained cardioprotected phenotype by activating pro-survival signaling pathways via the recruitment of stress-responsive transcription factors (STAT1 and STATS) leading to the upregulation of anti-apoptotic proteins that inhibit both the death receptor- and the mitochondria-dependent pathways of apoptosis. All studies will be conducted in an established murine model of ischemic PC. In Ajrn 1 we will determine whether ischemic PC inhibits cardiomyocyte apoptosis contributed to the delayed cardioprotective effects. Cardiac apoptosis will be evaluated by in situ hairpin-1-biotin ligation assay DNA laddering TUNEL assays and immunohistochemistry of active caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP). The influence of ischemic PC on the death receptor-mediated and the mitochondria-mediated pathways of apoptosis will be elucidated by examining their effects on the release of cytochrome c and Smac from mitochondria on the activation of caspases (caspase-3 8 and 9) and the cleavage of PARP and on the expression of pro- and anti-apoptotic proteins. In Aims 2 and 3 we will establish whether the delayed anti- apoptotic actions afforded by late PC are mediated by STAT1 and/or STATS. The individual roles of STAT1 and STATS in mediating apoptotic cell death (the mitochondria-mediated vs. the death receptor-mediated apoptosis) will be conclusively established by targeted knockout of the STAT1 gene and by genetic inhibition of STATS via an inducible cardiac-specific STATS knockout mouse model. In Aim 4 we will identify whether the delayed cardioprotective effects conferred by late PC require both Tyr-705 and Ser-727 phosphorylation of STATS by using a Tyr-705 dominant negative mutant of STATS and a Ser-727 mutant of STAT3 respectively. This proposal will provide important new insights into the signaling and molecular mechanisms whereby the late phase of ischemic PC reprograms the heart in the intact animal.

project_terms:
Abbreviations;Animals;Apoptosis;Apoptotic;BIRC4 gene;Biological Assay;CASP8 and FADD-like apoptosis regulating protein;Cardiac;Cell Death;Cessation of life;Cleaved cell;Complex;DAPI;DNA;Disruption;Doctor of Philosophy;Dominant-Negative Mutation;Formates;Funding;Gene Targeting;Genetic;Genetic Programming;Genetic Techniques;Genetically Engineered Mouse;Heart;Immunohistochemistry;In Situ;Individual;Infarction;Interferon Type II;Investigation;Ischemia;Ischemic Preconditioning;Knock-out;Late Effects;Ligation;Measurement;Measures;Mediating;Microscopic;Mitochondria;Modeling;Molecular;Molecular Genetics;Mus;Myocardial;Myocardial Infarction;Myocytes Cardiac;Pathway interactions;Phase;Phenotype;Phosphorylation;Physiology;Play;Poly(ADP-ribose) Polymerases;Protein Chemistry;Protein Isoforms;Proteins;Protocols documentation;Regulation;Relative (related person);Reperfusion Injury;Research Personnel;Role;STAT protein;STAT1 gene;STAT3 gene;Signal Pathway;Signal Transduction;Site;Somatomedins;Stress;TdT-Mediated dUTP Nick End Labeling Assay;Techniques;Testing;Up-Regulation (Physiology);Work;biotin 1;caspase;caspase-3;caspase-8;caspase-9;cytochrome c;in vivo;insight;interdisciplinary approach;mouse model;mutant;preconditioning;pro-apoptotic protein;programs;protective effect;receptor;response;size;transcription factor


application_id: 7441311
project_number: 2R56NS038041-05A1
project_title: Neuropeptidase Function
administering_ic: NINDS
award_notice_date: 2007-06-20
application_type: 2
activity_code: R56
ic: NS
serial_number: 038041
suffix: A1
program_official: STEWART, RANDALL R
project_start_date: 2001-07-15
project_end_date: 2012-06-30
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Our goal is to understand substrate recognition catalytic function and the action of inhibitors inneuropeptidases enzymes that inactivate or modify peptide neurotransmitters or neurohormones. Wepropose to study specificity and function using two related neuropeptidases neurolysin and thimetoligopeptidase as model systems. These zinc metallopeptidases inactivate the neuropeptide neurotensinand are potential therapeutic targets for psychotic disorders and treatment of pain. They have an unusualproperty shared by a number of neuropeptidases. The cleavage sites they recognize on bioactive peptidesare unusually diverse with no apparent common features. The basis for this unusual property and otheraspects of enzyme function and inhibition will be explored by combining high-resolution structuredetermination with functional studies of the enzymes. Based on prior work we hypothesize that broadsubstrate recognition occurs primarily through the interaction between the C termini of substrate peptidesand an unusual binding surface which allows for a variety of different peptide conformations and bindingcontacts. We also suggest that a hinge-like conformational change in the enzymes accompanies catalysisand that an unusual inhibitor C28 disrupts enzyme function by preventing this motion. Four specific aimsare proposed: 1) to determine crystal structures of enzymes complexed with peptides and peptide analogs inorder to visualize the structural basis for broad specificity 2) to test and refine our models of recognition bymodulating the specificity of the enzyme through mutagenesis 3) to examine the proposed mechanism ofC28 inhibition using velocity sedimentation analysis and other assays 4) to extend our studies to puromycinsensitive aminopeptidase in order to assess the generality of recognition mechanisms.Relevance to public health. The proposed research will provide an understanding of enzymes that areinvolved in controlling communication between cells in the nervous system. Knowledge of these enzymeswill allow us to manipulate their activity in order to treat diseases of the nervous system as well as otherdisorders

project_terms:
Accounting;Addiction Drug;Alzheimer's Disease;Binding (Molecular Function);Biological;Biological Assay;Biological Models;Catalysis;Cells;Centrifugation;Characteristics;Cleaved cell;Collection;Communication;Complex;Data;Decompression Sickness;Depth;Disease;Electrostatics;Endopeptidases;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Goals;Grant;Hydrolysis;Knowledge;Metalloproteases;Modeling;Motion;Multienzyme Complexes;Mutagenesis;Mutagenesis Site-Directed;Mutate;Nervous system structure;Neurodegenerative Disorders;Neurohormones;Neuromodulator;Neuropeptides;Neurotensin;Neurotransmitters;Numbers;Opioid Peptide;Pain;Pattern;Peptide Conformation;Peptide Fragments;Peptide Hydrolases;Peptide Library;Peptides;Play;Property;Proteins;Psychotic Disorders;Range;Regulation;Research;Resolution;Role;Signal Sequences Peptide;Site;Sites Active;Specificity;Structure;Substrate Specificity;Surface;Testing;Therapeutic;Validation;Work;Zinc;base;inhibitor/antagonist;interest;nervous system disorder;neurolysin;novel;novel therapeutics;peptide analog;preference;prevent;public health medicine (field);puromycin-sensitive aminopeptidase;sedimentation velocity;tau Proteins;therapeutic target;thimet oligopeptidase


application_id: 7440803
project_number: 3R01DA011551-09S1
project_title: Structure and Function of CB2 Cannabinoid Receptor
administering_ic: NIDA
award_notice_date: 2007-06-21
application_type: 3
activity_code: R01
ic: DA
serial_number: 011551
suffix: S1
program_official: HILLERY, PAUL
project_start_date: 1998-09-30
project_end_date: 2009-04-30
study_section: Molecular, Cellular and Developmental Neurosciences 5[MDCN-5]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term goal of this research proposal is to identify the molecular basis underlying the functions ofthe CB2 cannabinoid receptor. To achieve this purpose the following steps will be taken. In Aim 1 and 2the interactive mutagenesis molecular modeling and new compound testing studies will be carried out.This combined approach has advanced our understanding and should continue to reveal new insights onhow cannabinoid ligands are recognized by their receptors the origin of receptor subtype-selectivity andhow _these receptors are activated/inactivated. Cannabinoid receptors share many of the conservedsequence motifs seen in other well-studied G protein-coupled receptors (GPCRs) such as rhodopsin andbiogenic amine receptors. However several helix-bending residues and motifs and a key disulfidebridge present in many other GPCRs are missing in cannabinoid receptors. In Aim 3 Ligand bindingcrevice exposure of two transmembrane domains of CB2 cannabinoid receptor will be mapped usingsubstituted-cysteine accessibility method. This approach should elucidate structural and functionalconsequences of the sequence divergence in these trasmembrane domains of cannabinoid receptors. InAim 4 Disulfide bond formation of CB2 receptor will be determined directly by the state-of-artmethodologies of mass spectrometry. Investigating the unique disulfide bond or absence of a disulfidebond should provide important helix folding information of CB2 receptor and this will have importantimplications regarding ligand binding crevice and activation mechanisms of this receptor. Finally in Aim5 effort will be devoted to over-express and purify large amounts of functional CB2 receptor. Thischallenging task if successfully completed should have a significant impact by providing the badlyneeded pure receptor proteins for future high-resolution biophysical studies. Overall This study shouldhelp us to understand in more molecular detail the structure and function of CB2 receptor. CB2 isprimarily distributed in the immune system. It is very important for the immune-modulatory effects ofmarijuana. In the long run this study should also help us to develop better cannabinoid mimetics for thetreatment of immune system illnesses such as inflammation and autoimmune diseases. The drugs thatsoecifi(;allv taroeted at CB2 should be devoid of [}svchoactive side effects of marijuana.

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


application_id: 7440576
project_number: 1R21AG031876-01
project_title: Aberrant Protein Complexes in CSF as Biomarkers of Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2008-08-25
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: AG
serial_number: 031876
program_official: HSIAO, JOHN
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1 CND-E (90)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of a sufficiently sensitive and specific objective 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) quantifying levels of the protein-protein complex in small volumes of ventricular CSF from autopsy-verified subjects with non-AD pathologies MCI LAD and age-matched control subjects using an enzyme linked immunoassay developed in our laboratory based on the trapping one component of the complex and quantifying the other component ; 2) quantifying levels of the protein-protein complex in lumbar CSF from living probable AD and age-matched control subjects using the ELISA and 3) using sequential immunoprecipitation SDS-PAGE and mass spectrometry to examine individual components of the protein complex in ventricular CSF from MCI LAD and age-matched control subjects. 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 a biomarker of AD and MCI. PUBLIC HEALTH RELEVANCE: 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 of the process of neuron degeneration and loss and 2) the lack of a sufficiently 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) and that 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:
Affect;Age;Alzheimer disease prevention;Alzheimer's Disease;American;Amyloid;Amyloid beta-Protein Precursor;Antibodies;Apolipoprotein E;Autopsy;Binding Proteins;Biological Assay;Biological Markers;Blotting Western;Buffers;Cause of Death;Cerebrospinal Fluid;Chemicals;Clinic;Clinical;Cognitive;Communities;Complex;Condition;Count;Coupled;Cuprozinc Superoxide Dismutase;Data;Dementia;Diagnosis;Diagnosis clinical;Diagnostic;Diagnostic Procedure;Diagnostic Sensitivity;Disease;Disease Progression;Early Diagnosis;Effectiveness;Electrophoresis;Elevation;Enzyme Immunoassay;Enzymes;Etiology;Fractionation;Frontotemporal Dementia;Future;Gel;Genotype;Immunoassay;Immunoprecipitation;Individual;Intervention;Interview;Laboratories;Legal patent;Lewy Body Disease;Life;Link;Literature;Location;Measures;Memory Disorders;Memory Loss;Modification;Molecular Weight;Nature;Nerve Degeneration;Numbers;Pathogenesis;Pathologic;Pathology;Phase;Plasma;Population;Prealbumin;Primary Health Care;Process;Prostaglandins;Protein Processing Post-Translational;Proteins;Psyche structure;Range;Rate;Research;Retinol Binding Proteins;Sampling;Score;Senile Plaques;Sensitivity and Specificity;Series;Serotransferrin;Specificity;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spectrum Analysis Mass;Staging;Staining method;Stains;Structure;Superoxide Dismutase;Supranuclear Palsy Progressive;Testing;Therapeutic Intervention;Thinking function;Time;United States;Validation;Ventricular;base;beta-2 Microglobulin;carbonate dehydratase;cognitive function;concept;copper zinc superoxide dismutase;improved;interest;liquid chromatography mass spectrometry;mild cognitive impairment;nervous system disorder;neurofibrillary tangle formation;neuroimaging;neuropathology;neuropsychological;novel;novel diagnostics;post gamma-globulins;pre-clinical;prevent;public health medicine (field);tandem mass spectrometry;tau Proteins;two-dimensional


application_id: 7440190
project_number: 5R42AA014554-03
project_title: Transgenic plant cells as a source of hepatoprotective drugs
administering_ic: NIAAA
award_notice_date: 2008-05-29
opportunity_number: RFA-AA-06-007
application_type: 5
activity_code: R42
ic: AA
serial_number: 014554
program_official: OROSZ, ANDRAS
project_start_date: 2003-09-30
project_end_date: 2010-05-31
study_section: ZAA1-DD(74)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic liver damage (ALD) is among the top ten causes of death in the USA but existing therapeutic interventions are relatively ineffective. Hepatocytes are susceptible to damage probably because they have a high level of alcohol dehydrogenase (ADH) which metabolizes alcohol to form acetaldehyde and reactive oxygen species (ROS) which are both cytotoxic. Close similarities between eukaryotic cells suggest that alcohol-resistant plant cells are a potential source of hepatoprotective compounds particularly if these plant cells have been "engineered" to metabolize alcohol rapidly by ADH. In the preceding phase 1 research transgenic tobacco cells expressing rat liver ADH and a cellular screen for hepatoprotection were developed. In this phase 2 proposal mutant cultures from this transgenic plant will be selected for resistance to alcohol-induced toxicity. Extracts from this resistant sub-population will then be screened for the presence of cytoprotective metabolites against alcohol-induced toxicity in hepatocytes. Greater genetic diversity can be introduced by investigation of protective metabolites that have been evolved "naturally" by plants. In aquatic plant species fermentation reactions become important energy sources particularly in root tissue when oxygen tension is low. This induces ADH with prolonged very high rates of alcohol metabolism to acetaldehyde (Vartapetian & Jackson 1997). Some of these species should have evolved metabolites that protect against intracellular generation of ROS and acetaldehyde and some of these might also protect hepatocytes from alcohol. Extracts from ~75 native aquatic plant species were immediately available to the project and ~30 have now been screened. Several of these extracts are highly protective to hepatocytes. In phase 2 this screening will continue and the two approaches will be combined by culturing and selecting mutant populations of those aquatic plant species with greatest hepatoprotective activity. Subsequently the protective activity in these transgenic plants will be optimized and extracts and semi-purified compounds evaluated in animal models of ALD in vivo. Several patentable therapeutic products are predicted which will be commercialized with a partner in phase 3. The development of the technology also extends existing intellectual property licensed exclusively to Naprogenix by the University of Kentucky Research Foundation.

project_terms:
Acetaldehyde;Acute;Alcohol Hepatotoxicity;Alcohol dehydrogenase;Alcoholic liver damage;Alcohols;Animal Model;Antioxidants;Biological Factors;Cause of Death;Cell Line;Cells;Chromatography High Pressure Liquid;Chronic;Class;Compatible;Condition;Daughter;Development;Economics;Energy-Generating Resources;Engineering;Ethanol;Ethanol Metabolism;Ethanol toxicity;Eukaryotic Cell;Fermentation;Foundations;Fractionation;Generations;Genes;Genome Plant;Genomics;Geographic Locations;Hepatocyte;Hepatoprotective Agent;Human;In Vitro;Intellectual Property;Investigation;Kentucky;Killings;Libraries;Licensing;Liver;Modeling;Mus;Mutagenesis;Mutation;Oxygen measurement partial pressure arterial;Pathology;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Plant Extracts;Plant Leaves;Plant Roots;Plants;Population;Production;Proteins;Protoplasts;Rate;Rattus;Reaction;Reactive Oxygen Species;Research;Resistance;Resources;Screening procedure;Small Business Technology Transfer Research;Source;Staging;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Tobacco;Toxic effect;Transgenic Organisms;Transgenic Plants;Universities;Variation (Genetics);cell injury;commercialization;concept;cytotoxic;high throughput screening;in vivo;in vivo Model;innovation;mutant;novel;problem drinker;size;technology development


application_id: 7440187
project_number: 5R01AG026147-03
project_title: LDLR Genetics Splicing and AD Risk
administering_ic: NIA
award_notice_date: 2008-05-21
opportunity_number: PAS-03-128
application_type: 5
activity_code: R01
ic: AG
serial_number: 026147
program_official: MILLER, MARILYN
project_start_date: 2006-08-15
project_end_date: 2010-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia i.e. loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol e.g. Alzheimer's Disease (AD). Indeed a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease apoE is known more widely for its role in cholesterol delivery and homeostasis; apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression and the haplotypes defined by these functional SNPs are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds.

project_terms:
3' Untranslated Regions;Accounting;Alleles;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease risk;Amino Acids;Amyloid beta-Protein;Antibodies;Apolipoprotein E;Binding (Molecular Function);Biological;Blood Vessels;Blotting Western;Brain;Cell model;Cell surface;Cells;Cholesterol;Cholesterol Homeostasis;Codon Nonsense;Collaborations;Culture Media Conditioned;DNA;Deposition;Disease;Disease Association;Disease susceptibility;Dominant-Negative Mutation;Endosomes;Enhancers;Event;Exons;Extracellular Space;Family;Frequencies (time pattern);Gender;Gene Fusion;Genes;Genetic;Genotype;Golgi Apparatus;Gonadal Steroid Hormones;Haplotypes;Homeostasis;Human;Hypercholesterolemia Familial;Immune Sera;Immunoprecipitation;In Vitro;Individual;Kentucky;LDL Cholesterol Lipoproteins;LDL-Receptor Related Protein 1;Label;Life;Ligand Binding;Ligands;Link;Lipids;Lipoproteins;Liver;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Mediating;Mutation;Neurons;Nobel Prize;Pattern;Phenotype;Physiologic pulse;Plasma;Polymorphism Genetic;Population;Principal Investigator;Process;Protein Binding;Protein Isoforms;Proteins;Publishing;Pulse taking;RNA Splicing;Reading;Receptors Cell Surface;Relative (related person);Religion and Spirituality;Reporter;Reporting;Research Personnel;Risk Factors;Role;Sampling;Series;Sex Characteristics;Site;Stability mRNA;Transmembrane Domain;Universities;Variant;Vesicle;Woman;Work;apolipoprotein E-3;apolipoprotein E-4;base;case control;disease phenotype;extracellular;gain of function;genetic variant;human tissue;in vivo;insight;member;novel;programs;protein function;receptor;receptor binding;receptor expression;receptor function;sugar;trend;uptake


application_id: 7440181
project_number: 5F30ES013372-05
project_title: Arsenite inhibition of mitotic progression
administering_ic: NIEHS
award_notice_date: 2008-06-05
opportunity_number: PA-01-132
application_type: 5
activity_code: F30
ic: ES
serial_number: 013372
program_official: HUMBLE, MICHAEL C
project_start_date: 2004-06-15
project_end_date: 2009-06-14
study_section: Special Emphasis Panel[ZRG1-F10(20)L]
contact_pi_person_id: 7888753
contact_pi: TAYLOR, BEN F
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This project will determine whether the mechanism by which arsenate induces mitotic effects on the Anaphase Promoting Complex (APC) mediate arrest. We hypothesize that arsenite inhibits the APC and subsequently mitotic progression. The APC orchestrates progress through the cell cycle and mitosis by targeting specific mitotic substrates for proteasomal degradation via ubiquitination. Specific aim 1 will determine whether arsenite treatment inhibits APC substrate degradation necessary for mitotic exit. In Specific aim 2 we will immunoprecipitate (IP) the APC and identify its subunits in order to investigate arsenite binding to APC subunits using radiolabeled Na[73As]O2. Determination of arsenite binding requires resolution of APC subunits using SDS-PAGE examination of protein banding pattern using Sipro-Red and fluorescence imaging and subsequent autoradiography to elucidate bands incorporating radiolabeled arsenite. Western blot analysis of SDS-PAGE resolved APC subunits will be used to identify specific APC subunits. Once arsenite association is determined the proteins will be excised from the gel and identity confirmed by mass spectrometry. Specific aim 3 will determine whether arsenite inhibits APC ubiquitin ligase activity. Isolated APC will be used in an ubiquitin conjugating assay with radiolabeled APC substrates treated with or without arsenite. Reaction products will be resolved on SDS-PAGE and autoradiography will be used to determine the degree of substrate laddering due to ubiquitin conjugation. Identification of the molecular targets of arsenite is important for chemotherapeutic drug development.

