# projects

application_id: 7574189
project_number: 1R03DA025948-01
project_title: Development of Antagonists for M5 Muscarinic Acetylcholine Receptor
administering_ic: NIDA
award_notice_date: 2009-02-10
opportunity_number: PAS-07-327
application_type: 1
activity_code: R03
ic: DA
serial_number: 025948
program_official: HILLERY, PAUL
project_start_date: 2009-02-15
project_end_date: 2011-01-31
study_section: Special Emphasis Panel[ZRG1 MNPS-C (09)]
contact_pi_person_id: 9208440
contact_pi: ZHENG, GUANGRONG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Drug abuse continues to cause great societal burden. Despite intensive efforts effective pharmacotherapeutic treatments for drug dependence are still lacking indicating new strategies and targets are needed. A growing body of evidence supports our hypothesis that selective antagonism at the M5 muscarinic acetylcholine receptor (mAChR) represents a novel target for the treatment of drug dependence. The rewarding effects of most drugs of abuse are believed to be mediated by the mesolimbic dopaminergic pathway projecting from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to the nucleus accumbens (NAc) and striatum respectively. The M5 receptor is the only subtype localized on dopaminergic neurons of the VTA and SNc. Microinfusion of the non-selective mAChR antagonist scopolamine into the VTA or SNc substantially reduces DA release in NAc or striatum respectively. Although there are no selective M5 receptor antagonists currently available behavioral studies using mice lacking functional M5 receptors have shown a reduction in reward and withdrawal responses following morphine and cocaine administration and also a reduction in the rate of cocaine self-administration. These results show a role of the M5 receptor in modulating cocaine and opiate addiction. Furthermore co-administration of scopolamine with cocaine reduces self-administration of cocaine by rhesus monkeys and scopolamine has been shown to be effective for detoxification of heroin addicts in clinical studies. We reasoned that the effectiveness of scopolamine is due to antagonism of the M5 receptor; however the involvement of other subtypes can not be ruled out. To date the physiological and pharmacological roles of the M5 mAChR are still obscure and research has been hampered by the lack of subtype-selective M5 ligands. The objective of this application is to discover potent and selective M5 receptor antagonists which in our long-term goal can be developed into medical treatments for drug dependence. We expect that compounds developed in this research project will also serve as pharmacological tools useful for studying physiological functions of the M5 receptor. New compounds will be designed and synthesized based on the structural scaffold of literature reports on low selectivity and low potency M5 antagonists. Compounds synthesized will be characterized for receptor binding affinities in recombinant Chinese hamster ovarian (CHO- K1) cells expressing the individual human muscarinic receptor subtypes ability to inhibit carbachol-induced phosphatidylinositol (PI) hydrolysis in CHO cells expressing hM5 receptors and by inhibition of oxotremorine- evoked dopamine release from superfused rat striatal slices (functional assay). PUBLIC HEALTH RELEVANCE: These studies will pioneer the development of selective M5 receptor antagonists which have potential as efficacious treatments for drugs of abuse.

project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;Affinity;Behavioral;Binding (Molecular Function);Biological Assay;Carbachol;Carboxylic Acids;Cells;Chinese Hamster;Chinese Hamster Ovary Cell;Classification;Clinical Research;Cocaine;Corpus striatum structure;Development;Dopamine;Drug Addiction;Drug Metabolic Detoxication;Drug abuse;Effectiveness;Esters;Evaluation;Exhibits;Goals;Heroin;Human;Hydrolysis;Individual;Ligands;Literature;Macaca mulatta;Measures;Mediating;Medical;Membrane;Modification;Morphine;Mus;Muscarinic Acetylcholine Receptor;Muscarinic M1 Receptor;Muscle Rigidity;Nucleus Accumbens;Opiate Addiction;Ovarian;Oxotremorine;Pathway interactions;Phosphatidylinositols;Physiological;Rattus;Receptor Inhibition;Recombinants;Reporting;Research;Research Project Grants;Rewards;Role;Scopolamine;Self Administration;Slice;Substantia nigra structure;Testing;Ventral Tegmental Area;Withdrawal;analog;base;design;dopaminergic neuron;drug of abuse;novel;pars compacta;pharmacophore;public health relevance;receptor;receptor binding;receptor function;response;scaffold;tool

public_health_relevance:
These studies will pioneer the development of selective M5 receptor antagonists which have potential asefficacious treatments for drugs of abuse.