project_terms:
Arsenates;Arsenites;Autoradiography;Binding (Molecular Function);Biological Assay;Blotting Western;Cell Cycle;Gel;Mediating;Mitosis;Mitotic;Molecular Target;Pattern;Proteins;Radiolabeled;Reaction;Resolution;Spectrum Analysis Mass;Ubiquitin;Ubiquitination;anaphase-promoting complex;drug development;fluorescence imaging;radiotracer;ubiquitin ligase


application_id: 7439099
project_number: 5P30NS051220-04
project_title: UK Spinal Cord & Brain Injury Research Center Core Grant
administering_ic: NINDS
award_notice_date: 2008-04-16
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
program_official: MILLER, THOMAS
project_start_date: 2005-05-01
project_end_date: 2010-04-30
study_section: Neurological Sciences and Disorders B Study Section[NSD-B]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application is in response to the NINDS Program Announcement requesting institutional center core grants to support neuroscience research. Accordingly the current application seeks to create the UK Spinal Cord & Brain Injury Research Center (SCoBIRC) Core Grant to accelerate the research projects of 10 NINDS-funded investigators who are currently Pis on 12 NINDS R01s and to enhance . The application asks for support for five core facilities: an Administrative and Bioinformatics Core an Animal Surgery & TBI/SCI Model Core a Behavioral Testing Core a Microscopy Image Analysis & Stereology Core and a Pharmacokinetics and Biomarker Core. Although some of the proposed technologies are currently in place in the laboratories of individual investigators none of the cores currently exists. The proposal is for these resources to be centralized in some cases upgraded and added to with additional equipment. Dedicated technical support is requested for each of the cores to insure that they will be run efficiently with minimal downtime and equipment failure and serve to enhance the productivity of SCoBIRC and other NINDS-supported investigators. It is also expected that these cores will promote communication of data and foster overall collaboration. All of the participating investigators have documented needs for the use of most of the core facilities: 6 of 10 will use all 5 cores 3 will use 4 of the cores and only 1 will use 3 of them. Use of the cores will be shared with other non-qualifying neurological investigators. The PI has had considerable administrative experience and each of the Core Directors is fully qualified to direct the use of the proposed technologies. They will be backed up in 4 of the 5 cases with equally experienced Assistant Directors and dedicated technical staff who will perform pilot studies train new investigators handle scheduling maintain supplies and equipment maintenance. The performance of the cores will be reviewed quarterly by a Steering Committee consisting of all of the qualifying investigators. It is anticipated that the existence of these cores will greatly enhance the accomplishment of the SCoBIRC mission which is directed at the discovery and clinical translation of therapeutic approaches for spinal cord and brain injury. In addition these facilities will make available centralized technologies which will benefit UK neurological research in general and improve the ability of both experienced and young investigators to compete for extramural funding.


application_id: 7438935
project_number: 1R01EY018836-01
project_title: Intrinsic anti-angiogenic activity of siRNA
administering_ic: NEI
award_notice_date: 2008-03-07
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: EY
serial_number: 018836
program_official: SHEN, GRACE L
project_start_date: 2008-04-01
project_end_date: 2012-03-30
study_section: Special Emphasis Panel[ZRG1 CB-G (90)]
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_terms:
2-thiouridine;Accounting;Adaptor Signaling Protein;Adopted;Affect;Age related macular degeneration;Angiogenesis Modulating Agents;Apoptosis;Architecture;Ascaridil;Biology;Blindness;Blood Vessels;Breast;Cell Proliferation;Cell surface;Cells;Chemicals;Choroidal Neovascularization;Class;Cleaved cell;Clinical Trials;Clinical Trials Phase II;Complex;DICER1 protein human;Data;Development;Disease;Double Stranded RNA Virus;Drug Delivery Systems;Elderly;Endothelial Cells;Epidemic;Exudative age-related macular degeneration;Eye;Fire - disasters;Gene Mutation;Genes;Genetic;Goals;Growth;Immune;Immune response;Immune system;Immunity Natural;Incidence;Individual;Infiltration;Inhibition of Cell Proliferation;Interferons;Interleukin-12;Investigation;Kinetics;Laser injury;Lasers;Lead;Length;Leukocytes;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Medicine;Modeling;Modification;Molecular;Molecular Profiling;Mus;Mutation;Nature;Nobel Prize;Ophthalmology;Panthera leo;Pathway interactions;Patients;Pharmacogenetics;Positioning Attribute;Prevalence;Process;Property;RNA;RNA Interference;RNA Double-Stranded;RNA Messenger;RNA-Induced Silencing Complex;Retina;Role;Signal Pathway;Signal Transduction;Surface;System;TLR3 protein human;Techniques;Testing;Therapeutic;Thrombospondin 1;Toxic effect;Transcript;United States;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor-1;Work;angiogenesis;chemokine;concept;cost;design;gene therapy;in vivo;insight;interest;mRNA Transcript Degradation;mouse model;neovascular;nonhuman primate;novel;novel strategies;pigment epithelium-derived factor;programs;public health medicine (field);receptor;response;thrombospondin 2;tool


application_id: 7438512
project_number: 1R01NS061975-01
project_title: Combinatory strategies to functional remyelination after spinal cord injury
administering_ic: NINDS
award_notice_date: 2008-01-22
opportunity_number: PAS-07-189
application_type: 1
activity_code: R01
ic: NS
serial_number: 061975
program_official: KLEITMAN, NAOMI
project_start_date: 2008-04-01
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-Y (06)]
contact_pi_person_id: 8141627
contact_pi: CAO, QI LIN
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Demyelinated axons persist in the injured spinal cord chronically and remyelination of demyelinated but otherwise intact axons represents an important repair strategy to facilitate functional recovery after SCI. Adult spinal cord has a limited capacity to spontaneously remyelinate despite the fact that oligodendrocyte precursor cells (OPCs) which have the capacity to remyelinate become active and proliferate in response to the injury. The differentiation of and remyelination by endogenous OPCs is inhibited in the injured spinal cord. Transplantation of neural stem cells (NSCs) or glial progenitors has also proven effective to increase remyelination after SCI but with varying degrees of success. The majority of grafted NSCs differentiate into astrocytes and their differentiation into oligodendrocytes (OLs) or neurons is inhibited in the injured spinal cord. Similarly differentiation from grafted glial progenitors is also restricted in the injured spinal cord and many transplanted glial progenitors remain undifferentiated or differentiate into astrocytes. Understanding the mechanism(s) that restrict the differentiation of and remyelination by the endogenous and grafted NSC or OPCs in the injured spinal cord should lead to new therapeutic strategies to repair SCI. The presence of inhibitory factors in the injury microenvironment may contribute to the restriction of the oligodendrocyte differentiation and remyelination. Our preliminary data showed that reactive astrocytes from the injured spinal cord inhibit OL differentiation of adult OPCs by increasing expression of bone morphogenetic proteins (BMPs). The absence of sufficient signals to stimulate differentiation of OPCs and myelination by mature OLs in the injured spinal cord may also contribute to the limited remyelination after SCI. Our preliminary data showed that increasing expression of growth factors such as the multi- neurotrophin D15A or CNTF promoted the remyelination by grafted OPCs in the injured spinal cord. We hypothesize that the combination of blocking inhibitory BMP signaling to promote OPC differentiation and increasing the expression of growth factors to enhance their maturation and remyelination may work synergistically to promote more extensive remyelination and lead to greater electrophysiological and locomotor behavioral recovery after SCI. In this application we will use objective and sensitive electrophysiological and behavioral analyses to test this hypothesis in a well characterized chemically demyelinated model and also clinically-relevant contusive SCI model in adult rats. Based on our published and preliminary data four specific aims are proposed: 1. To determine whether astrocytes from the injured spinal cord inhibit differentiation of and remyelination by adult OPCs by increased secretion of BMPs. 2. To test the hypothesis that blocking inhibitory BMP signaling will promote the differentiation maturation and remyelination of grafted adult OPCs in the demyelinated spinal cord. 3. To test the hypothesis that combination of blocking inhibitory BMP signaling to promote the differentiation and increasing the expression of growth factors that enhance the maturation of and myelination by OLs will work synergistically to promote the differentiation maturation and remyelination of grafted adult OPCs and functional recovery in the demyelinated spinal cord. 4. To test whether the optimal combinatorial strategies established in Aims 1-3 will lead to more extensive remyelination by transplanted OPCs and further functional recovery in the more clinically relevant contusion SCI model. PUBLIC HEALTH RELEVANCE: Spinal cord injury is a devastating injury for patients and their families and is a significant health care and financial burden on society. Therapeutic intervention(s) that would restore partial function would increase the quality of life of those patients. In this proposal we will use combinatorial strategy to promote remyelination and functional recovery in clinically-relevant contusive SCI model in adult rats.

project_terms:
Adult;Astrocytes;Axon;BMP2 gene;Behavioral;Bone Morphogenetic Proteins;Cell Differentiation process;Ciliary Neurotrophic Factor;Coculture Techniques;Complex;Contusions;Data;Demyelinations;Development;Environment;Family;Ganglia Spinal;Growth Factor;Healthcare;In Vitro;Injection of therapeutic agent;Injury;Injury of central nervous system;Lead;Lesion;Modeling;Modification;Myelin;Neurons;Oligodendroglia;Patients;Process;Proliferating;Publishing;Quality of life;Rattus;Reactive Inhibition;Recovery;Recovery of Function;Severities;Signal Transduction;Societies;Spinal Cord;Spinal cord injury;Testing;Therapeutic Intervention;Time;Transplantation;Transplants Cell;Undifferentiated;Work;astrogliosis;base;behavior test;bone morphogenetic protein 2;clinically relevant;combinatorial;functional loss;in vivo;inhibitor/antagonist;injured;irradiation;myelination;nerve stem cell;neurotrophic factor;novel therapeutics;oligodendrocyte precursor;precursor cell;progenitor;public health medicine (field);repaired;response to injury;success;transcription factor


application_id: 7437425
project_number: 5K01DA018772-04
project_title: A Pharmacological Analysis of Delta 9-THC in Humans
administering_ic: NIDA
award_notice_date: 2008-06-03
opportunity_number: PA-95-049
application_type: 5
activity_code: K01
ic: DA
serial_number: 018772
program_official: LYNCH, MINDA
project_start_date: 2005-06-01
project_end_date: 2010-05-31
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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):    Dr. Lile's graduate and post-doctoral research focused on the neuropharmacological basis of stimulant addiction and how the neurotransmitter systems that mediate the effects of stimulants could be targeted for medications development. The career development and research plan proposed in this application outlines the training that will enable him to apply his previous experience along with new methodolgies to an emerging area of research the treatment of cannabis-related disorders. Despite the fact that cannabis use is more prevalent than for any other illicit drug and can progress to abuse and dependence there are no pharmacotherapies for these disorders and little clinical research has been conducted to this end. The experiments described here were designed to identify the neurotransmitter systems that are involved in the effects of the primary active constituent of cannabis delta 9-THC in humans. The primary outcome variable for these experiments is the interoceptive cue produced by delta 9-THC. The interoceptive effects of delta 9- THC will be measured using the drug-discrimination procedure which is a pharmacologically specific and sensitive means to characterize the profile of a drug. Because cannabis-related disorders are associated with maladaptive changes in behavior and cognition additional experimental measures to assess reinforcement subjective ratings impulsivity psychomotor performance learning and memory will also be taken. The role of the cannabinoid opioid GABA and dopamine systems will be investigated which will reveal targets for future research efforts. Dr. Lile will be sponsored by Dr. Kelly an expert in cannabis research in humans. The conduct of these experiments and the training described in this proposal will occur at the University of Kentucky which has an extensive community of scientists engaged in basic and clinical research related to drug addiction. This award will allow Dr. Lile to develop as an independent investigator and to establish a program of human research concentrated on cannabis-related disorders.

project_terms:
Addiction Drug;Agonist;Aminobutyric Acid;Aminobutyric Acids;Area;Attenuated;Award;Behavior;Behavioral;Cannabinoids;Cannabis;Chronic;Clinical Research;Cognition;Cognitive;Communities;Cues;Dependence;Development;Disease;Disorder Cannabis-Related;Dopamine;Drug Combinations;Drug abuse;Ensure;Future;Goals;Human;Hydromorphone;Illicit Drugs;Impulsivity;Institutes;Kentucky;Learning;Measures;Mediating;Memory;Methylphenidate;Nabilone;Neurotransmitters;Opioid;Oral;Outcome;Pharmaceutical Preparations;Pharmacotherapy;Postdoctoral Fellow;Prevention;Procedures;Psychological reinforcement;Psychomotor Performance;Psychostimulant dependence;Rate;Research;Research Personnel;Role;Scientist;Stimulus;System;Techniques;Testing;Tetrahydrocannabinol;Training;Triazolam;Universities;base;cannabinoid receptor;career;design;dopamine system;drug discrimination;drug of abuse;experience;gamma-Aminobutyric Acid;novel;programs;reinforcer;research and development;research study


application_id: 7437281
project_number: 5R01DK067413-04
project_title: Insulin Control of Gene Transcription Through Sensitin
administering_ic: NIDDK
award_notice_date: 2008-05-30
application_type: 5
activity_code: R01
ic: DK
serial_number: 067413
program_official: SILVA, CORINNE M
project_start_date: 2005-07-15
project_end_date: 2010-06-30
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 1858075
contact_pi: VILLAFUERTE, BETTY C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Insulin resistance leading to type 2 diabetes generally involve defects in insulin signaling at the postreceptor level. Activation of the PI 3'-kinase to Akt pathway plays a significant role in insulin signaling but the events downtream of Akt are largely unknown. Recently we identified a novel Akt substrate which binds to the insulin-responsive elements (IREs) of insulin-like growth factor binding protein-3 (IGFBP-3) and other insulin-responsive genes. The IRE-binding protein "sensitin" cDNA encodes a 120 kDa cytoplasmic protein. After adding insulin the protein is cleaved to a 50 kDa fragment which localizes predominantly to the nucleus and transactivates IREs. PI 3'-kinase inhibition decreases both Ser/Thr phosphorylation and proteolysis of sensitin. Based on our preliminary data the long-term goal of our investigation is to employ the IRE of IGFBP-3 as a model system to delineate the signaling pathway by which insulin induces genomic effects through the action of a specific trans-acting factor sensitin that binds to the IRE. This application has the following aims: 1) To test the hypothesis that sensitin is subject to regulated phosphorylation by insulin using 2-D phosphomapping and mass spectrometry to localize residues of sensitin phosphorylated by insulin in HepG2 cells and the effect of phosphorylation on insulin-induced transcription assessed by mutational analysis. 2) To test the hypothesis that proteolytic cleavage of sensitin is required for transactivation of the IRE and the corollary hypothesis that nuclear translocation of sensitin is secondary to cleavage of the protein. We will identify the cleavage sites by microsequencing mutate the proteolytic domain to test its role in nuclear translocation and IRE transcription; and mutate the Akt phosphorylation site to determine if dephosphorylation prevents nuclear translocation or proteolysis of sensitin. 3) To determine the physiological significance of phosphorylation and proteolysis of sensitin in a rat diabetes model we will compare the phosphorylation and proteolysis of sensitin in vitro by hepatic cytosolic extracts from diabetic obese and lean control rats and determine whether sensitin mutation conferring protease- and phosphorylation-resistance increase the diabetes susceptibility of obese rats or worsen glucose control in diabetic rats. This study may lead to better understanding of insulin-regulated gene transcription and may provide insights into linked to the pathogenesis of type 2 diabetes mellitus.

project_terms:
1-Phosphatidylinositol 3-Kinase;Animals;Binding (Molecular Function);Binding Proteins;Biological;Biological Models;Cell Nucleus;Cells;Characteristics;Cleaved cell;Cysteine;Cytoplasmic Protein;DNA Complementary;Data;Defect;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Elements;Endopeptidases;Epidemic;Event;Gene Targeting;Genes;Genomics;Goals;Hepatic;In Vitro;Insulin;Insulin Resistance;Insulin-Like Growth Factor Binding Protein 3;Investigation;Lead;Link;Liver;Liver Extract;Localized;Mediating;Metabolic;Modeling;Mutate;Mutation;Nuclear Translocation;Obesity;Pathogenesis;Pathway interactions;Peptide Hydrolases;Peptides;Phosphorylation;Phosphorylation Site;Phosphotransferases;Physiological;Play;Predisposition;Prevalence;Process;Protease Domain;Protein Dephosphorylation;Proteins;Proteolysis;Proto-Oncogene Proteins c-akt;Ras/Raf;Rattus;Recombinants;Regulation;Research Personnel;Resistance;Role;Secondary to;Serine/Threonine Phosphorylation;Signal Pathway;Signal Transduction;Site;Spectrum Analysis Mass;Testing;Trans-Activation (Genetics);Trans-Activators;Transcription Coactivator;Transcription Genetic;Transcriptional Activation;age related;base;blood glucose regulation;diabetic;diabetic rat;in vivo;insight;insulin signaling;novel;prevent;programs;receptor;response;sensitin;two-dimensional


application_id: 7436474
project_number: 1R01HL091893-01
project_title: The Platelet Secretory Machinery
administering_ic: NHLBI
award_notice_date: 2008-04-28
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 091893
program_official: MONDORO, TRACI
project_start_date: 2008-05-01
project_end_date: 2012-04-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adhesions;Agonist;Alpha Granule;Atherosclerosis;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Clot;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Categories;Cause of Death;Cell membrane;Cells;Cellular biology;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;DAB2 gene;Data;Defect;Development;Diagnostic Reagent;Disease;Drug Delivery Systems;Event;Exocytosis;Family;Forecast of outcome;Future;Goals;Hemorrhage;Hemostatic function;In Vitro;Inflammation;Knowledge;Lead;Learning;Lysosomes;Mediating;Membrane Fusion;Membrane Proteins;Molecular;Molecular Target;Mouse Strains;Mus;Myocardial Infarction;Pathology;Pathway interactions;Phenotype;Physicians;Platelet Activation;Play;Process;Protein Secretion;Proteins;Recombinant Proteins;Regulation;Reporting;Research;Risk;Role;SNAP receptor;Signal Transduction;Site;Stimulus;System;Techniques;Therapeutic;Therapeutic Agents;Thinking function;Thrombosis;Thrombus;Time;United States;VAMP-2;Work;Wound Healing;base;design;extracellular;falls;in vivo;in vivo Model;insight;neurotransmitter release;novel;novel therapeutics;programs;protein protein interaction;public health medicine (field);research study;response;soluble NSF attachment protein;stroke;syntaxin;syntaxin-2;target SNARE proteins;therapeutic target;vesicular SNARE proteins


application_id: 7436167
project_number: 5R01NS039254-09
project_title: Tat-mediated brain endothelial cell dysfunction
administering_ic: NINDS
award_notice_date: 2008-06-03
opportunity_number: PAS-03-165
application_type: 5
activity_code: R01
ic: NS
serial_number: 039254
program_official: WONG, MAY
project_start_date: 2000-04-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-AARR-A(07)M]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Impaired function of the brain vasculature can contribute to HIV trafficking into the CNS and the development of neurodegenerative changes associated with HIV infection. Indeed activation or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) induction of inflammatory responses and provide an entry route for the HIV into the CNS. The leading hypothesis of our research is that the viral gene product HIV Tat protein can be responsible for BMEC injury and impaired function of the BBB. Furthermore we hypothesize that alterations of redox balance may be the common denominator of Tat-induced activation and dysfunction of BMEC. In support of these hypotheses we obtained strong evidence that Tat treatment can dramatically downregulate peroxisome proliferator activated receptor (PPAR) activation and thus suppress physiological functions of these critical anti-inflammatory nuclear receptors. This research proposal will focus on the consequences of Tat-induced alterations of PPAR activation namely overexpression of proinflammatory genes dysregulation of junctional protein expression and disturbances of endothelial barrier function. In addition we hypothesize that Tat-induced alterations of BMEC redox status can lead to upregulation of the efflux transport systems on the brain endothelium and thus prevent an effective anti-HIV therapy in the CNS. The proposed research combines elements of clinical approaches such as disruption of the BBB and the development of drug resistance with molecular and vascular biology. It is based on the unique and innovative co-cultures of human brain endothelial cells with astrocytic cell lines which produce Tat (the SVGA-Tat cells). In addition part of the project involves animal studies. The long-term goals of this proposal are to determine the mechanisms responsible for Tat-induced injury to BMEC disruption of the BBB and HIV entry into the CNS. In a broader aspect this proposal will contribute to better knowledge of how injury to brain endothelium can contribute to the development of neuroAIDS.

project_terms:
1-Phosphatidylinositol 3-Kinase;AIDS Dementia Complex;AIDS neuropathy;Abbreviations;Affect;Animal Model;Animals;Anti-HIV Agents;Anti-HIV Therapy;Anti-Inflammatory Agents;Anti-inflammatory;Antiretroviral Therapy Highly Active;Astrocytes;Attenuated;Biological Models;Biology;Blood - brain barrier anatomy;Blood Vessels;Brain;Calcium;Cell Death;Cell Line;Cell physiology;Cells;Clinical;Coculture Techniques;Data;Development;Disease;Disruption;Down-Regulation;Drug resistance;Drug usage;Elements;Endothelial Cells;Endothelium;Endothelium Vascular;Equilibrium;Equus caballus;Excision;Exposure to;Functional disorder;Funding;Genes;Goals;Grants Applications;HIV;HIV Infections;HIV drug resistance;HIV-1;Human;Inflammatory;Inflammatory Response;Injury;Ink;Inositol;Intercellular Junctions;Knowledge;Lead;Manuscripts;Mediating;Mitogen-Activated Protein Kinase 3;Mitogen-Activated Protein Kinases;Molecular;Multidrug Resistance-Associated Proteins;NIH Program Announcements;Nerve Degeneration;Neuroglia;Neurologic;Neurons;Nuclear;Nuclear Receptors;Oxidation-Reduction;Oxidative Stress;P-Glycoprotein;P-Glycoproteins;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Physiological;Play;Process;Protein Kinase C;Protein Overexpression;Proteins;Publishing;Reaction;Receptor Activation;Receptor Signaling;Research;Research Personnel;Research Proposals;Resistance;Role;Route;Signal Pathway;Signal Transduction;Staging;Stream;System;Therapeutic;Tight Junctions;Tissues;Up-Regulation (Physiology);Vascular Endothelial Growth Factor Receptor-2;Viral;Viral Proteins;Virus;abstracting;base;cell injury;cell type;innovation;monocyte;multidrug resistance-associated protein 2;neglect;novel;prevent;protein expression;stress-activated protein kinase 1;tat Protein;tat Protein HIV;trafficking;transcription factor;transcytosis;tripolyphosphate


application_id: 7436156
project_number: 5R01NS040919-08
project_title: Male Urogenital Function and Chronic Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2008-05-28
application_type: 5
activity_code: R01
ic: NS
serial_number: 040919
program_official: KLEITMAN, NAOMI
project_start_date: 2000-09-28
project_end_date: 2010-06-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Deficits in ejaculation urination and defecation are among of the most devastating outcomes of spinal cord injury (SCI) severely affecting quality of life. The neural mechanisms are poorly understood making restoration of function following traumatic SCI a difficult task. In humans SCI occurs predominantly in young males and compromises sexual function leaving most patients infertile. Moreover bladder dysfunction is common due to the loss of synergy between the bladder and its outlet for voiding urine. In many patients conscious control of defecation is also lost resulting in fecal incontinence and chronic constipation. Since normal ejaculation micturition and defecation require sequential contraction of perineal muscles that depend upon an intact segmental reflex arc and brainstem integration we have developed and characterized an in vivo brainstem-spinal cord electrophysiological animal model to study the neurological causes of ejaculatory and eliminative dysfunctions following severe mid-thoracic SCI. Our previous studies with this model have shown that chronic bilateral lesions of the dorsal 3/5 of T8 spinal cord is correlated with (i) impaired bladder/sexual reflexes (ii) changes in lumbosacral neural circuits mediating perineal muscle function and (iii) loss of ascending and descending connections between the genitalia/pelvic organs and the medullary reticular formation. Studies in our current grant (NS40919) address important questions regarding the neural control/coordination of smooth and striated muscles sub-serving sexual bladder and bowel functions in male rats using specific chronic lesions restricted to the dorsal 3/5 of the T8 cord. Results from our current data have raised new questions regarding injury-induced plasticity in these neural circuitries. The overall aim for this renewal grant is to use our model to investigate these injury-induced changes in order to allow us to more specifically ascertain the spinal cord regions and specific neural circuitry which should be targeted for therapeutic interventions designed to improve the control/coordination of sexual bladder and bowel functions following chronic SCI. The knowledge gained from these studies will help direct future experiments that will be geared toward the development of therapeutic interventions that will promote functional recovery following SCI. Parallel electrophysiological neuroanatomical and behavioral studies are once again proposed.

project_terms:
24-Dinitrophenol;Accidental Injury;Acute;Address;Affect;Animal Model;Animals;Anus;Appendix;Area;Axon;Behavioral;Bilateral;Bladder;Bladder Dysfunction;Brain Stem;Caliber;Catheters;Cell Nucleus;Cells;Chest;Chronic;Clinical;Collaborations;Colon;Complement;Conscious;Constipation;Cutaneous;Data;Defecation;Development;Distal;Dorsal;Ejaculation;Electric Stimulation;Electrophysiology (science);Epithelium;Fecal Incontinence;Feces;Felis catus;Female;Fiber;Florida;Foreskin of penis;Functional Imaging;Functional disorder;Funding;Future;Genitalia;Genitourinary system;Genus Cola;Glans penis;Grant;Harvest;Healthy People 2000;Herpesvirus 1 Suid;Human;Immunohistochemistry;Infertility;Infusion procedures;Injection of therapeutic agent;Injury;Interneurons;Intestines;Knowledge;Label;Lateral;Left;Lesion;Location;Medial;Mediating;Modeling;Monitor;Motor Neurons;Movement;Muscle;Muscle function;Nerve;Neurologic;Neurons;Numbers;Organ;Outcome;Pathway interactions;Patients;Pelvic Cancer;Pelvis;Phase;Phenotype;Pressure- physical agent;Principal Investigator;Process;Purpose;Quality of life;Rattus;Reading;Recovery of Function;Reflex action;Reporting;Research Personnel;Research Priority;Reticular Formation;Sensory;Sex Functioning;Sexual Dysfunction;Side;Site;Skeletal muscle structure of perineum;Spinal;Spinal Cord;Spinal cord injury;Staining method;Stains;Stimulus;Striated Muscles;Study Section;Surgical incisions;Synapses;Techniques;Therapeutic Intervention;Thoracic spinal cord structure;Tracer;Universities;Urethra;Urethral sphincter;Urination;Urine;Viral;Viscera;Visceral;Work;base;cancer pain;cryostat;dorsal column;implantation;improved;in vivo;injured;interest;male;neural circuit;neuromechanism;neuroregulation;penis;programs;radiofrequency;reproductive;research study;response;restoration;size;spinal pathway;stroke;therapy design;urinary;white matter;white matter damage


application_id: 7435368
project_number: 5K05CA096558-05
project_title: Psychological and Behavioral Impact of Cancer Screening
administering_ic: NCI
award_notice_date: 2008-06-24
opportunity_number: PAR-00-039
application_type: 5
activity_code: K05
ic: CA
serial_number: 096558
program_official: PERKINS, SUSAN N
project_start_date: 2004-07-01
project_end_date: 2011-06-30
study_section: Education Study Section (G)[NCI-G]
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
project_abstract:
DESCRIPTION (provided by applicant):  While cancer screening can reduce mortality and morbidity participation in cancer screening can have a negative psychological and behavioral impact even when no malignancy is detected.  Understanding and management of the potential negative impact of cancer screening is the focus of the research and mentoring activities for this award.  The PI has spent over 20 years conducting research in behavioral oncology and mentoring pre- and postdoctoral trainees.  His career has focused on the psychological social and behavioral dimensions of cancer detection diagnosis treatment and recovery.  This award will enable him to continue to develop his research and mentoring activities.  The research builds on the Pl's ongoing study (R01 CA94036) of psychological and behavioral outcomes of transvaginal (TVS) screening for ovarian cancer and the Pl's recent study of psychological and behavioral outcomes of benign breast biopsy (BBB).  Three synergistic studies are proposed: (1) prospective longitudinal study of psychological and behavioral outcomes of an abnormal TVS screening result; (2) development and evaluation of brief psychoeducational interventions for managing the negative psychological and behavioral impact of BBB; and (3) development of brief psychoeducational interventions for managing the negative impact of an abnormal TVS screening result.  The mentoring plan builds on the Principal Investigator's prior experience as PI for three pre-and postdoctoral research training grants.  Mentoring will be provided for 4-6 trainees each year.  All trainees participate in an existing research training program in behavioral oncology.  The training program consists of core elements: (1) coursework; (2) participation in behavioral oncology research; and (3) participation in national professional meetings.  These core elements enable achievement of training objectives: (1) knowledge of the behavioral oncology literature; (2) knowledge of the medical basis of cancer; (3) participation in all phases of research; (4) acquisition of skills critical to both quantitative and qualitative research; (5) familiarity with medical settings in which cancer detection diagnosis and treatment occurs; and (6) professional development.  The overall goal of the training program is to prepare trainees for careers as independent investigators in behavioral oncology.

project_terms:
Accounting;Acquaintances;Address;Adherence (attribute);Adjuvant Therapy;Adoption;Advocate;Affect;Affective;Age;Age-Years;Aging Demographic;Analysis of Variance;Anxiety;Appendix;Appointment;Area;Arts;Attention;Attitude;Authorship;Award;Back;Basic Science;Behavior;Behavioral;Behavioral Medicine;Behavioral Model;Behavioral Sciences;Belief;Benign;Biopsy;Breast;Breast Self-Examination;Budgets;Cancer Control;Cancer Detection;Cancer Etiology;Caring;Categories;Cause of Death;Cessation of life;Characteristics;Class;Clinic;Clinical;Clinical Management;Clinical Trials Design;Code;Cognition;Cognitive;Colon Rectum;Communication;Comparative Study;Computer information processing;Condition;Consent;Consent Forms;Contraceptive Usage;Contraceptives Oral;Control Groups;Controlled Clinical Trials;Controlled Clinical Trials Randomized;Coping Behavior;Costs and Benefits;Counseling;Coupled;Data;Data Analyses;Detection;Development;Diagnosis;Diagnostic;Diffuse;Dimensions;Discipline;Discipline of Nursing;Discipline of obstetrics;Disease;Disease regression;Disorder by Site;Distant;Distress;Doctor of Philosophy;Early Diagnosis;Educational Materials;Educational Status;Educational aspects;Educational process of instructing;Effectiveness of Interventions;Electronics;Elements;Eligibility Determination;End Point;Enrollment;Ensure;Environment;Epidemiologic Studies;Equilibrium;Evaluation;Event;Exhibits;Expectancy;Exposure to;Faculty;Familiarity;Family;Family Cancer History;Family history of;Fatigue;Feedback;Feeling;Female;Financial cost;Fine needle aspiration biopsy;First Degree Relative;Focus Groups;Follow-Up Studies;Foundations;Friends;Funding;Funding Agency;Future;Goals;Grant;Grant Review;Growth;Head;Health;Health behavior;High-Risk Cancer;Incidence;Income;Individual;Individual Differences;Informed Consent;Internet;Intervention;Intervention Studies;Interview;Joints;Kentucky;Knowledge;Lead;Life;Lifetime Risk;Link;Literature;Location;Logistics;Longitudinal Studies;Lung;Mails;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of breast;Malignant neoplasm of ovary;Mammography;Manuals;Manuscripts;Marketing;Mass Screening;Measures;Mediation;Medical;Medical Records;Medical center;Medicine;Mental Depression;Mentors;Methodology Research;Methods;Metric;Minor;Modality;Modeling;Monitor;Moods;Morbidity - disease rate;Mortality Vital Statistics;Motivation;Multivariate Analysis;Names;National Research Service Awards;Nature;Neuro-Oncological Ventral Antigen 2;Non-Malignant;Notification;Numbers;Occupations;Odds Ratio;Oral;Outcome;Outcome Measure;Paper;Participant;Patient Self-Report;Peer Review;Perception;Personal Satisfaction;Persons;Phase;Physiological;Play;Polishes (substance);Population;Population Research;Positioning Attribute;Postmenopause;Predisposition;Premenopause;Prevention;Principal Investigator;Probability;Procedures;Process;Professional Practice;Professional Role;Protocols documentation;Psychologist;Psychology;Psychology Health;Publications;Purpose;Qualitative Research;Quality of life;Questionnaires;Race;Randomized;Range;Rate;Reaction;Reading;Recommendation;Recording of previous events;Records;Recovery;Recruitment Activity;Regression Analysis;Regressions Logistic;Rehabilitation therapy;Relative (related person);Reporting;Request for Applications;Research;Research Activity;Research Design;Research Personnel;Research Project Grants;Research Training;Resolution;Resort;Resources;Review Literature;Risk;Risk Estimate;Risk Factors;Role;Role playing therapy;Sample Size;Sampling;Sampling Studies;Scanning;Schedule;Schools;Score;Screening Result;Screening for Ovarian Cancer;Screening for cancer;Screening procedure;Second Degree Relative;Secure;Senior Scientist Award;Severities;Shapes;Shipping;Ships;Side;Skills Coping;Social Control Informal;Social Environment;Social Sciences;Social support;Societies;Solid;Source;Staging;Standards of Weights and Measures;Strategic Planning;Stress;Structure;Students;Study Section;Suggestion;Sum;Supervision;Support of Research;Surgeon;Symptoms;System;Tape Recording;Target Populations;Techniques;Telephone;Telephone Interviews;Test Result;Testing;Tests Chi-Square;Thinking function;Time;Training;Training Programs;Translating;Trauma;Travel;Treatment Efficacy;Ultrasonography;Uncertainty;Universities;Upper arm;Visits Clinic;Week;Woman;Women's Group;Work;Writing;abstracting;anticancer research;base;behavior measurement;biopsychosocial;cancer diagnosis;cancer risk;cancer therapy;career;cohort;college;comparison group;coping;cost;cost effectiveness;cyclobutanecarbonylcarnitine;data acquisition;day;demographics;depressive symptoms;design;disturbance in affect;experience;falls;follow-up;health belief;implementation research;indexing;instructor;interest;literature survey;male;member;oncology;optimism;parity;positive mood;posters;pre-doctoral;programs;prospective;prospectuses;protective behavior;psychoeducational intervention;psychologic;psychosocial;research and development;research study;response;role model;size;skill acquisition;skills;social;social cognitive theory;stressor;success;symposium;theories;therapy development;trend;university student


application_id: 7435217
project_number: 5K01CA106599-05
project_title: Regulation of apoptosis by Bcl-XL Bak and Bax
administering_ic: NCI
award_notice_date: 2008-06-24
opportunity_number: PAR-03-104
application_type: 5
activity_code: K01
ic: CA
serial_number: 106599
program_official: SCHMIDT, MICHAEL K
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The development of cancer involves genetic changes leading to alterations in the control of tissue development and homeostatic maintenance which is tightly regulated by the cellular suicide program apoptosis. Many tumor cells are resistant to intrinsic and extrinsic apoptotic stimuli probably due to impaired apoptotic pathways in these cells. Bcl-2 family proteins are major regulators of the cellular response to apoptotic signals. Among them anti-apoptotic Bcl-XLand pro-apoptotic Bak and Bax have-been shown to play an essential role during apoptosis. Initial studies suggest that in addition to their functions at mitochondria Bcl-2 proteins also localize on the endoplasmic reticulum (ER) and function to regulate a parallel pathway of apoptosis. Experiments in this proposal are designed to elucidate the detailed molecular mechanisms of Bcl-2 proteins regulating apoptosis. The following specific aims are proposed: 1) Investigate the electrophysiological properties of Bcl-XL Bak and Bax on the ER membrane and their contribution to the induction of membrane permeabilization during apoptosis. A novel patch-clamp approach to record single ion channel activity will be used to characterize Bcl-2 proteins on the ER membrane. The electrophysiological properties of purified recombinant as well as reexpressed Bcl-XL Bak and Bax proteins on the ER membrane will be studied. The hypothesis that Bak and Bax form lipidic pores on membranes during apoptosis will also be examined; 2) Study the distinct apoptotic pathways mediated by Bcl-2 family proteins localized on different organelles. Efforts will be made to better characterize caspase pathways mediated by Bak or Bcl-XL localized on the ER or mitochondria using a RNAi approach. The importance of intracellular localizations of pro- and anti-apoptotic Bcl-2 proteins for the regulation of apoptosis will be studied by selectively targeting these proteins to specific organelles. The possible role of Ca2+ in the regulation of distinct apoptotic pathways will be investigated; and 3) Determine whether the expression of Bak and Bax affects cellular physiology and thus cellular response to death signals. Oligonucleotide-based microarray analysis will be performed to examine the changes in gene expression patterns in response to Bak or Bax expression. Genes whose expression may be involved in apoptosis regulation will be further studied.

project_terms:
Address;Affect;Agonist;Animals;Apoptosis;Apoptotic;BCL2L1 protein human;Bax protein;Biochemical Genetics;Cell Line;Cell Lineage;Cell Membrane Permeability;Cell physiology;Cells;Cessation of life;Characteristics;Condition;Development;Embryo;Endoplasmic Reticulum;Fibroblasts;Gene Expression;Genes;Global Change;Goals;Hematopoietic;Homeostasis;ITPR1 gene;In Vitro;Intracellular Membranes;Ion Channel;Localized;Maintenance;Malignant Neoplasms;Mediating;Membrane;Microarray Analysis;Mitochondria;Molecular;Molecular Profiling;Mus;Mutation;Nuclear;Oligonucleotides;Organelles;Pathway interactions;Pattern;Play;Property;Protein Family;Protein Overexpression;Proteins;RNA Interference;Recombinants;Regulation;Research;Research Project Grants;Resistance;Role;Signal Transduction;Stimulus;Tissues;bak protein;bcl-xlong protein;caspase;cell suicide;cell type;design;neoplastic cell;novel;patch clamp;pro-apoptotic protein;programs;reconstitution;research study;response


application_id: 7435192
project_number: 5R01HL068007-08
project_title: Network mechanisms for respiratory rhythm generation
administering_ic: NHLBI
award_notice_date: 2008-07-12
application_type: 5
activity_code: R01
ic: HL
serial_number: 068007
program_official: TWERY, MICHAEL
project_start_date: 2001-07-01
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1-RES-D(03)S]
contact_pi_person_id: 1896681
contact_pi: MELLEN, NICHOLAS M
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): New evidence indicates that two mechanistically distinct spatially separate networks can independently generate respiratory rhythm. We propose that the two networks in concert meet the conflicting demands of adaptive-ness and robustness required for the maintenance of blood-gas homeostasis. This new finding puts emphasis on the role of network interactions in rhythm generation. Because preparations currently available allow easy access to neurons but are too reduced (transverse slice preparation) or retain the networks of interest but do not allow easy access to them (en bloc preparation) we have developed a tilted saggital slice preparation that retains the networks present en bloc but affords good access to the networks of interest. We used optical recordings using a membrane permeable Ca++ indicator to determine the best parameters for cutting the slice and use optical recording techniques routinely to monitor local network activity along the column of respiration modulated neurons in ventrolateral medulla that are exposed at the surface of the saggital slice. We will use optical signals to identify 2 classes of endogenously bursting respiratory neurons for detailed investigation using intracellular recording techniques. These endogenous bursters differ in that one population changes its bursting frequency as a function of membrane potential (voltage-dependent endogenous burster; VDEB) while the other does not (voltage-independent endogenous burster; VIEB). Due to this difference VDEB cycle period can be altered by transient de- or hyperpolarizing impulses; while VIEBs will be less sensitive to such inputs. This provides a mechanism for our hypothesis; we propose that VDEBs mediate cycle-to-cycle adaptiveness to respiratory rhythm-generating networks while VIEBs maintain network stability by rapidly restoring baseline rhythm. We propose to test this hypothesis at the network level by selectively modulating VIEB and VDEB networks and at the single neuron level by characterizing perturbation responses in synaptically isolated VIEBs and VDEBs.

project_terms:
Blood gas;Breathing;Class;Complex;Condition;Conflict (Psychology);Coupling;Data;Dyes;Frequencies (time pattern);Generations;Grant;Homeostasis;In Vitro;Investigation;Light;Maintenance;Mammals;Mediating;Membrane;Membrane Potentials;Monitor;Neurons;Optics;Pacemakers;Physiological;Play;Population;Preparation;Property;Research;Respiration;Respiratory Burst;Rest;Role;Signal Transduction;Slice;Solutions;Structure;Surface;System;Techniques;Testing;Title;Trees;Work;base;design;insight;interest;neural circuit;optic imaging;postsynaptic;research study;respiratory;response;voltage


application_id: 7433828
project_number: 5R01CA120606-02
project_title: Patient Navigation for Cervical Cancer in Appalachia
administering_ic: NCI
award_notice_date: 2008-06-12
application_type: 5
activity_code: R01
ic: CA
serial_number: 120606
program_official: KOBRIN, SARAH
project_start_date: 2007-06-01
project_end_date: 2012-04-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
project_terms:
Address;Adherence (attribute);Aftercare;Age Group Unspecified;Appalachian Region;Appointment;Breast;Cancer Burden;Case Management;Case Manager;Cervical Cancer Screening;Cessation of life;Communities;County;Dependence;Development;Disease;Enrollment;Funding;Health;Health Personnel;Health Promotion;Institution;Intervention;Interview;Invasive;Kentucky;Life;Literature;Malignant neoplasm of cervix uteri;Medicaid;Modeling;Mortality Vital Statistics;Numbers;Nurses;Pap smear;Patients;Population;Randomized;Rate;Recommendation;Recruitment Activity;Risk;Role;Rural;Rural Population;Schedule;Screening procedure;Services;Standards of Weights and Measures;Test Result;Training;Treatment Cost;Woman;Women's Group;Work;base;cancer prevention;design;experience;falls;follow-up;improved;innovation;middle age;older women;outreach program;prevent;programs;public health medicine (field);rural area;treatment program;willingness


application_id: 7433743
project_number: 5K01DK076743-02
project_title: Mass Spectrometry Analysis of Notch4 Networks in Diabetes-Related Tubule Injury
administering_ic: NIDDK
award_notice_date: 2008-07-01
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DK
serial_number: 076743
program_official: RANKIN, TRACY L
project_start_date: 2007-07-01
project_end_date: 2010-06-30
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
The Candidate's overall career goal is to establish and maintain an independent proteomic and molecular biology-based program focused on investigation of events that mediate diabetic nephropathy (DN). DN is the leading cause of end-stage renal disease (ESRD). There are no current treatments that completely prevent progression to ESRD. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets for the diagnosis prevention and treatment of DN. Tubulointerstitial fibrosis (TF) is a prominent feature of progressive DN that is mediated by transforming growth factor-beta (TGF-beta). Notch4 is a fascinating membrane-bound transcription regulator that was recently implicated in TGF signaling and renal disease. Our preliminary findings indicate that Notch4 activation inhibits TGF-beta signaling in cultured renal tubular cells and show decreased expression of Notch4 in tubular cells from diabetic mice as compared with controls. This suggests a hypothesis that down-regulation of Notch4 activity promotes the TGF-beta-mediated effects in DN. This project will develop Notch4-deficient diabetic mice. Renal pathophysiology experiments will be performed to delineate the in vivo role of Notch4 in diabetes-mediated TF and TGF signaling. It is anticipated that these animals will also provide a better model for the study of TF as none of the current diabetic animal models exactly mimic the TF observed in diabetic humans. Accumulating evidence suggests a key role of TGF-mediated epithelial to mesenchymal transition (EMT) in diabetes-associated TF. We have recently developed models for TGF-mediated EMT in human kidney (HK) tubule cell lines. We will also develop HK models for glucose and advanced glycation end product (AGE)-mediated EMT. We will use these cellular models in combination with active Notch4 transfection and RNAi-mediated Notch4 knockdown to dissect the role of Notch4 in different components of signaling and transcription activity in EMT. Lastly we will use state-of-the-art proteomic techniques with the Notch4-deficient diabetic mice to define Notch4-mediated protein expression and organelle localization in DN. In addition to molecular insight provided by these studies the animal model and pathophysiology training obtained during this Career Development Award will provide valuable resources for the Candidate to expand his diabetes-related program and obtain independent-level funding.

project_terms:
Address;Animal Model;Animals;Arts;Binding (Molecular Function);Cell Line;Cell model;Cells;Cellular biology;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Diagnosis;Down-Regulation;End stage renal failure;Event;Fibrosis;Functional disorder;Funding;Glucose;Glycosylation End Products Advanced;Goals;Human;Injury;Investigation;Kidney;Kidney Diseases;Mediating;Membrane;Mentors;Modeling;Molecular;Molecular Biology;Molecular and Cellular Biology;Organelles;Prevention;Proteins;Proteomics;RNA Interference;Regulation;Renal tubule structure;Research;Research Career Programs K-Series;Resources;Role;Signal Transduction;Spectrum Analysis Mass;Stimulus;Study models;Techniques;Training;Transcription Genetic;Transfection;Transforming Growth Factor beta;Tubular formation;base;career;diabetic;epithelial to mesenchymal transition;fascinate;improved;in vivo;insight;notch protein;novel;prevent;programs;protein expression;research study;therapeutic target;tool


application_id: 7433707
project_number: 5R21CA124881-02
project_title: Internet Based Voucher Reinforcement for Smoking Cessation
administering_ic: NCI
award_notice_date: 2008-06-23
opportunity_number: PA-04-034
application_type: 5
activity_code: R21
ic: CA
serial_number: 124881
program_official: MORGAN, GLEN D
project_start_date: 2007-07-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-RPHB-H(90)]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Internet-Based Voucher Reinforcement for Smoking Cessation: Tobacco use continues to be the number one preventable cause of morbidity and mortality in the United States. In no other population are the prevalence rates and problems of smoking more apparent and pronounced than those in rural populations where access to treatment is limited. Current smoking cessation interventions are modestly effective which suggest the need for therapies that are more intensive innovative and accessible. Voucher-based abstinence reinforcement therapy is a highly intensive approach wherein patients earn monetary vouchers that can be exchanged for goods and services contingent on documented abstinence. To improve the accessibility of this intensive therapy to smokers who want to quit smoking a novel voucher based abstinence reinforcement therapy for smoking has been developed wherein smoking status is frequently monitored and reinforced via the internet. With this internet based intervention real-time video of smokers providing CO samples are collected and verified for smoking status. Patients are then provided feedback and reinforcement based on their verified smoking status. This innovative approach may be well suited for rural smokers who are in need of accessible intensive smoking cessation interventions. This grant application proposes exploratory research to adapt implement and evaluate a novel internet based voucher reinforcement intervention for smoking cessation in heavy smokers in rural Kentucky. A pilot study is proposed in which rural smokers in Kentucky (N=80) will be randomly assigned to one of two groups: contingent vs. noncontingent vouchers group. For 6 weeks CO samples will be collected and verified twice daily from all participants using an internet based CO monitoring system. Participants assigned to the contingent vouchers group will receive monetary vouchers if they provide a CO sample <4ppm. Participants in the noncontingent vouchers group will receive vouchers independent of their CO sample. Overall the application proposes research to develop and evaluate an intensive and accessible smoking cessation intervention for heavy smokers in rural communites and provide the empirical basis for future research.

project_terms:
Abstinence;Appalachian Region;Daily;Data;Disease;Effectiveness;Elements;Feedback;Frequencies (time pattern);Future;General Population;Grants Applications;Health Personnel;Health Services Accessibility;Healthcare;Internet;Intervention;Kentucky;Medical;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Numbers;Outcome;Participant;Patients;Personal Satisfaction;Pilot Projects;Population;Prevalence;Psychological reinforcement;Randomized;Rate;Research;Research Project Grants;Rural;Rural Community;Rural Population;Sampling;Services;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Smoking Status;System;Technology;Testing;Time;Tobacco;Tobacco use;United States;Week;Withholding Treatment;base;design;health disparity;improved;innovation;novel;prevent;public health medicine (field);smoking cessation;voucher


application_id: 7433536
project_number: 3U01DA016205-05S1
project_title: Central States Criminal Justice Drug Abuse Center
administering_ic: NIDA
award_notice_date: 2007-05-31
opportunity_number: RFA-DA-02-011
application_type: 3
activity_code: U01
ic: DA
serial_number: 016205
suffix: S1
program_official: CHANDLER, REDONNA
project_start_date: 2002-09-30
project_end_date: 2008-08-31
study_section: ZDA1-MXS-M(10)
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The U.S. criminal justice system is awash with drug abusers (Leukefeld Tims & Farabee 2002). Howeverfew approaches have been developed which focus on criminal justice involved drug abusers as theytransition from prison to community treatment (Inciardi et al 2002; Pickens Leukefeld & Schuster 1991).This is alarming because it is estimated that 500000 prisoners will return to the community each year for thenext several years (DO J 1999) and 83% of those returning are estimated to be drug abusers (Mumola1999). This application is presented to focus on examining community transitions by establishing the CentralStates Criminal Justice Drug Abuse Treatment Research System (CJ-DATS) Center. The overall aim of theCentral States CJ-DATS Center is to develop information to improve transition interventions for criminal justiceinvolved drug abusers which reduce recidivism reduce drug abuse and reduce related crime. Theestablished experience of the University of Kentucky Center on Drug and Alcohol Research is described tocontinue to carry out rural/urban theoretically grounded criminal justice studies which build upon currentresearch. These studies include two on-going NIDA trials which are examining an enhanced Probationer HIVintervention and an enhanced Drug Court employment intervention as well as a project which is examiningprison and community health services utilization among drug abusing prisoners in 5 prisons with 12 monthfollow-up from prison to the community. This application also describes four Central States CenterCommittees that will be established to (1) Plan (2) Implement (3) Collect/Analyze Data and (4) DevelopPublications in concert with the Principal Investigator the Center Steering Committee and the CenterAdvisory Board. Letters of commitment from a State Corrections Commissioner a State Substance AbuseDirector 6 criminal justice agencies and 8 community treatment agencies present rural and urban subjectavailability of 15709 criminal justice participants and 13087 community treatment participants for the firstyear and subsequent years. In addition two study protocols are presented as multi-site trials across CJ-DATS Centers to enhance prison/community transitions: (1) An enhanced employment intervention focusedon obtaining maintaining and upgrading employment and (2) A case management/criminal thinking errorenhanced intervention.

project_terms:
Case Management;Communities;Community Health Services;Crime;Data Analyses;Drug Courts;Drug abuse;Drug abuser;Employment;HIV;Intervention;Justice Criminal;Kentucky;Letters;National Institute of Drug Abuse;Participant;Pharmaceutical Preparations;Principal Investigator;Prisoner;Prisons;Protocols documentation;Publications;Research;Rural;Site;Substance abuse problem;System;Universities;alcohol research;criminal thinking;experience;follow-up;health care service utilization;improved;probationer;recidivism;systems research


application_id: 7433305
project_number: 5F32DE018068-02
project_title: Role of cytolethal distending toxin in periodontitis
administering_ic: NIDCR
award_notice_date: 2008-04-04
opportunity_number: PA-06-373
application_type: 5
activity_code: F32
ic: DE
serial_number: 018068
program_official: FRIEDEN, LESLIE A
project_start_date: 2007-06-01
project_end_date: 2009-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 8628812
contact_pi: RABIN, SHIRA D
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): As one of the most common bacterial diseases of humans periodontal disease afflicts as much as 50% of the adult population and results in destruction of the connective tissues and bone that anchor the teeth. Aggregatibacter (Actinobacillus) actinomycetemcomitans (Aa) is an oral bacterium that is associated with various forms of human periodontal diseases. Interestingly the factors produced by Aa that are involved in virulence appear to target host immune cells rather than the tissues that support the teeth. We have identified a toxin in Aa that is related to the E. coli cytolethal distending toxin (Cdt) but differs by targeting lymphocytes rather than epithelial cells. Our hypothesis is that the Aa Cdt causes immunosuppression thus allowing Aa to successfully colonize the human gingiva in high numbers. However the specific role that Cdt plays in the pathogenesis of human periodontal disease remains to be determined. Our preliminary data and data from the closely related H. ducreyi Cdt on macrophages and dendritic cells suggest that the toxin induces cell death in non-proliferating immune cells. These data suggest that cell cycle progression is not required for cytotoxicity and that the mechanism of Cdt action may be more complicated than previously thought. The goal of this study is to understand if Cdt contributes to periodontal disease by targeting non- proliferating immune cells and to determine if the toxin represents a potential therapeutic target for intervention against human periodontal diseases. In our first Aim we will determine if the mechanism of Cdt intoxication is similar for non-proliferating immune cells and epithelial cells. This will be accomplished by measuring lethality binding internalization and DMA damage to non-proliferating macrophages dendritic cells and lymphocytes compared to proliferating lymphocytes and epithelial cells. In our second Aim we will generate a mutant of Aa that is unable to express Cdt in order to assess the virulence of this organism using a mouse model of periodontitis. Mice will be infected orally with either normal or Cdt-defective Aa organisms and the degree of alveolar bone loss supporting the teeth number of bacteria and viability of infiltrating immune cells will be measured. The successful demonstration of an in vivo role for this toxin in periodontal disease will confirm a role for Cdt in Aa infections. Understanding the biological role of Cdt and its mechanism of action will allow us to investigate it as a new potential target for therapeutic intervention of periodontal disease thus providing an alternative to the use of antibiotics. Furthermore compounds that inhibit immunosuppression caused by Cdt may also have utility to increase immune function in other immunosuppressive diseases.

project_terms:
Actinobacillus actinomycetemcomitans;Address;Adult;Affect;Alveolar Bone Loss;Antibiotics;Antigen-Presenting Cells;Apoptosis;Bacteria;Bacterial Infections;Binding (Molecular Function);Biological;Bone and Bones;Cell Cycle;Cell Cycle Progression;Cell Death;Cells;Connective Tissue;DNA Damage;DNA Fragmentation;Data;Dendritic Cells;Disease;Epithelial Cells;Escherichia coli;Gingiva;Goals;Hemophilus ducreyi;Human;Immune;Immune response;Immunosuppressive Agents;Infection;Intervention;Intoxication;Knock-out;Lymphocyte;Measures;Monitor;Mus;Natural immunosuppression;Numbers;Operon;Organism;Pathogenesis;Periodontal Diseases;Periodontitis;Phase;Play;Population;Production;Proliferating;Role;Site;Staging;T-Lymphocyte;Therapeutic Intervention;Therapeutic immunosuppression;Thinking function;Tissues;Tooth structure;Toxin;Virulence;Work;bone loss;cell type;cytokine;cytolethal distending toxin;cytotoxic;cytotoxicity;immune function;in vivo;macrophage;mouse model;mutant;oral bacteria;therapeutic target


application_id: 7432867
project_number: 1G20RR023941-01A1
project_title: Enhancement of BBSRB Vivarium
administering_ic: NCRR
award_notice_date: 2008-04-28
opportunity_number: PAR-07-342
application_type: 1
activity_code: G20
ic: RR
serial_number: 023941
suffix: A1
program_official: MCCULLOUGH, WILLIE
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: Scientific and Technical Review Board on Biomedical and Behavioral Research Facilities[STRB]
contact_pi_person_id: 8180010
contact_pi: SMILEY, JEFFREY R.
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky (UK) requests $500000 toward a $1144973 project to equip four vacant rodent housing rooms in the vivarium of the new Biomedical/Biological Sciences Research Building (BBSRB) with individually ventilated caging. External research funding at UK has grown dramatically from $173.6 million in FY 01 to $290.4 million in FY 06. Explosive growth in the use of rodents particularly transgenic and knockout rats and mice has also created an urgent challenge to meet new demand for rodent housing and to accommodate the environmental needs of substantially greater populations of genetically modified rodents. Long-term project goals are 1) to support continued growth of biomedical research through expansion of quality animal resources and 2) to provide the highest quality environmental conditions possible for research animals. Specific aims are 1) to expand rodent housing capacity in the BBSRB vivarium and 2) to enhance biosecurity and environmental quality for rodent populations in the BBSRB. This project will relieve overcrowded rodent housing conditions in other UK animal facilities; permit separation of transgenic breeding colonies from experimental animals; accommodate growth in GMR populations; and increase the percentage of rodents at UK housed in IVC caging. This last transition is seen as vital to improving health and environmental conditions for rodent populations. The urgent need to address the proposed aims is a result of a record of success during the last decade by UK to cultivate and grow a dynamic biomedical research enterprise. Anticipated outcomes are maintenance of high quality research and enhanced research productivity.

project_terms:
Address;Animal Experimentation;Animals;Biological Sciences;Biomedical Enhancement;Biomedical Research;Breeding;Condition;Environmental Health;Funding;Goals;Growth;Housing;Kentucky;Knock-out;Maintenance;Mus;Outcome;Population;Productivity;Rattus;Research;Rodent;Transgenic Organisms;Universities;animal facility;animal resource;biosecurity;improved;success


application_id: 7431788
project_number: 5R03AR053641-02
project_title: Circadian Regulation of Myod1 Transcription
administering_ic: NIAMS
award_notice_date: 2008-05-14
opportunity_number: PAR-06-111
application_type: 5
activity_code: R03
ic: AR
serial_number: 053641
program_official: BOYCE, AMANDA T
project_start_date: 2007-06-01
project_end_date: 2010-05-31
study_section: ZAR1-EHB-M(O1)
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
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 myogenic differentiation 1 (Myodl) gene encodes a basic helix-loop-helix transcription factor that is a master regulator of skeletal muscle lineage determination during embryonic development. The post-natal function of Myodl is not well understood but a deficit in the specific tension of Myodl (-/-) mice in addition to their impaired regenerative ability intimate a significant role in adult skeletal muscle. We recently identified the Myodl transcript in adult skeletal muscle as having a robust circadian pattern of expression and this pattern of expression was absent in muscle of homozygous Clock mutant mice suggesting Myodl is a clockcontrolled gene. The long-range goal of the project is to understand the circadian function of Myodl in adult skeletal muscle. As a first step toward this goal the objective of this proposal will be to determine if the coreclock transcription factors Clock and Email are directly involved in the regulation of Myodl transcription. The primary hypothesis of this application is that Myodl is a direct transcriptional target of the CLOCK:BMAL1 heterodimer. The hypothesis will be tested by pursuing the following three specific aims: 1) use the Myodl DRRIoxP and CEIoxP mice to determine the role of the distal regulatory region (DRR) and the core enhancer (CE) of the Myodl promoter in the circadian regulation of Myodl transcription 2) determine the ability of core-clock transcription factors CLOCK and BMAL1 to transactivate Myodl reporter genes and 3) determine if CLOCK and BMAL1 are bound to the endogenous Myodl promoter by chromatin immunoprecipitation (ChIP) assay. The discovery of Myodl as a circadianly expressed gene is an exciting discovery because it provides a completely novel paradigm for thinking about the post-natal function of Myodl and establishes a potential link between master regulators of circadian rhythms and tissue-specific expression. A better understanding of how Myodl transcription is regulated in the adult is expected to provide a foundation for understanding the mechanisms underlying the altered expression of Myodl in such diseases as muscular dystrophy and sarcopenia.

project_terms:
Adult;Antibodies;BHLH Protein;Binding (Molecular Function);Binding Sites;Biological Assay;Circadian Rhythms;Creatine Kinase;Daily;Disease;Distal;Down-Regulation;Electronic Mail;Electrophoretic Mobility Shift Assay;Embryonic Development;Enhancers;Exhibits;Foundations;Gene Targeting;Genes;Genes Reporter;Goals;In Vitro;Link;Maintenance;Metabolic;Mice Knockout;Mice Mutant Strains;Modeling;Molecular;Mus;Muscle;Muscular Dystrophies;Mutate;Natural regeneration;Pattern;Phenotype;Polymerase Chain Reaction;Promotor (Genetics);Proteins;Range;Regulation;Regulatory Element;Regulatory Sequences Nucleic Acid;Role;Skeletal muscle structure;Testing;Thinking function;Tissues;Transcript;Transcription Genetic;Transfection;Transgenic Organisms;base;chromatin immunoprecipitation;design;functional disability;in vivo;insight;mature animal;mutant;myogenesis;novel;research study;sarcopenia;transcription factor


application_id: 7430477
project_number: 5R01AA014623-04
project_title: Zinc and Alcohol-Induced Oxidative Liver Injury
administering_ic: NIAAA
award_notice_date: 2008-05-29
opportunity_number: PA-02-035
application_type: 5
activity_code: R01
ic: AA
serial_number: 014623
program_official: OROSZ, ANDRAS
project_start_date: 2005-08-10
project_end_date: 2010-05-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 6870954
contact_pi: ZHOU, ZHANXIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcoholic liver disease (ALD) is a major health problem but well-established and effective forms of therapy are lacking. Our long-term goal is to develop therapeutic agents that effectively correct the fundamental cellular disturbances resulting from excessive alcohol consumption. A number of hypotheses regarding the mechanisms by which alcohol causes cell injury have been suggested with oxidative stress being a leading putative etiologic factor. Thus antioxidant therapy has gained increasing attention in prevention of ALD. Zinc is an essential trace element with potent antioxidant functions. Cellular zinc homeostasis is regulated by metallothionein (MT). The MT-bound zinc can be released under oxidative stress condition. Hepatic zinc depletion in liver has long been noted in alcoholic liver disease. A mechanistic link between hepatic zinc depletion and cell injury however has not been established. This project proposes to test the hypothesis that hepatic zinc depletion is a critical mediator in alcohol-induced oxidative stress thus zinc supplementation should attenuate alcohol-induced oxidative liver injury. A novel MT-null (MT-KO) mouse model along with wild type 129/Sv mice will be chronically fed liquid alcohol diet. The specific aims are as follow: (1) To define the importance of hepatic zinc depletion in the development of ALD the effect of dietary zinc deficiency and its supplementation on hepatic zinc status and oxidative liver injury will be determined in mice after chronic alcohol exposure: (2) To evaluate the therapeutic potential of zinc in controlling ALD the effects of dietary zinc supplementation on alcohol-induced liver injury in mice previously exposed to alcohol will be examined; (3) To determine whether zinc protects against ALD through inhibition of oxidative stress the effects of dietary zinc supplementation on ROS accumulation ROS-generating and ROS-scavenging systems in the liver will be analyzed in mice after chronic alcohol exposure; (4) To understand the molecular mechanisms by which zinc inhibits alcohol-induced oxidative stress the effects of dietary zinc supplementation on gene expression in the liver will be determined by DMA microarray and Real-Time RTPCR. The effects of zinc on the activities of zinc finger transcription factors also will be examined. These studies will provide fundamental understanding of the role of zinc in the pathophysiology of ALD and pave the way to novel therapeutical approaches to prevention and treatment of this disease.

project_terms:
129/Sv Mouse;Alcoholic Liver Diseases;Alcohols;Antioxidants;Attention;Attenuated;Binding (Molecular Function);Blood;Cessation of life;Chronic;Condition;Cytoprotection;Development;Diet;Dietary Zinc;Disease;Endotoxins;Ethanol Metabolism;Failure (biologic function);Functional disorder;Gene Expression;Generations;Goals;Health;Heavy Drinking;Hepatic;Homeostasis;Injury;Iron;Ligands;Link;Liquid substance;Liver;Mediating;Mediator of activation protein;Metallothionein;Mice Knockout;Molecular;Mus;Numbers;Oxidative Stress;Pathogenesis;Physiological;Prevention;Prevention approach;Production;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Supplementation;System;Testing;Therapeutic;Therapeutic Agents;Time;Trace Elements;Transcription Genetic;United States Food and Drug Administration;Zinc;Zinc Fingers;Zinc deficiency;alcohol exposure;antioxidant therapy;cell injury;cysteine rich protein;feeding;metalloenzyme;mouse model;novel;novel therapeutics;prevent;transcription factor;zinc thionein


application_id: 7430397
project_number: 5R01DK071349-05
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2008-05-19
opportunity_number: RFA-DK-04-010
application_type: 5
activity_code: R01
ic: DK
serial_number: 071349
program_official: LAUGHLIN, MAREN R
project_start_date: 2005-06-01
project_end_date: 2010-05-31
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: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Obesity is the most common and powerful force for creating insulin resistance and metabolic syndromehowever the molecular basis of this association is not well understood. In this proposal three independentlyfunded researchersPhilip Kem MD a clinical investigator and Charlotte Peterson PhD and Robert McGeheePhD with significant experience in muscle and adipocyte biology respectivelywill formalize a collaborativeeffort as a natural extension of previous work and shared interests in the fields of obesity insulin resistance andtissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely fromectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further wehypothesize that excess IMCL accumulation is dependent on secretory proteins derived from a complexinterplay between adipocytes and macrophages in adipose tissue. To test these hypotheses we will examinethe interactions among adipocytes macrophages and muscle cells isolated and cultured from subjects that aremoderately obese with insulin resistance and impaired glucose tolerance (IGT) but who do not yet have fastinghyperglycemia. This study population has elevated IMCL and is at high risk for obesity complications but avoidsthe pathophysiologic complications of glucotoxicity. These subjects will be compared to moderately obesesubjects with normal glucose tolerance (NOT). Aim 1 will explore mechanisms that contribute to IMCLandelucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obesesubjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activityunder differing extracellular fatty acid concentrations. Lipid accumulation and oxidation and insulin-mediatedglycogen synthesis and signaling will be assessed. Aim 2 will determine if the IMCL accumulation is dependenton adipose tissue secretory proteins. We will use co-cultures of adipocytes myoblasts and adipose stromalvascular cells to examine IMCL and the development of insulin resistance. Aim 3 will determine whether thestromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultureswith muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophageaccumulation 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. Co-culture studies will also be used with muscle and stromal cells before and after pioglitazone treatment. Theseexperiments will provide mechanistic insight into the link between obesity and muscle function leading tometabolic syndrome. _^___

project_terms:
Adipocytes;Adipose tissue;Blood Vessels;Cells;Clinical Investigator;Coculture Techniques;Complex;Development;Doctor of Philosophy;Fasting;Fatty Acids;Funding;Gene Expression;Glycogen;Human;Hyperglycemia;Insulin;Insulin Resistance;Link;Lipids;Mediating;Metabolic;Metabolic syndrome;Molecular;Muscle;Muscle Cells;Muscle function;Myoblasts;Obesity;Pioglitazone;Population Study;Role;Signal Transduction;Stromal Cells;Testing;Tissues;Week;Work;adipocyte biology;base;cytokine;experience;extracellular;glucose tolerance;impaired glucose tolerance;improved;insight;interest;macrophage;monocyte;obesity risk;oxidation;research study;response;secretory protein;stem


application_id: 7429961
project_number: 3R01DK055030-07S1
project_title: LEUKOCYTE ADHESION IN COPPER DEFICIENT MICROCIRCULATION
administering_ic: NIDDK
award_notice_date: 2007-05-24
application_type: 3
activity_code: R01
ic: DK
serial_number: 055030
suffix: S1
program_official: MAY, MICHAEL K
project_start_date: 1999-08-01
project_end_date: 2009-03-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 2291964
contact_pi: SCHUSCHKE, DALE A
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Regulation of the microvascular response to inflammatory stimuli is highly dependent upon theinteractions between neutrophils and the endothelium. We have shown a significant role for dietarycopper in various endothelial interactions in the inflammatory process including nitric oxide(NO)-mediated vasodilation macromolecular leakage and thrombosis. Recently we have studied therole of dietary copper in microvascular control mechanisms with an emphasis on leukocyte/endothelialadhesion. We have demonstrated that dietary copper restriction causes tissue-specific changes inneutrophil/endothelial adhesion and transmigration. Neutrophil accumulation the expression of theadhesion molecule ICAM-1 and the transcription factor NF-kB are all greater in the lungs ofcopper-deficient rats compared to copper-adequate controls. Based on these results we hypothesize thatdietary copper deficiency has a priming effect on leukocytes and pulmonary vascular endothelial ceilssuch that the lung becomes hypersensitive to inflammatory stimuli and more susceptible to thedevelopment of acute lung injury. Therefore the specific aims of this study are to: 1) determine the role ofdietary copper in leukocyte/endothelial cell interactions in the lung microcirculation; 2) determine themechanisms by which copper deficiency primes cells for acute inflammation and 3) determine at whatconcentration of dietary copper the inflammatory mechanisms become enhanced in the in vivo animalmicrocirculation. Aim #1 will use both in vivo and in vitro models of the lung microcirculation to studyleukocyte/endothelial cell adhesion and chemotaxis. Aim #2 will study the role of copper in the NF-kBsignaling pathway and in neutrophil priming. Aim #3 will examine these mechanisms under conditions ofcopper-marginal diets. These experiments have particular relevance since analysis of typical Westerndiets suggest that 1/3 to 1/2 of those diets may provide less than the RDA of 900mg Cu/day.

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


application_id: 7428888
project_number: 5R01DC002736-11
project_title: Functional Domains and Expression of Olfactory Receptors
administering_ic: NIDCD
award_notice_date: 2008-05-15
application_type: 5
activity_code: R01
ic: DC
serial_number: 002736
program_official: DAVIS, BARRY
project_start_date: 1995-08-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-K(03)M]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Belief;Biological Process;Cell Adhesion;Cells;Chemicals;Cilia;Code;Condition;Data;Defect;Energy Metabolism;Environment;Epithelium;Epithelium Olfactory;Event;Face;Flagella;Gel;Gene Expression;Gene Silencing;Gene Targeting;Genes;Genes Regulator;Goals;Home environment;Individual;Ion Transport;Knock-out;Lead;Link;Maintenance;Measures;Molecular;Mus;Neurons;Neurons Afferent;Neurosciences Research;Odors;Pattern;Phenotype;Population;Positioning Attribute;Production;Property;RNA Messenger;Regulation;Signal Transduction;Sorting - Cell Movement;Spermatogenesis;Stem cells;Structure;Synaptic Transmission;System;Testing;Tissues;Transcription Genetic;Translating;base;cell injury;cell type;chromatin remodeling;cilium biogenesis;deprivation;experience;interest;knockout gene;neurogenesis;olfactory receptor;precursor cell;progenitor;relating to nervous system;tool;transcription factor


application_id: 7428830
project_number: 5R01HL082791-03
project_title: Vascular Smooth Muscle Hyper-contractility and Hypertension in Type-II-Diabetes
administering_ic: NHLBI
award_notice_date: 2008-05-28
application_type: 5
activity_code: R01
ic: HL
serial_number: 082791
program_official: GAO, YUNLING
project_start_date: 2006-06-01
project_end_date: 2011-05-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): Sixteen million Americans have type II diabetes and vascular complications are the most common causes of morbidity and mortality in diabetic patients. Abnormalities in blood vessel constriction or dilatation (vasomotion) detected in early diabetes can result in blood flow dysregulation and increased peripheral resistance thereby contributing to diabetic complications. We and others found that db/db and high fat diet-induced type II diabetic mice are hypertensive and vascular smooth muscle tissues isolated from these animals exhibit a significantly increased contractile response to stimuli. However the molecular mechanisms are unknown. In preliminary studies we observed that Ca2+sensitization of contractions are significantly increased in vascular smooth muscle tissues isolated from type II diabetic mice. We found that CPI-17 PKCbetall RhoA and ROCK four key players of Ca2+ sensitization signaling are significantly up-regulated/ activated in diabetic arteries. Moreover inhibiting PKC or ROCK diminished the enhanced Ca2+ sensitization of contractions in vascular smooth muscle tissue isolated from db/db mice. Therefore we hypothesize that in type II diabetes activated PKCbetall and RhoA/ROCK activate CPI-17 and thereby significantly contribute to type II diabetic vascular smooth muscle hyper-contractility and hypertension. Specific aims are: (1) To test the hypothesis that activation of CPI-17 is responsible for enhanced Ca2+ sensitization and vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (2) To test the hypothesis that the activation of PKCbetall and RhoA/ROCK are required for vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (3) To test the in vivo significance of the CPI-17 in vascular smooth muscle hyper-contractility and type II diabetes-associated hypertension by using pharmacological and genetic approaches. Both in vitro and in vivo methods will be employed. Isolated small mesenteric arteries will be used to investigating isometric contractions Ca2+ sensitization of contractions the mRNA protein and activities of CPI-17 RhoA/ROCK and PKC. In addition blood pressure will be measured in mice by using radiotelemetry and carotid artery catheter. The proposed study may provide new insight into the molecular mechanisms of vascular smooth muscle dysfunction in type II diabetes and into the pathogenesis of diabetes-associated hypertension.

project_terms:
Agonist;American;Animals;Arteries;Binding (Molecular Function);Blood Pressure;Blood Vessels;Blood flow;Cardiovascular Diseases;Carotid Arteries;Catheters;Complications of Diabetes Mellitus;Condition;Constriction procedure;Data;Development;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Diabetic Angiopathies;Diabetic Retinopathy;Diabetic mouse;Diet;Dilatation - action;Endothelium;Exhibits;Fatty acid glycerol esters;Functional disorder;GTP-Binding Proteins;Genetic;Goals;Hypertension;In Vitro;Isometric Contraction;Kidney Diseases;Measures;Mesenteric Arteries;Methods;Mice Transgenic;Molecular;Molecular Weight;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle Contraction;Muscle Smooth Vascular;Neuropathy;Other Finding;Pathogenesis;Pathological Dilatation;Patients;Peripheral Resistance;Phosphoric Monoester Hydrolases;Physiological;Play;Protein Kinase C;Proteins;RNA Messenger;Rate;Regulation;Research Personnel;Rho-associated kinase;Role;Scheme;Signal Pathway;Signal Transduction;Smooth muscle (tissue);Stimulus;Testing;Transcriptional Activation;Up-Regulation (Physiology);Vascular Smooth Muscle Tissue;Vasospasm;Work;db/db mouse;diabetic;in vivo;inhibitor/antagonist;insight;myosin phosphatase;novel therapeutics;programs;response;therapeutic target;vasomotion


application_id: 7428821
project_number: 5R01HL080429-03
project_title: Caspase Mediated Diaphragmatic Dysfunction
administering_ic: NHLBI
award_notice_date: 2007-11-29
application_type: 5
activity_code: R01
ic: HL
serial_number: 080429
program_official: HARABIN, ANDREA L
project_start_date: 2005-12-15
project_end_date: 2009-11-30
study_section: Special Emphasis Panel[ZRG1-MOSS-D(14)M]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-12-01
project_abstract:
DESCRIPTION (provided by applicant): Recent studies indicate that critically ill patients have profound respiratory muscle weakness. Infection (e.g. pneumonia) is common in these patients and likely an important contributor to the genesis of diaphragmatic weakness. The precise mechanisms by which infection induces respiratory muscle weakness remain however unclear. The purpose of the present proposal is to examine these issues in detail testing our central hypothesis that caspase activation plays a critical role in initiating diaphragm dysfunction in infection. This theory will be evaluated in three groups of studies carried out in mice and C2C12 cells: Objective I studies will test the hypothesis that caspase activation mediates reductions in diaphragm and limb muscle force generation in acute infection/inflammation. Two models of infection/inflammation will be studied (endotoxin injection and pseudomonas pneumonia) in both wild type and transgenic animals with altered caspase pathway genes. Fluorogenic and Western techniques will be used to assess caspase activation indices. Both the effect of specific caspase inhibitors and the responses of caspase pathway gene knockout transgenics will be used to determine which caspase pathways mediate force reductions. Objective II will test the hypothesis that activated caspase alters force via effects on three cellular targets i.e. specific contractile proteins sarcolemmal membrane support proteins and the calpain proteolytic system. These studies will use proteomic and single fiber techniques to identify specific contractile protein cleavage patterns assays to assess cell integrity and a variety of calpain activity assays to assess the downstream effects of caspase activation. Objective III will examine the upstream pathways of diaphragmatic caspase activation and test the specific hypotheses that both superoxide and nitric oxide radicals regulate inflammatory mediator induced caspase activation in muscle cells. These experiments will use both transgenic animal models and C2C12 cells to assess the effect of genetic and chemical inhibition of superoxide/nitric oxide on caspase responses.

project_terms:
Accounting;Acute;Animal Model;Animals;BAX gene;BCL-2 Protein;BCL2 gene;Bax protein;Biochemical;Biological Assay;Blotting Western;Bronchitis;Calpain;Caspase Inhibitor;Cells;Characteristics;Chemicals;Chronic Obstructive Airway Disease;Communities;Complement;Complication;Contractile Proteins;Critical Illness;Cytoskeletal Proteins;Development;Diaphragm (Anatomy);Disease;Endotoxins;Enzymes;Fiber;Free Radicals;Functional disorder;Gel;Gene Mutation;Generations;Genes;Goals;Heart failure;Image;In Situ;In Vitro;Individual;Infection;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Investigation;Ischemia;Knock-out;Leg;Ligation;Limb structure;Link;Magnetism;Measurement;Measures;Mediating;Mediator of activation protein;Membrane;Modeling;Models Experimental;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;Myocardium;Nitric Oxide;Nitric Oxide Synthase;Oranges;Organelles;Pathway interactions;Patients;Pattern;Perforation;Physiological reperfusion;Pilot Projects;Play;Pneumonia;Pneumonia Viral;Predisposition;Process;Protein Isoforms;Protein Overexpression;Proteins;Proteolysis;Proteomics;Pseudomonas;Purpose;Recurrence;Relative (related person);Reperfusion Therapy;Reporting;Research Design;Respiratory Failure;Respiratory Muscles;Risk;Role;Sarcolemma;Sepsis;Severities;Skeletal muscle structure;Skin;Spectrin;Substrate Fluorogenic;Superoxide Dismutase;Superoxides;System;TNF gene;Techniques;Testing;Time;Transgenic Animals;Transgenic Organisms;Ventilator;Virus Diseases;Work;caspase;caspase-3;caspase-8;caspase-9;cellular targeting;chemical genetics;cytochrome c;cytokine;indexing;inhibitor/antagonist;knockout gene;multicatalytic endopeptidase complex;muscle strength;protein degradation;protein function;receptor;research study;respiratory;response;theories


application_id: 7428806
project_number: 5R01HL068440-07
project_title: Factor XIII Activation and Substrate Specificity
administering_ic: NHLBI
award_notice_date: 2008-05-22
application_type: 5
activity_code: R01
ic: HL
serial_number: 068440
program_official: LINK, REBECCA P
project_start_date: 2002-07-08
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1-HEME-C(03)M]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): In blood clotting the enzyme thrombin cleaves fibrinogen sites for fibrin polymerization are revealed and fibrin clot formation begins. Activated Factor XIII is responsible for catalyzing the formation of covalent crosslinks between fibrin molecules and in fibrin-enzyme complexes. Factor XIII can be activated through cleavage of an activation peptide segment by thrombin or nonproteolytically in the presence of high calcium or high sodium/low calcium. The long-term objective of our research project is to examine in solution the structural features that govern the activation and substrate specificity of Factor XIII. Understanding these molecular details is critical considering the role of FXIII in increasing the risk of heart disease stroke and arteriosclerosis. The specific aims are an extension of ongoing studies and will address three hypotheses: 1) The reactive glutamines of certain FXIII substrates primarily target a distinctive surface within the transglutaminase active site region. Such studies are important since the substrate specificity of FXIII is not clearly defined 2) FXIII undergoes subtle conformational changes upon activation. The degree and surface coverage of these changes will increase following introduction of a substrate or inhibitor and 3) The FXIII activation peptide segment utilizes key positions to promote effective interactions with a thrombin surface whose properties are regulated by individual thrombin residues. A model system for such studies is FXIII V34L a common polymorphism that has been correlated with protection against myocardial infarction and is more susceptible to thrombin cleavage than the native sequence. To test these hypotheses a combination of kinetic studies hydrogen/deuterium exchange chemical modification methods MALDI-TOF mass spectrometry solution NMR and surface plasmon resonance methods will be used. Information will be obtained on the selectivity of FXIII for glutamine-containing substrates on the solvent accessibility changes that FXIII undergoes upon activation and ligand binding and on the kinetic/structural features of the thrombin - FXIII Activation Peptide complex. Lay Summary: Factor XIII is a key enzyme in the formation of blood clots. While very important for wound healing the clots can also increase risk for heart disease and stroke. Research will focus on understanding how Factor XIII is turned on and how it selects its targets. Studies may lead to novel medical strategies to control the actions of Factor XIII and the resultant clot architecture.

project_terms:
Address;Adopted;Amides;Amino Acid Substitution;Amino Acids;Antiplasmin;Architecture;Arteriosclerosis;Binding (Molecular Function);Binding Sites;Biological Assay;Biological Models;Blood;Blood Clot;Blood coagulation;Calcium;Catalytic Domain;Chemicals;Chromatography High Pressure Liquid;Cleaved cell;Coagulants;Coagulation Process;Complement;Complex;Deuterium;Docking;Enzymes;Event;Factor XIII;Factor XIIIa;Fibrin;Fibrinogen;Glutamine;Hydrogen;Hydrolysis;Individual;Kinetics;Lead;Ligand Binding;MALDI-TOF Mass Spectrometry;Maps;Medical;Methods;Modification;Molecular;Molecular Target;Monitor;Multienzyme Complexes;Myocardial Infarction;N-terminal;NOESY;Peptides;Plasminogen Activator Inhibitor 2;Polymorphism Genetic;Positioning Attribute;Property;Proteins;Rate;Reaction;Relative (related person);Reliance;Research;Research Personnel;Research Project Grants;Roentgen Rays;Role;Series;Site;Sites Active;Sodium;Solutions;Solvents;Structure;Substrate Specificity;Surface;Surface Plasmon Resonance;Testing;Thrombin;Time;Transglutaminases;Vitronectin;Wound Healing;base;clotting enzyme;crosslink;design;experience;extracellular;heart disease risk;inhibitor/antagonist;mutant;novel;polymerization;programs;size;stroke


application_id: 7428783
project_number: 5R21CA124811-02
project_title: Regulation of miRNA expression in breast cancer cells
administering_ic: NCI
award_notice_date: 2008-05-09
opportunity_number: PA-06-299
application_type: 5
activity_code: R21
ic: CA
serial_number: 124811
program_official: SONG, MIN-KYUNG H
project_start_date: 2007-06-01
project_end_date: 2010-05-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ERalpha) positive breast cancer. With adjuvant therapy however initially TAM-sensitive tumors become TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring small non-coding RNA molecules that are related to but distinct from small interfering RNAs (siRNAs). miRNAs are involved in regulating the translation and processing of mRNAs usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded. The human genome is thought to contain > 400 miRNAs. Abberant patterns of miRNA expression have been recently implicated in human breast cancer and one study showed that miRNAs were differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ERalpha and progesterone receptor expression tumor stage number of positive lymph nodes and vascular invasion. However to date no one has examined whether estradiol (E2) or selective ER modulators/antiestrogens affect the pattern of miRNA expression in human breast cancer or whether miRNA expression patterns correlate with acquired antiestrogen-resistance. Specific Aim 1 is to identify miRNAs that are regulated by estradiol (E2) and 4-hydroxytamoxifen (4-OHT) in antiestrogen-sensitive MCF-7 breast cancer cells. Aim 1 tests the hypothesis that E2 and 4-OHT differentially regulate the expression of miRNAs in human breast cancer cells. Further we suggest these miRNAs in turn regulate the mRNA stability of genes encoding proteins involved in differentiation and cell proliferation. Specific Aim 2 tests the hypothesis that miRNA expression is dysregulated in antiestrogen/TAM-resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2-regulated and 4-OHT-regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with patient response to tamoxifen therapy. It is our long term hope that miRNAs may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain TAM/antiestrogen-resistance and become invasive and metastatic.

project_terms:
3' Untranslated Regions;4-Hydroxy-Tamoxifen;Adjuvant Therapy;Affect;Binding (Molecular Function);Binding Sites;Biological Assay;Biological Markers;Blood Vessels;Breast Cancer Cell;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Class;Clinical;Cloning;Development;Diagnostic;Diagnostic Neoplasm Staging;Estradiol;Estrogen Antagonists;Estrogen Receptor Modulators;Estrogen Receptor alpha;Estrogens;Forecast of outcome;Functional RNA;Gene Targeting;Genes;Genome Human;Goals;Human;ICI 182780;Individual;Invasive;Lead;Luciferases Renilla;MCF7 cell;Malignant neoplasm of breast;Mammary Neoplasms;Measures;Mediating;Methods;MicroRNAs;Monitor;Numbers;Patients;Pattern;Phenotype;Positive Lymph Node;Prevention;Progesterone;Promotor (Genetics);Proteins;RNA;RNA Messenger;RNA Small Interfering;Regulation;Reporter;Reporting;Research;Resistance;Response Elements;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Selective Estrogen Receptor Modulators;Site;Stability mRNA;Tamoxifen;Testing;Therapeutic;Thinking function;Time;Transcript;Transfection;Translation Process;Tumor Suppressor Genes;Tumor stage;Untranslated Regions;cancer recurrence;cancer therapy;design;gene function;hormone therapy;inhibitor/antagonist;insight;lymph nodes;mRNA Transcript Degradation;novel;receptor expression;research study;resistance mechanism;response;treatment planning;tumor


application_id: 7426971
project_number: 1R25GM083835-01
project_title: Appalachian Kentucky Bridges to Success
administering_ic: NIGMS
award_notice_date: 2008-07-09
opportunity_number: PAR-07-039
application_type: 1
activity_code: R25
ic: GM
serial_number: 083835
program_official: SINGH, SHIVA P
project_start_date: 2008-07-11
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 IMM-A (50)]
contact_pi_person_id: 8581194
contact_pi: CASEY, BARETTA R.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV 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_terms:
Address;Appalachian Region;Awareness;Bachelor's Degree;Behavioral Sciences;Class;Collaborations;Collection;Communication;Communities;Data;Documentation;Educational Materials;Educational Status;Educational aspects;Educational process of instructing;Ensure;Faculty;Family;Financial Support;Goals;Grant;Institution;Instruction;Joints;Kentucky;Learning;Life;Mentors;Monitor;Natural Sciences;Numbers;Pamphlets;Participant;Press Releases;Process;Program Development;Program Evaluation;Rate;Recruitment Activity;Research;Resources;Rural;Rural Health;Scholarship;Science;Structure;Students;Support Groups;System;Time;Universities;Vocational Guidance;base;career;college;data management;experience;falls;follow-up;hazard;improved;programs;psychosocial;skills;success;university student


application_id: 7426869
project_number: 5R44RR021289-03
project_title: L1 retrotransposon-based mutagenesis for rat models of human diseases
administering_ic: NCRR
award_notice_date: 2008-09-12
opportunity_number: PA-06-120
application_type: 5
activity_code: R44
ic: RR
serial_number: 021289
program_official: RALL, WILLIAM F
project_start_date: 2005-02-14
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
budget_end_date: 2010-05-31
project_abstract:
DESCRIPTION (provided by applicant): In many aspects the rat is a better animal model than the mouse for functional genomic studies. The physiology and drug metabolism of rats and humans are more similar than that of mice and humans. The rat is larger than the mouse making many studies easier to perform and sampling more accurate. The recent completion of the Brown Norway rat genome improves further the potential of the rat as an excellent organism for studying human diseases. Unfortunately many genetic manipulation techniques available in the mouse such as random mutagenesis with a gene trap (both retroviral-based and non-retroviral-based) gene knock- outs gene knock-ins and conditional mutations have not been possible in the rat because there is no way to effectively harvest and culture rat embryonic stem cells. Existing methods for producing gene deletions in rats including cloning and chemical mutation are inefficient and not practical. This deficiency leads to a severe bottleneck in our ability to create rat models of human disease. The product that will arise from this proposal will be rats with single gene knockouts for use as models of human disease in research and drug discovery (MutaRat Animal Models). Transposagen has developed a novel technology based on human L1 retrotransposons to generate animals with a high rate of random gene mutations in germ cells.In MutaRats mutagenesis will occur in sperm and oocytes and some offspring will contain single gene disruptions. These offspring can be used to establish authentic gene knockout rat lines. In Phase I we successfully developed and characterized MutaMice generating 22 potential founders.We have subsequently developed similar "mutator" founder rats (MutaRats) and in Phase II we intend to characterize these rats and use them to generate rats with stable singe gene deletions (gene knockout MutaRat Animal Models). Specific aim 1 isto screen existing MutaRatfounder lines to determine the line with the highest frequency of mutation. This line will then be bred to establish a breeding colony that can be used to obtain single gene knockout rats in Specific Aim 2. We do not intend to characterize the phenotypes of these lines nor to establish breeding colonies of individual knockout rat linesas part of this proposal but instead to establish a sperm bank comprising sequenced insertional gene disruptions the MutaRat Germ Line Resource. In Specific Aim 3 we will develop the MutaRat Germ Line Resourceof cryopreserved sperm from rats with single gene knockouts. We estimate that we will have a sperm bank with at least 100 different gene knockouts by the endof this project in December 2008. This MutaRat Germ Line Resource will be the only technology capable of creating and rapidly mapping random gene knockouts in rats. Knockout ratswill be provided to the academic community in accordance with the NIH policy on sharing of model organisms for biomedical research and will be distributed by the National Rat Resource and Research Center. In Phase III we will establish a distribution partnership with an existing laboratory animal company to market establish and validate (as necessary) and distribute these lines and others as they are developed. The innovation of this proposal is the use of a novel retrotransposon technology to create the only system able to rapidly create and map insertional deletions in the rat and other mammals. This technology is expected to offer significant advantages in cost and speed when compared with existing mutagenesis systems available in mice and to generate novel gene knockout models that have not previously been available in any vertebrate. Transposagen's MutaRat Animal Models will contribute to human health by providing new vertebrate models of disease for studying pathogenesis and for discovery and development of pharmaceutical compounds.

project_terms:
Animal Model;Animals;Animals Laboratory;Biological Assay;Biomedical Research;Breeding;Cells;Chemicals;Cloning;Communities;DNA;Data;Development;Disease model;Disruption;Exhibits;Exons;Freezing;Frequencies (time pattern);Gene Deletion;Gene Mutation;Generations;Genes;Genetic;Germ;Germ Cells;Germ Lines;Harvest;Health;Human;Individual;Inherited;Introns;Knock-out;Location;Mammals;Maps;Marketing;Methods;Modeling;Mus;Mutagenesis;Mutagenesis Insertional;Mutation;Oocytes;Organism;Pathogenesis;Pathology;Pattern;Pharmacologic Substance;Phase;Phenotype;Physiology;Policies;Polymerase Chain Reaction;Population;Process;Production;Rat Strains;Rat Transgene;Rate;Rattus;Rattus norvegicus;Research;Resources;Retrotransposition;Retrotransposon;Sampling;Speed (motion);Sperm Banks;System;Tail;Techniques;Technology;Testing;Transgenes;United States National Institutes of Health;base;cost;desire;drug discovery;drug metabolism;embryonic stem cell;functional genomics;genetic manipulation;genome rat;human disease;improved;innovation;knockout gene;male;new technology;novel;size;sperm cell;success


application_id: 7426830
project_number: 5F32HD050043-03
project_title: Heat Shock Factor Function in Spermatogenesis
administering_ic: NICHD
award_notice_date: 2008-04-29
opportunity_number: PA-03-067
application_type: 5
activity_code: F32
ic: HD
serial_number: 050043
program_official: MOSS, STUART B
project_start_date: 2006-05-01
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1-F06(20)L]
contact_pi_person_id: 8179373
contact_pi: WILKERSON, DONALD C.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The work presented in this grant is focused on the long term goal of better understanding the roles of HSF1 and HSF2 in spermatogenesis and early embryogenesis. According to the Center for Disease Control (CDC) infertility affects approximately 6.1 million women and their partners in the United States. Defective expression of heat shock factors leads to several phenotypes including infertility in both males and females. To identify the role(s) of HSF1 and HSF2 in reproduction these factors must be thoroughly characterized in vivo at various stages of spermatogenesis. The role of HSF2 bookmarking the hsp70i gene in mature spermatozoa must be evaluated. Finally all gene targets bound by HSF1 and HSF2 must be identified.

project_terms:
Address;Affect;Antibodies;Apoptosis;Binding (Molecular Function);Biological Assay;Blotting Western;Cell Nucleus;Cell physiology;Cells;Cellular Stress;Centers for Disease Control and Prevention (U.S.);Chromatin Structure;Cloning;Complex;Cytoplasm;DNA;DNA Binding;Defect;Deoxyribonuclease I;Development;Disruption;Electrophoretic Mobility Shift Assay;Elements;Embryo;Embryonic Development;Exhibits;Family;Fellowship;Female;Fertility;Fertilization;Gene Targeting;Genes;Germ Cells;Goals;Grant;Heat shock proteins;Heat-Shock Response;Hypersensitivity;Immunologic Immunofluorescence;Individual;Infertility;Infertility Male;Lead;Localized;Maps;Meiosis;Mice Knockout;Mitotic;Modification;Mus;Names;Numbers;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Physical condensation;Play;Promoter Regions (Genetics);Promotor (Genetics);Property;Protein Phosphatase 2A Regulatory Subunit PR53;Proteins;Reporting;Reproduction;Role;Sperm Count Procedure;Spermatogenesis;Spermatogenic Cell;Staging;Stress;Structure of blastomere;Subfecundity;TATA-Box Binding Protein;Testing;Thinking function;Transcription Genetic;United States;Woman;Work;base;chromatin immunoprecipitation;condensin;embryo cell;heat shock transcription factor;heat-shock factor 2 human;in vivo;male;member;size;sperm cell;stem;ward


application_id: 7425950
project_number: 5K08MH070840-05
project_title: ADHD Stimulants and D4 Knockout Mice
administering_ic: NIMH
award_notice_date: 2008-03-01
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: MH
serial_number: 070840
program_official: CHAVEZ, MARK RAY
project_start_date: 2004-04-01
project_end_date: 2010-03-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1915629
contact_pi: GLASER, PAUL E A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_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): Dr. Glaser is a dedicated physician/scientist who is strongly committed to a career as an academic physician. He is currently an Assistant Professor on a tenure-track at the University of Kentucky. His scientific goal is to understand the neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD) and its treatments. With his joint appointments in Psychiatry and Anatomy & Neurobiology he will be receiving laboratory and resource support from both departments. During the entire award period Dr. Glaser will be spending 75% of his time with laboratory related activities. In addition to research he will be spending 15% of his time pursuing clinical activities primarily in the areas of Child Psychiatry and Pediatrics in the treatment of children and adults with symptoms of ADHD. 10% of his time will be devoted to the teaching of residents and students as well as educational activities. His sponsor Dr. Gerhardt is a leader in the field of neuropsychopharmacology of dopamine modulating medications as well as a recent co-collaborator in the field of ADHD. The neuroscience community at the University of Kentucky will also provide a rich source for collaboration and intellectual support. Additional support will be provided by co-sponsor Dr. F. Xavier Castellanos at NYU a leader in translational ADHD research. The primary goal of Dr. Glaser's proposal is to investigate physiologically-relevant differences in dopaminergic activity evoked by different isomers of amphetamine found in clinically prescribed medications for ADHD using a novel combination of voltammetric and microdialysis in the mouse striatum and nucleus accumbens. A secondary goal is to investigate the possible contribution that dopamine D4 receptors (D4R) may have to dopaminergic function in the mouse.  Dr. Glaser will utilize mice designed by Dr. Grandy at the Oregon Health Sciences University that are missing the D4R (D4R knockout mice) to specifically investigate differences in their baseline behavior and stimulant induced behaviors. The integrated training mentorship research and teaching of Dr. Glaser provided by this award will allow him to develop as an independent investigator dedicated to using basic neuroscience to solve important problems which physicians face everyday in the treatment of children and adults with ADHD and potentially will lead to better understanding and superior treatments for ADHD thus reducing its burden on today's schools health systems and society.

project_terms:
Activities Educational;Adderall;Adult;Affect;Alleles;Amphetamines;Animals;Appointment;Area;Attention;Attention deficit hyperactivity disorder;Award;Behavior;Behavioral;Brain;Bypass;Child;Child Psychiatry;Clinical;Collaborations;Commit;Communities;Corpus striatum structure;DRD4 protein human;Data;Dextroamphetamine;Disease;Dopamine;Drug Kinetics;Drug usage;Educational process of instructing;Electrochemistry;Exhibits;Face;Genetic;Glutamates;Goals;Health Sciences;Health system;Heterozygote;Isomerism;Joints;Kentucky;Kinetics;Knock-out;Laboratories;Lead;Levoamphetamine;Literature;Locomotion;Measurable;Measures;Medial;Mentorship;Metabolism;Methods;Methylphenidate;Mice Knockout;Microdialysis;Mus;Nerve Endings;Neurobiology;Neuropharmacology;Neurosciences;Norepinephrine;Novelty-Seeking Behaviors;Nucleus Accumbens;Oregon;Pediatrics;Pharmaceutical Preparations;Physicians;Play;Potassium;Prefrontal Cortex;Psychiatry;Research;Research Personnel;Resolution;Resources;Ritalin;Role;Salts;Schools;Science of Anatomy;Scientist;Serotonin;Societies;Source;Stereoisomer;Students;Symptoms;Techniques;Thinking function;Time;Today;Training;Universities;Wild Type Mouse;Work;awake;base;career;clinical effect;clinical efficacy;design;dopamine D4 receptor;frontal lobe;in vivo;novel;professor;receptor;response


application_id: 7425331
project_number: 5R01NS040334-07
project_title: TRANSGENETIC STUDIES OF PRION DISEASE IN CERVIDS
administering_ic: NINDS
award_notice_date: 2008-06-03
application_type: 5
activity_code: R01
ic: NS
serial_number: 040334
program_official: WONG, MAY
project_start_date: 2000-08-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-CNBT(01)]
contact_pi_person_id: 7875112
contact_pi: TELLING, GLENN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Our broad long-term objective is to address the mechanisms by which species barriers and strain specificities control the pathogenesis and transmission of chronic wasting disease (CWD) a contagious disease of deer and elk belonging to a group of fatal transmissible neurodegenerative disorders of animals and humans caused by prions. Our major objectives are to use proven transgenic (Tg) approaches to study the means by which primary structure elements of the prion protein (PrP) and prion strain properties influence CWD transmission barriers to address the origins of CWD and the prevalence of CWD strains and to determine the mechanism of prion transmission among cervids. Three Specific Aims are proposed: (1) To use Tg mice expressing cervid (Cer) PrP [Tg(CerPrP)] that simulate disease in deer and elk to study the mechanisms of CWD transmission among cervids and sub-clinical CWD replication in the absence of accumulation of conventional forms of pathogenic PrP; (2) To use Tg approaches to assess the influence of CWD strain variation and CerPrP polymorphisms on CWD pathogenesis and to address the disease-causing potential of CWD strains in other species; and (3) To probe the molecular basis of species-dependent CWD transmission barriers using novel chimeric murine/CerPrP constructs and an innovative combination of Tg approaches and in vitro PrP amplification. Addressing the mechanism of CWD transmission will lead to better CWD control in cervid populations and allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD. The proposed studies will also further our understanding of the general molecular events underlying prion propagation species barriers and prion strains that will ultimately result in rational therapeutic and diagnostic approaches for human and animal prion diseases and will provide important information about the molecular nature of the infectious agent in the contexts of clinical and sub-clinical prion disease.

project_terms:
Address;Affect;Animals;Biochemical;Biological;Biological Assay;Blood;Body Fluids;Bos taurus;Brain;Cattle;Cell Line;Cells;Chronic;Clinical;Deer;Development;Diagnostic;Disease;Elements;End Point;Endopeptidases;Equus caballus;Event;Excretory function;Exposure to;Genotype;Hand;Hippocampus (Brain);Human;In Vitro;Infectious Agent;Investigation;Lead;Leucine;Livestock;Methionine;Mice Knockout;Modeling;Molecular;Molecular Conformation;Molecular Probes;Mus;Nature;Neuraxis;Neurodegenerative Disorders;Neurons;PAWR protein;Pathogenesis;Pathology;Peptide Hydrolases;Polymorphism Genetic;Population;Positioning Attribute;PrPSc Proteins;Predisposition;Prevalence;Prion Diseases;Prions;Production;Property;Reporting;Research;Research Personnel;Resistance;Resources;Risk;Risk Assessment;Role playing therapy;Sampling;Simulate;Skeletal muscle structure;Source;Specificity;Structure;Therapeutic;Time;Titrations;Transgenic Organisms;Variant;Wasting Disease Chronic;Wasting Syndrome;base;cervid;design;disease transmission;disorder control;innovation;neuropathology;novel;programs;transmission process


application_id: 7425072
project_number: 5R01AG026307-03
project_title: Repetitive Thought Stress and Immunity in Older Adults
administering_ic: NIA
award_notice_date: 2008-04-02
opportunity_number: PA-05-027
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2011-04-30
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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 stressors on the immune system are particularly relevant for older adults: Potent stressors such as bereavement become more common with age immune reactions to stress grow larger with age and vulnerability to immunological dysregulation and immunologically mediated disease increases with age. Previous studies have linked stressors in old age with increased distress and physiological dysregulation including depression high levels of cortisol poor responses to vaccination and high levels of the proinflammatory cytokine IL-6. The proposed research will address limitations of the extant literature by focusing on the prospective effects of stressors among older adults and by including individual differences in repetitive thought (RT) that is the cognitive interpretation and processing of stressful events. Individual differences in RT can create vulnerability or resilience to stressors: Negative uncontrolled and intrusive thought (e.g. worry) can prolong and amplify negative consequences whereas positive and controlled thought (e.g. reflection) can buffer against negative consequences and promote positive consequences such as growth. In this 5-year longitudinal prospective study married adults aged 60 or older (N = 183) will be interviewed and will collect saliva samples for cortisol every 6 months; they will be vaccinated annually against influenza and serum for antibody and IL-6 will be collected before and after vaccination and at the end of influenza season. The primary aim of the study is to test the following predictions: (1) stressors and RT predict psychological and physiological indices of health or dysregulation; (2) RT moderates the effects of stressors; (3) psychological indices (e.g. depression) mediate the relationship between stressors and RT and physiology. A secondary aim of the study is to relate cortisol autonomic activity and inhibition IL-6 and antibody to each other and to evidence of influenza infection. Another secondary aim is to validate the dimensional structure of RT in older adults and link trait RT (e.g. trait worry) to episodic RT (e.g. thoughts about a specific stressor). Relevance to public health: Stress in older adults can increase their vulnerability to both mental and physical illness. This research will test whether thought styles such as worry put older adults at greater risk. This knowledge could be used to identify and intervene with the most at-risk individuals.

project_terms:
Address;Adult;Affect;Age;Antibodies;Antibody Formation;Bereavement;Buffers;Cognitive;Disease;Distress;Elderly;Environment;Event;Growth;Health;Hydrocortisone;Immune;Immune system;Immunity;Individual;Individual Differences;Influenza;Influenza virus vaccine;Interleukin-6;Interview;Knowledge;Link;Literature;Measures;Mediating;Mental Depression;Neurosecretory Systems;Perception;Personal Satisfaction;Pharmaceutical Preparations;Physiological;Physiology;Process;Prospective Studies;Psyche structure;Psychosocial Stress;Purpose;Reaction;Regulation;Research;Research Personnel;Risk;Saliva;Sampling;Seasons;Series;Serum;Stress;Stressful Event;Structure;Sympathetic Nervous System;Testing;Thinking function;Vaccinated;Vaccination;Vaccines;Well in self;cytokine;improved;indexing;programs;prospective;psychologic;public health medicine (field);resilience;response;stressor;thought control;trait;young adult


application_id: 7424938
project_number: 5R01CA116658-04
project_title: Regulation of Cell Survival and Tumor Progression by Akt
administering_ic: NCI
award_notice_date: 2008-04-25
application_type: 5
activity_code: R01
ic: CA
serial_number: 116658
program_official: JHAPPAN, CHAMELLI
project_start_date: 2005-08-01
project_end_date: 2010-05-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): Akt is the focal point of a number of signaling pathways that regulate cell survival and tumor progression. Akt interacts with and modifies via phosphorylation many substrates involved in these cellular events. Owing to its anti-apoptotic properties Akt plays a key role in promoting human cancer. Thus the identification of molecules that interact with Akt may lead to a better understanding of the role of Akt in various local signaling networks and enable the development of strategies for specifically blocking signaling pathways involved in cancer development and progression.   Par-4 is a leucine zipper domain protein that when ectopically expressed induces apoptosis in cancer cells but not in normal or immortalized cells. Apoptosis by ectopic Par-4 occurs by inhibition of NF-kappaB activity. As cancer cells contain reasonable levels of endogenous Par-4 we sought to determine whether Par-4 exists in an inactive form. Our Preliminary Studies reveal that Akt1 binds and inactivates endogenous Par-4 rendering it ineffective in apoptosis-induction. Moreover inactivation of Akt1 releases Par-4 to induce apoptosis implying that endogenous Par-4 is functionally active in the absence of Akt1. In view of the pro-survival functions of Akt1 and the pro-apoptotic functions of Par-4 the objective of this proposal is to study the molecular basis and functional relevance of the interaction between Akt1 and Par-4 in prostate cancer cell survival and tumor progression. Toward this end we propose the following specific aims: Aim 1 elucidate the molecular basis for the isoform-specific effects of Akt on Par-4; Aim 2 determine the mechanism for cytoplasmic retention and inactivation of Par-4 by Akt1; and Aim 3 determine the downstream effects and functional relevance of Par-4 inhibition by Akt1 in tumor growth. Because PTEN loss is a well defined genetic lesion that elevates Akt activity and neutralizes the apoptotic pathway in the prostate and contributes to prostate tumors in mouse models this study will focus on the prostate cancer cell background to study the Akt1-Par-4 interaction. However as the Akt1-Par-4 interaction occurs in diverse tumor cell types we anticipate that the findings of this study will have broad implications in cancer. The findings will be further developed in future studies to design therapeutic strategies that can prevent Par-4 binding to Akt1 and induce apoptosis and tumor growth regression.

project_terms:
Address;Apoptosis;Apoptotic;BIRC4 gene;Binding (Molecular Function);Biological;Cell Nucleus;Cell Proliferation;Cell Survival;Cell membrane;Cell model;Cell physiology;Cells;Clinical;Cytoplasm;Development;Disease regression;Epithelial Cells;Event;Future;Gene Proteins;Genetic;Human;Induction of Apoptosis;Inhibition of Apoptosis;Ionizing radiation;LY294002;Lead;Lesion;Leucine Zippers;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;NF-kappa B;Nuclear;Nuclear Translocation;Numbers;PAWR gene;PTEN gene;Pathway interactions;Phosphorylation;Phosphorylation Site;Play;Principal Investigator;Property;Prostate;Prostatic Neoplasms;Protein Isoforms;Proteins;RNA Small Interfering;Reading;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Specimen;Tertiary Protein Structure;Testing;Therapeutic;Tissues;Transcription Genetic;Tumor Suppressor Proteins;angiogenesis;base;cancer cell;cell motility;cell type;chemotherapeutic agent;cytokine;design;glucose metabolism;immortalized cell;mouse model;neoplastic cell;novel;prevent;pro-apoptotic protein;research study;small hairpin RNA;trafficking;tumor;tumor growth;tumor progression


application_id: 7423952
project_number: 5R01DK074566-02
project_title: INTRACELLULAR ENERGY DELIVERY AND DIABETIC WOUNDS
administering_ic: NIDDK
award_notice_date: 2008-03-19
application_type: 5
activity_code: R01
ic: DK
serial_number: 074566
program_official: JONES, TERESA L Z
project_start_date: 2007-05-15
project_end_date: 2011-03-31
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: 2008-04-01
project_terms:
Acute;Adenosine Triphosphate;Affect;American;Amputation;Animals;Biochemical;Caliber;Cardiopulmonary Bypass;Caring;Cell membrane;Cells;Chronic;Chronic Care;Chronic lung disease;Condition;Country;Cytosol;Data;Development;Diabetes Mellitus;Diabetic Foot;Diabetic wound;Disease;Ear structure;Encapsulated;Family suidae;Generations;Glycolysis;Goals;Grant;Growth Factor;Healed;Human;Hypoxia;Immune System Diseases;Infection;International;Invasive;Ischemia;Legal patent;Lipids;Lower Extremity;Medicine;Modeling;Myocardial Infarction;Neuropathy;Numbers;Operative Surgical Procedures;Organ Transplantation;Oryctolagus cuniculus;Patients;Penetration;Perfusion;Phase;Procedures;Process;Rattus;Reporting;Research Personnel;Shock;Skin;Spinal cord injury;Sterile coverings;Supply Energy;Sus scrofa;Techniques;Testing;Thick;Tissues;Trauma;Ulcer;United States National Institutes of Health;Up-Regulation (Physiology);Vesicle;Wound Healing;base;cost;day;diabetic;diabetic wound healing;healing;heart preservation;improved;innovation;inorganic phosphate;novel strategies;productivity loss;programs;protective effect;research study;stroke;success;sufan;wound


application_id: 7423868
project_number: 5P20RR016481-08
project_title: KY-IDeA Networks of Biomedical Research Excellence
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
program_official: CANTO, MARIA TERESA
project_start_date: 2001-09-30
project_end_date: 2009-08-21
study_section: ZRR1-RI-7(01)
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The University of Louisville in collaboration with the University of Kentucky will lead the development of the Kentucky Infrastructure for Biomedical Research excellence (KY-INBRE). The goal of this KY-INBRE proposal is to build on the successes of the existing KY-BRIN its infrastructure and its network of biomedical researchers to increase the capacity for research in Kentucky. The plan is to build a research core that will provide 11 researchers with the necessary support to become competitive for independent federal funding within 5 years. The research core will consist of 10 researchers in the 4 public comprehensive universities Northern Kentucky University Western Kentucky University Eastern Kentucky University and Morehead State University one junior researcher at the University of Louisville and will include the recruitment of a neuroscience faculty member to Western Kentucky University. This core will initially contain a portfolio of 7 genomics and 4 neuroscience research projects. The research core will be supported through further development of the centralized genomics and bioinformatics facilities at the University of Louisville and the University of Kentucky. These facilities contain open access tools and resources that are critical to the success of Kentucky research institutions as a whole in their pursuit of research excellence. A steering committee will guide the development of the KY-INBRE faculty mentors will guide the career development goals of the PIs and an external advisory committee of experts will provide critique of the INBRE-progress. An outreach core will provide opportunities in summer research for undergraduate students in the 13 affiliated institutions of the KY-BRIN. This core will continue to develop the pipeline from undergraduate institutions to the graduate level programs in biomedical research and it will complement the activities of the research core where students will become engaged in research its excitement its challenges and its rewarding career opportunities.


application_id: 7419083
project_number: 1R01DA022967-01A2
project_title: African American Female Drug Users: HIV Health Disparities & Criminality
administering_ic: NIDA
award_notice_date: 2008-04-01
opportunity_number: PA-07-114
application_type: 1
activity_code: R01
ic: DA
serial_number: 022967
suffix: A2
program_official: JONES, DIONNE
project_start_date: 2008-04-01
project_end_date: 2013-01-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL 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: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Accident and Emergency department;African American;Alcohols;Biological Assay;Chlamydia;Class;Communities;Data;Dependence;Development;Drug abuse;Drug abuser;Drug usage;Drug user;Economics;Event;Factors Enabling;Female;Foundations;Fright;Future;Gender;General Population;Goals;Gonorrhea;Grants Applications;HIV;Health;Health Personnel;Health Planning;Health Policy;Health Services;Health Status;Healthcare;Hepatitis C;Hepatitis C virus;Hospitalization;Imprisonment;Incidence;Individual;Inpatients;Intervention;Interview;Jail;Justice Criminal;Kentucky;Knowledge;Life;Literature;Location;Mediating;Medical;Mental Health;Modeling;Multivariate Analysis;NIH Program Announcements;Numbers;Participant;Patient Self-Report;Pattern;Pharmaceutical Preparations;Physicians;Population;Prevalence;Prevention intervention;Prisoner;Prisons;Race;Rate;Recruitment Activity;Reporting;Reporting Data;Research;Risk Behaviors;Sampling;Series;Seroprevalences;Services;Severities;Sexually Transmitted Diseases;Structure;Substance abuse problem;Supervision;Surveys;System;Time;Trust;Universities;Unsafe Sex;Woman;Women's Health;Work;alcohol research;base;criminal offending;design;experience;follow-up;health care service utilization;health disparity;innovation;offender;probation;public health medicine (field);racism;recidivism;service utilization;time use


application_id: 7418878
project_number: 1R01DA024598-01
project_title: Social networks and HIV risk among rural drug users
administering_ic: NIDA
award_notice_date: 2008-04-03
opportunity_number: PA-07-103
application_type: 1
activity_code: R01
ic: DA
serial_number: 024598
program_official: HARTSOCK, PETER
project_start_date: 2008-04-05
project_end_date: 2013-01-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acquired Immunodeficiency Syndrome;Affect;Appalachian Region;Area;Automobile Driving;Behavior;Blood;Centers for Disease Control and Prevention (U.S.);Characteristics;Communities;Data;Disease;Disease regression;Drug abuse;Drug usage;Drug user;Epidemic;Face;Goals;Growth;HIV;HIV Infections;Health Resources;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Human immunodeficiency virus test;Incidence;Individual;Individual Adjustment;Infection;Injecting drug user;Injection of therapeutic agent;Intervention;Interview;Interviewer;Kentucky;Measures;Medical Surveillance;Mental Health;Modeling;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Drug Abuse;Object Attachment;Participant;Pathway Analysis;Pharmaceutical Preparations;Population;Prescriptions Drug;Prevalence;Prevention;Principal Investigator;Psychiatric Diagnosis;Questionnaires;Recruitment Activity;Reporting;Research;Research Priority;Respondent;Risk;Risk Behaviors;Risk Factors;Rural;Rural Population;Sampling;Serologic tests;Seroprevalences;Social Network;Structure;Testing;Thinking function;Time;United States;Urban Population;Ursidae Family;design;health disparity;innovation;multilevel analysis;programs;public health medicine (field);response;rural area;transmission process;urban area


application_id: 7418754
project_number: 1R01HL088989-01A1
project_title: Role of B cells in host defense against Pneumocystis
administering_ic: NHLBI
award_notice_date: 2007-12-05
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 088989
suffix: A1
program_official: PEAVY, HANNAH H
project_start_date: 2007-12-06
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1 AARR-C (04)]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adoptive Transfer;Affect;Anti-Retroviral Agents;B-Lymphocytes;CD4 Positive T Lymphocytes;Cell Communication;Cell Count;Cell Survival;Cell physiology;Cells;Dendritic Cells;Disease;Drug Combinations;Generations;Genes MHC Class II;Goals;HIV;Host Defense;Immune response;Immunoglobulin Class Switching;Immunoglobulin G;Immunologic Deficiency Syndromes;Indium;Individual;Infection;Interleukin-10;Kinetics;Lung;Memory;Mice Transgenic;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nature;Opportunistic Infections;Patients;Personal Satisfaction;Phase;Pneumocystis;Pneumocystis Infections;Pneumonia Pneumocystis carinii;Predisposition;Production;Resistance;Role;SCID Mice;Signal Transduction;T-Cell Proliferation;T-Lymphocyte;TNF gene;TNFRSF5 gene;Time;Vaccine Adjuvant;Viral Load result;Week;cytokine;design;discount;in vitro Assay;in vivo;lymph nodes;memory CD4 T lymphocyte;prevent;research study;response


application_id: 7418320
project_number: 5R21DA023049-02
project_title: Modafinil and Smoking Cessation
administering_ic: NIDA
award_notice_date: 2008-03-04
opportunity_number: PA-06-331
application_type: 5
activity_code: R21
ic: DA
serial_number: 023049
program_official: MONTOYA, IVAN
project_start_date: 2007-05-10
project_end_date: 2011-06-30
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 8535709
contact_pi: MARTIN, CATHERINE ANNE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_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 R21 application is a Phase II clinical trial exploring the efficacy of modafinil as a smoking cessation aid. It builds on a Phase I Clinical Trial (R03) that explored the safety of modafinil in combination with nicotine and the effects of modafinil on nicotine withdrawal. Modafinil administration was safe decreased appetite and cigarette craving and enhanced attention after 24 hrs of tobacco deprivation in tobacco smokers. This proposal is responding to the RFA: "Women Gender Differences and Drug Abuse" in that it is developing and testing a theoretically-based drug treatment that addresses a gender-specific issue. It addresses the observation that weight gain following smoking cessation is a significant deterrent to treatment efficacy among women. Further the application is consistent with the goals of the R21 mechanism in that it is testing a novel intervention with significant potential to have a major impact on smoking cessation among women. Although the mainstays of pharmacological interventions for smoking cessation bupropion and nicotine replacement can double smoking cessation rates the majority of smokers continue to smoke especially women. Cigarette smoking is the leading cause of preventable death and disease and may have greater health risks for females than males so exploration of novel pharmacological interventions is imperative. Modafinil has particular promise as a smoking cessation aid in that it has the potential to ameliorate multiple symptoms of nicotine withdrawal including 1) craving 2) inattention 3) depressed mood and 4) increased appetite and weight gain. This Phase II clinical trial will be a randomized double blind placebo-controlled smoking cessation intervention that will compare the efficacy of 200 mg of modafinil and placebo on smoking cessation. In addition modafinil effects on nicotine withdrawal symptoms will be assessed including craving inattention depressed mood and increased appetite and weight gain in nicotine-dependent smokers undergoing smoking cessation treatment. Finally personality measures that evaluate depressed mood and inattention will be obtained since these variables have been associated with increased risk for cigarette smoking. This combination of measures of smoking cessation nicotine withdrawal symptoms and personality measures that are associated with risk for smoking will aid in evaluating whether modafinil is a smoking cessation aid and will also allow examination of possible mechanisms for the effects of modafinil on smoking cessation. If shown to be effective modafinil could be added to the current pharmacotherapies for smoking cessation and may have particular benefit for female smokers for whom weight gain is a significant deterrent to smoking cessation. Most smokers trying to quit often fail because of increased cigarette craving inattention appetite and weight. We have shown that the medication modafinil decreases appetite and cigarette craving and improves concentration when smokers first stop smoking. This suggests that modafinil will help smokers stop smoking by decreasing appetite and craving and increasing concentration. Modafinil may be particularly helpful for women smokers who have concerns about weight since modafinil decreases appetite when smokers are in nicotine withdrawal.

project_terms:
Abstinence;Acute;Address;Age;Attention;Body Weight;Build-it;Bupropion;Bupropion/Nicotine;Cessation of life;Cigarette;Clinical Trials Phase I;Clinical Trials Phase II;Cotinine;Data;Depressed mood;Desire for food;Disease;Double-Blind Method;Drug abuse;Exploratory/Developmental Grant;Female;Future;Gender;General Population;Goals;Health;Intervention;Laboratories;Laboratory Study;Lead;Measures;Modafinil;Monitor;Nicotine;Nicotine Withdrawal;Outcome;Personality;Pharmaceutical Preparations;Pharmacotherapy;Placebo Control;Placebos;Randomized;Rate;Relapse;Risk;Safety;Sex Characteristics;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Sum;Symptoms;Testing;Tobacco;Treatment Efficacy;United States Dept. of Health and Human Services;Weight;Weight Gain;Withdrawal;Withdrawal Symptom;Withholding Treatment;Woman;Work;base;cigarette smoking;clinical efficacy;cognitive function;craving;day;deprivation;design;improved;inattention;increased appetite;male;nicotine replacement;novel;prevent;response;smoking cessation;tobacco abstinence;urinary


application_id: 7418207
project_number: 5R01DC005989-05
project_title: Functional Analysis of Inner Ear Gap Junctions
administering_ic: NIDCD
award_notice_date: 2008-05-12
application_type: 5
activity_code: R01
ic: DC
serial_number: 005989
program_official: WATSON, BRACIE
project_start_date: 2004-07-15
project_end_date: 2011-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to investigate functions of gap junctional coupling in the inner ear. A gap junctional channel is an intercellular cytoplasmic conduit and is encoded by the connexin gene family in mammals. Six connexin isoforms assemble to form a hexadal connexon (hemichannel) and dock with another connexon in the opposite cell membrane to form an intercellular gap junctional channel through which molecules up to 1 kDa can pass. Cx26 and 30 are the predominant isoforms in cochlear supporting cells. Each connexin mutation can induce hearing loss. It has been found that gap junctions between supporting cells have various asymmetrical voltage gates indicative of the occurrence of heterotypic and heteromeric hybrid channel configurations in the cochlea. The working hypothesis of this project is that Cx26 and 30 may dock to form heterotypic and heteromeric channels with specific permeability to selectively transfer ions and molecules in the cochlea; asymmetric heterotypic channels may also induce directional intercellular transfer in this multicellular system. Specific aim (SA) 1 is to define connexin-specific functions in the cochlea. We will use immunofluorescent staining to identify connexin expression and distributions patch clamp recording to measure channel conductance and gating to identify channel types and configurations and fluorescent probes to assess connexin channel permeability. Charge and size selectivity in gap junctional permeability will be assessed by use of multiple florescent probes with patch clamp recording. Fluorescence recovery after photo bleaching (FRAP) with confocal microscopy will also be employed to quantitatively define gap junctional permeability. The asymmetry of transjunctional diffusion between cochlear supporting cells and directional passage in the cochlear sensory epithelium will be defined by FRAP measurement and time-lapse fluorescent microscopy (SA2). SA3 is to define the activity and permeability of connexin hemi channels in native cochlear supporting cells to further elucidate structure-function relationship of gap junctional coupling in the cochlea. SA 4 is to test the K+-recycling hypothesis that has long been proposed but has yet to be tested. We will use patch clamp technique to directly record K+ passage between cochlear supporting cells. SA5 is to explore the effect of supporting cell's junctional coupling on outer hair cell electro motility. Undoubtedly completion of these studies will contribute signaificantly towards understanding the mechanisms of gap junctional coupling in the inner ear and in turn develop therapeutic and protective interventions for this common hereditary deafness.

project_terms:
Back;Cell membrane;Cells;Charge;Cochlear structure;Complex;Condition;Connexins;Connexon;Coupling;Cytoskeleton;Deafness;Diffusion;Docking;Dyes;Endolymph;Epithelium;Excision;Extracellular Space;Fluorescence;Fluorescence Recovery After Photobleaching;Fluorescent Dyes;Functional disorder;Gap Junctions;Gene Family;Goals;Hair Cells;Hair Cells Outer;Hearing;Hybrids;Inherited;Intervention;Ions;Kinetics;Labyrinth;Location;Mammals;Measurement;Measures;Mechanics;Membrane;Membrane Potentials;Metabolic;Microscopy;Microscopy Confocal;Molecular;Movement;Mutation;Nutrient;Outer Supporting Cell;Patch-Clamp Techniques;Performance;Perfusion;Permeability;Physiological;Play;Potassium;Potassium Channel;Probes Fluorescent;Property;Protein Isoforms;Recovery;Recycling;Research Personnel;Role;Sensory;Staining method;Stains;Structure-Activity Relationship;Supporting Cell;System;Testing;Therapeutic;Tight Junctions;Time;Work;cell motility;cell type;extracellular;gap junction channel;hearing impairment;in vivo;patch clamp;prevent;programs;research study;size;small molecule;time use;uptake;voltage


application_id: 7417511
project_number: 5U10NS058967-02
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2008-06-03
opportunity_number: RFA-NS-06-009
application_type: 5
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2012-04-30
study_section: ZNS1-SRB-K(41)
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY 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_terms:
Academic Medical Centers;Accident and Emergency department;Acute;Adult;Advanced Cardiac Life Support;Agreement;Air;Ambulances;American College of Surgeons;Brain;Caring;Cities;Clinical Trials;Collaborations;Communication;Consent;County;Disease model;Doctor of Medicine;Emergency Medicine;Emergency Situation;Emergency medical service;Emergency treatment;Enrollment;Environment;Evaluation;Faculty;Faculty Medical;Fire - disasters;Goals;Government;Head;Hospitals;Hospitals Community;Hospitals University;Hospitals Urban;Internet;Kentucky;Medical;Medical center;Medicine;Neurological emergencies;Neurology;Operative Surgical Procedures;Patients;Physicians;Positioning Attribute;Principal Investigator;Provider;Randomized;Recruitments Patient;Rehabilitation therapy;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Population;Science of neurosurgery;Services;Speed (motion);Spinal Cord;Spinal cord injury;Therapies Investigational;Trauma;Trauma Centers;Universities;Veterans;base;clinical research site;college;design;experience;member;nervous system disorder;professor;response;treatment trial


application_id: 7417486
project_number: 5R01CA113932-04
project_title: Increasing Colorectal Cancer Screening in Rural Kentucky
administering_ic: NCI
award_notice_date: 2008-04-01
application_type: 5
activity_code: R01
ic: CA
serial_number: 113932
program_official: BRESLAU, ERICA S
project_start_date: 2005-05-01
project_end_date: 2010-03-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky's Cancer Control Program Department of Behavioral Science  Kentucky Cancer Program and community partners are proposing a five-year community-based participatory project to increase colorectal cancer screening in rural Appalachian Kentucky (51 counties in eastern Kentucky). Compared with the rest of the U.S. Appalachian Kentucky is medically underserved economically distressed and disproportionately burdened with different types of cancer. Data from the Behavioral Risk Factor Surveillance System indicates that approximately 36% of respondents in Appalachian Kentucky reported screening for colorectal cancer (FOBT or flexible sigmoidoscopy or colonoscopy) in accordance with guidelines of the US Preventive Services Task Force compared to 43.5% in Kentucky and 53% nationwide.  Specific aims of this project are to: 1) Build on a foundation of community partnerships in Appalachian Kentucky and develop a network of community partners capable of fostering colorectal cancer screening; 2) Use results from a pilot project and in collaboration with community partners pretest an intervention to increase screening for colorectal cancer in rural Appalachian Kentucky; 3) Recruit primary health care providers for the project conduct a baseline assessment and implement an intervention to increase colorectal cancer screening in primary care practices; and 4) Evaluate the effectiveness of the intervention in increasing colorectal cancer using a randomized design involving primary care practices assigned to intervention or control based on a readiness to change score and conduct qualitative key informant interviews and process evaluations. Methods for achieving these aims are described in detail in Section D (Research Design and Methods) and include conducting focus groups recruiting 64 primary care practices (32 control 32 intervention) delivering an educational intervention consisting of 4 modules collecting colorectal cancer screening data from 60 medical records/intervention practice and assessing the impact of the intervention.

project_terms:
Advisory Committees;Behavioral Risk Factor Surveillance System;Behavioral Sciences;Cancer Control;Collaborations;Colonoscopy;Colorectal Cancer;Communities;Community Networks;County;Data;Distress;Educational Intervention;Effectiveness of Interventions;Evaluation;Flexible fiberoptic sigmoidoscopy;Focus Groups;Fostering;Foundations;Guidelines;Health Personnel;Intervention;Interview;Kentucky;Malignant Neoplasms;Medical Records;Methods;Pilot Projects;Preventive;Primary Health Care;Process;Randomized;Readiness;Recruitment Activity;Reporting;Research Design;Respondent;Rest;Rural;Score;Screening for Colorectal Cancer;Services;Universities;base;cancer type;design;medically underserved;programs


application_id: 7417309
project_number: 2P42ES007380-12
project_title: Core E: Superfund Inter-Disciplinary Training Core
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 9008
contact_pi_person_id: 8534462
contact_pi: BACHAS, LEONIDAS G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Activities Educational;Address;Affect;Applied Research;Basic Science;Bioinformatics;Chemicals;Collaborations;Collection;Communication;Communities;Complex;Depth;Detection;Dimensions;Discipline;Ecology;Economics;Educational workshop;Effectiveness;Engineering;Environment;Ethics;Evaluation;Evaluation Methodology;Faculty;Funding;Generations;Goals;Graduate Education;Human;Individual;Institution;Internet;Interview;Kentucky;Knowledge;Laws;Learning;Legal;Life;Mentors;Methods;Minority;Monitor;Nutritional;Outreach Community;Pamphlets;Participation Community;Postdoctoral Fellow;Principal Investigator;Problem Solving;Process;Proteomics;Published Comment;Recruitment Activity;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Science;Science of nutrition;Scientist;Series;Societies;Students;Study Interdisciplinary;System;Systems Biology;Toxic effect;Toxicology;Training;Training Programs;Translations;Travel;United States Environmental Protection Agency;Universities;base;college;environmental toxicology;interest;knowledge base;member;next generation;outreach;programs;remediation;research and development;skills;social;socioeconomics;superfund chemical;superfund site;symposium


application_id: 7417308
project_number: 2P42ES007380-12
project_title: Core D: Community Outreach Core (SCAN)
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 9007
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Affect;Anthropometry;Attitude to Health;Behavior;Body Composition;Characteristics;Characteristics Social;Chronic Disease;Collaborations;Communities;Community Actions;Community Services;Diet;Diet Records;Dietitian;Educational aspects;Environmental Health;Environmental Pollution;Exercise;Exposure to;Face;Family;Fatty acid glycerol esters;Fiber;Food;Funding;Health;Health Knowledge Attitudes Practice;Health Professional;Health education;Individual;Intake;Invasive;Kentucky;Knowledge;Litigation;Measures;Metabolic;Nutrition Assessment;Nutritional status;Outcome Measure;Outreach Community;Participant;Pharmacists;Physicians;Play;Purpose;Quality of life;Questionnaires;Rate;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Scanning;Science of nutrition;Services;Site;Testing;Title;Toxic effect;Trust;Waste Sites Hazardous;design;improved;insight;interest;nutrition education;programs;public health medicine (field);superfund chemical;superfund site


application_id: 7417306
project_number: 2P42ES007380-12
project_title: Core C: Research Translation Core
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 9004
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Academia;Basic Science;Biochemical;Biomedical Research;Biosensor;Cardiovascular Diseases;Chemical Exposure;Chemicals;Clinical;Communication Tools;Communities;Diabetes Mellitus;Diffusion;Disease;Effectiveness;Ensure;Environment;Environmental Health;Environmental Pollution;Exposure to;General Population;Government;Guidelines;Health;Health Professional;Human;Hypertension;Individual;Industry;Information and Communication Theory;Investigation;Kentucky;Knowledge;Letters;Malignant Neoplasms;Nanotechnology;Outcome;Plants;Research;Research Institute;Research Project Grants;Research Outcomes;Role;Science of nutrition;Services;Targeted Research;Techniques;Technology;Translating;Translational Research;Translations;Universities;Water;college;novel;programs;public health medicine (field);remediation


application_id: 7417305
project_number: 2P42ES007380-12
project_title: Core B: Research Support Core
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 9005
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Address;Area;Arts;Basic Science;Binding (Molecular Function);Bioinformatics;Biological;Biometry;Blood Vessels;Chemistry Analytical;Computer Analysis;Consultations;Data;Data Analyses;Databases;Diet;Disease;Educational workshop;Ensure;Environmental Pollutants;Equipment;Experimental Designs;Expertise Technical;Feedback;Generations;Genomics;Health Services Research;Human Resources;Individual;Kentucky;Mediating;Modeling;Pathology;Pathway interactions;Polychlorinated Biphenyls;Procedures;Process;Proteomics;Quality Control;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Research Support;Role;Sampling;Science of nutrition;Services;Structure;Support of Research;Surveys;Systems Biology;Technology;Tools Software;Toxic effect;Toxicology;Training;Training Support;Universities;cost effectiveness;crosslink;data management;innovative technologies;new technology;predictive modeling;programs;success;superfund chemical;tool


application_id: 7417304
project_number: 2P42ES007380-12
project_title: Core A: Administrative Core
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 2008-04-01
project_end_date: 2013-03-31
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 9009
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
project_abstract:
The Administrative Core (Core A) will oversee the entire Superfund Basic Research Program through amanagement mechanism that allows efficient and accountable oversight and maximum interdisciplinary andmultidisciplinary interactions among all participants. The Administrative Core will be responsible for thecoordination planning assessment project accounting and administrative support to the researchpersonnel of the University of Kentucky SBRP. A major objective of the Administrative Core is to facilitatethe execution of an interdisciplinary research theme through administrative support and fiscal accountability.The Administrative Core will work especially closely with the Research Translation Core (Core C) to optimizecommunication with NIEHS EPA and state and local constituents; communication is also facilitated by anactive website that is managed by Core C with input from the Administrative Core. Research efforts will becoordinated through biweekly meetings of faculty students and research staff as well as seminars wherenew findings and planned activities and ideas will be discussed. It will also be critical to discuss researchfindings for informative/educational activities technology transfer training policy and translational purposesas part of the objectives of the Research Translation Community Outreach and Training Cores. TheAdministrative Core will implement feedback and cross-talk between all project and core activities to allow formaximum integration. For example optimal detection and remediation of Superfund pollutants must belinked to risk assessment and biomedical aspects of degradation products. Accountability of the Universityof Kentucky SBRP activities including the quality of science and administration will be achieved throughregular consultations with both the External and Internal Advisory Boards. Research quality assessment andstatistical consultation will be managed through the Research Support Core. General fiscal responsibilitiesor project accounting will be coordinated through the Administrative Office in conjunction with the Universityof Kentucky Research Foundation. Our Program Coordinator together with the Program Director will serveas a regular contact among all SBRP activities including Research Projects and Cores and will coordinateall reports required by the sponsoring agencies.

project_terms:
Accountability;Accounting;Activities Educational;Basic Science;Budgets;Communication;Consultations;Daily;Detection;Education and Outreach;Ensure;Faculty;Feedback;Floor;Foundations;Government Agencies;Health Sciences;Housing;Individual;Kentucky;Link;Officials Government;Outreach Community;Participant;Policies;Psychological Transfer;Publications;Purpose;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Risk Assessment;Science;Services;Students;Study Interdisciplinary;Support of Research;Technology Transfer;Time;Translations;United States Environmental Protection Agency;Universities;Work;interdisciplinary collaboration;multidisciplinary;pollutant;programs;remediation;success


application_id: 7417303
project_number: 2P42ES007380-12
project_title: Project 7: Chloro-Organic Degradation by Nanosized Metallic Systems and by Chelat
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 0010
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Advanced Development;Anions;Carbon;Characteristics;Chelating Agents;Chemicals;Chlorine;Closure;Development;Educational workshop;Effectiveness;Environment;Enzymes;Equilibrium;Flushing;Foundations;Free Radicals;Future;Generations;Glucose;Health Benefit;Hydrogen;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;In Situ;Iron;Iron Chelating Agents;Kinetics;Lead;Life;Maps;Membrane;Metals;Methods;Modeling;Monitor;Morphology;Nanostructures;Nanotechnology;Nanotubes;Natural regeneration;Numbers;Operative Surgical Procedures;Parents;Pathway interactions;Phase;Phenols;Pollution;Polychlorinated Biphenyls;Polymers;Production;Property;Range;Rate;Reaction;Reagent;Research;Roentgen Rays;Role;Salts;Sampling;Site;Soil;Solvents;Spectrum Analysis;Structure;Superoxides;Surface;System;Techniques;Technology;Testing;Toxic effect;Trichloroethylene;Vascular Endothelial Cell;Vinyl Chloride;Water;Work;base;biodegradable product;catalyst;cost;dechlorination;diphenyl;enzyme immobilization;gluconate;glucose oxidase;improved;innovation;membrane assembly;nanoparticle;nanosized;nanostructured;novel strategies;organic acid;oxidation;particle;pollutant;reaction rate;remediation;size;superfund site;surfactant;technology development


application_id: 7417300
project_number: 2P42ES007380-12
project_title: Project 6: Sensing Superfund Chemicals with Recombinant Systems
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 0004
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Bacteria;Binding (Molecular Function);Biological;Biosensing Techniques;Biosensor;Cells;Chemicals;Class;Coupled;Detection;Development;Ecology;Elements;Emerging Technologies;Engineering;Environment;Environmental Monitoring;Exhibits;Funding;Genes;Genetic Engineering;Goals;Health;Human;In Situ;Indium;Methods;Microfluidic Analytical Techniques;Microfluidics;Molecular;Molecular Biology;Monitor;Nanotechnology;Nature;Numbers;Operon;Pathway interactions;Plasmids;Poisons;Polychlorinated Biphenyls;Proteins;Recombinants;Reporter;Reproduction spores;Research Personnel;Sampling;Signal Transduction;System;Technology;Time;Toxic effect;Trademark;Transformation Bacterial;Work;analytical method;bacterial resistance;base;cost;design;field study;genetic regulatory protein;improved;miniaturize;pollutant;public health medicine (field);sensor;success;superfund chemical;tool


application_id: 7417257
project_number: 2P42ES007380-12
project_title: Project 4: The Impact of Obesity on PCB Toxicity
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 0008
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Abdomen;Abdominal aorta structure;Acute-Phase Proteins;Adipocytes;Adipose tissue;Adverse effects;Agonist;Angiotensin II;Aortic Aneurysm;Aortic Aneurysm Abdominal;Apolipoprotein E;Biological;Blood Vessels;Body Weight;Cardiovascular Diseases;Cause of Death;Chronic;Data;Deposition;Diet;Dietary Intervention;Disease;Exhibits;Family;Fatty Acids;Fatty Acids Omega-3;Fatty Acids Polyunsaturated;Fatty acid glycerol esters;Figs - dietary;Gene Expression;Greater sac of peritoneum;Health Benefit;In Vitro;Incidence;Infiltration;Inflammation;Inflammatory;Laboratories;Ligands;Linoleic Acids;Linolenic Acids;Lipids;Measures;Models Experimental;Mortality Vital Statistics;Mus;Obesity;Obesity associated cardiovascular disease;Obesity associated disease;Oxidative Stress;Polychlorinated Biphenyls;Predisposition;Production;Regulation;Research;Role;Sampling;Severities;Signal Pathway;Signal Transduction;Strikes Employee;Toxic effect;Translating;Vascular Diseases;Vascular System;Weight Gain;Work;adipocyte differentiation;adipokines;base;cytokine;in vivo;lipophilicity;macrophage;male;receptor;remediation;response


application_id: 7417256
project_number: 2P42ES007380-12
project_title: Project 3: Vascular Mechanisms of PCB-Induced Brain Metastases
administering_ic: NIEHS
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-C (S7)]
subproject_number: 0009
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Advocate;Animal Model;Behavioral;Biological Models;Blood - brain barrier anatomy;Blood Vessels;Brain;CD36 gene;Cancer Patient;Caveolae;Caveolins;Cell surface;Cerebrum;Clinical;Data;Development;Diet;Dietary Factors;Dietary Fats Unsaturated;Dietary Fatty Acid;Dietary Intervention;Disease;Disruption;Elements;Endothelial Cells;Endothelium;Endothelium Vascular;Event;Exposure to;Family;Fatty Acids;Fatty Acids Omega-3;Fatty Acids Omega-6;Fatty Acids Polyunsaturated;Fatty acid glycerol esters;Forecast of outcome;Functional disorder;Funding;Goals;Hazardous Substances;Health;Human;Inflammatory Response;Injury;Knowledge;Linoleic Acids;Localized;Malignant Neoplasms;Manuscripts;Mediating;Membrane;Membrane Microdomains;Metastatic malignant neoplasm to brain;Modeling;Molecular;Molecular Biology;Mus;Neoplasm Metastasis;Neurologic;Pathology;Pathway interactions;Play;Polychlorinated Biphenyls;Property;Proteins;Publishing;Receptor Signaling;Research;Research Proposals;Risk;Role;Science of nutrition;Signal Pathway;Signal Transduction;System;Tight Junctions;Toxic effect;abstracting;alpha-Linolenic Acid;base;caveolin 1;environmental toxicology;in vivo;innovation;neoplastic cell;protein expression;public health medicine (field);receptor;rho;superfund chemical;translational approach;tumor;uptake