application_id: 7572826
project_number: 5R01AG029623-04
project_title: Role of TWEAK in Skeletal Muscle Metabolism
administering_ic: NIA
award_notice_date: 2009-03-24
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2012-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
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: 2009-04-01
project_abstract:
DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a number of chronic diseases including aging cancer diabetes sepsis AIDS chronic obstructive pulmonary disease chronic heart failure and cystic fibrosis. Beyond a reduced survival rate muscle atrophy is also related to poor functional status and health-related quality of life in these and many other conditions such as starvation immobilization and disuse. However effective treatments require insight into the etiology of skeletal muscle atrophy. In our search to identify potential regulatory molecules that play an important role in the acquisition and maintenance of skeletal muscle mass we have accumulated several lines of evidence that support a key role for TNF-related weak-inducer of apoptosis (TWEAK) in regulation of skeletal muscle mass. These findings include: 1) Exogenous addition of recombinant TWEAK protein inhibits myoblast differentiation; 2) Inhibition of TWEAK activity using a blocking peptide promotes differentiated functions of myoblasts; 3) TWEAK accelerates degradation of specific muscle proteins in differentiated myoblasts; and 4) Chronic administration of TWEAK in mice reduces body and skeletal muscle weights and induces degradation of muscle proteins suggesting that TWEAK is a powerful muscle wasting molecule. Based on our strong preliminary data we hypothesize that: a) Deletion of TWEAK in mice will cause accretion of skeletal muscle mass and prevent muscle loss in response to aging tumor growth and diabetes; and b) TWEAK effects on myogenic cells are mediated through activation of signaling pathways independent of the Fn14 receptor. In this grant using TWEAK-knockout and transgenic mice we will evaluate the role and mechanisms of action of TWEAK in skeletal muscle. Our specific aims are to investigate: I) The consequence of disruption of TWEAK gene on the acquisition and maintenance of skeletal muscle mass under normal and pathological conditions; II) The key cellular processes that TWEAK affects in skeletal muscles; and III) The molecular pathways through which TWEAK regulates acquisition and maintenance of skeletal muscle mass. The successful completion of the propsoed work should provide the first experimental proof for involvement of TWEAK in the regulation of skeletal muscle mass and could lead to identification of TWEAK as a novel molecular target for future development of therapies to prevent muscle loss.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Actins;Affect;Age;Aging;Apoptosis;Apoptosis Promoter;Area;Attenuated;Body Weight;Cell physiology;Cells;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complementary DNA;Complication;Cystic Fibrosis;Cytoplasmic Tail;Data;Dexamethasone;Diabetes Mellitus;Differentiation Antigens;Dominant-Negative Mutation;Endotoxins;Etiology;Event;Fiber;Future;Genes;Grant;Heart failure;Immobilization;Inflammatory;Knock-out;Knockout Mice;Lead;Ligand Binding;Ligand Binding Domain;Maintenance;Malignant Neoplasms;Mediating;Molecular;Molecular Target;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Myoblasts;Myogenic Regulatory Factors;Myogenin;Outcome;Pathway interactions;Peptides;Physiological;Play;Process;Production;Proteins;Recombinants;Regulation;Role;Screening procedure;Sepsis;Signal Pathway;Skeletal muscle structure;Small Interfering RNA;Somatomedins;Starvation;Stimulus;Survival Rate;Techniques;Transgenic Mice;Tropomyosin;Troponin;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-Beta;Two-Hybrid System Techniques;Weight;Work;Yeasts;base;cDNA Library;caspase;cytokine;effective therapy;functional status;health related quality of life;in vivo;insight;muscle form;muscle metabolism;neutralizing antibody;novel;overexpression;prevent;protein degradation;receptor;research study;response;therapy development;tumor growth;wasting;yeast two hybrid system


application_id: 7570071
project_number: 5R01DC007176-05
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2009-02-15
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2010-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-03-01
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. The present research is designed to investigate gustatory innervation in support of two long terms goals: 1) to determine the cellular and molecular mechanisms that allow gustatory neurons to innervate the correct target (taste buds) with a specific mount of innervation and 2) to determine if and/or how these connections are important for central gustatory development or taste function. The proposed project focuses on the role of neurotrophins in regulating gustatory neuron number and peripheral and central targeting during embryonic development. It is known that the number of gustatory ganglion neurons that will exist at birth to innervate taste buds on the tongue and palate is somehow determined by brain-derived neurotrophic factor (BDNI0 and neurotrophin-4 (NT4). However the mechanism(s) by which BDNF and NT4 regulate innervation are unknown and could involve any number of different developmental processes during numerous different embryonic stages. The proposed studies combine in situ hybridization cell counting tract tracing immunohistochemistry and SEM in gene knockout mice to: 1) determine when and where the embryonic taste system is exposed to BDNF and NT4 2) determine when BDNF and NT4 regulate gustatory neuron number and whether this regulation is accomplished by reducing proliferation or by increasing cell death 3) determine whether BDNF and/or NT4 is required for initial target invasion and 4) determine if BDNF and/or NT4 regulate the central distribution of tongue and palatal sensory afferents. Together these studies test the hypotheses that: 1) NT4 is expressed along gustatory fiber projection pathways and regulates gustatory neuron survival before initial innervation of peripheral and central targets and 2) BDNF is expressed in gustatory epithelia and regulates neuron survival after initial peripheral and central target innervation. Because these experiments examine how neurotrophins regulate the amount and location of sensory innervation this project has important implications for the potential therapeutic use of these powerful signaling molecules in controlling neural regeneration following injury.

project_terms:
Afferent Neurons;Axon;Biological Assay;Birth;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Cell Count;Cell Cycle;Cell Death;Cell Nucleus;Cessation of life;Computer Systems Development;Development;Developmental Process;Embryo;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Future;Ganglia;Genes;Genotype;Goals;Growth;Hybrids;Immunohistochemistry;In Situ Hybridization;Injury;Knockout Mice;Knowledge;Label;Location;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Myxoid cyst;Nerve Fibers;Nerve Regeneration;Neurites;Neuronal Differentiation;Neurons;Oral cavity;Palate;Pathway interactions;Pattern;Peripheral;Principal Investigator;Process;Regulation;Research;Robin bird;Role;Sensory;Sensory Ganglia;Signal Pathway;Signaling Molecule;Staging;Structure of geniculate ganglion;System;Taste Buds;Taste Perception;TdT-Mediated dUTP Nick End Labeling Assay;Testing;The Sun;Therapeutic Uses;Time;Tongue;Withdrawal;axon regeneration;design;ganglion cell;nerve supply;neural circuit;neuron development;neuron loss;neurotrophic factor;neurotrophin 4;postnatal;programs;receptor;research study;response;synaptogenesis;tongue papilla


application_id: 7569403
project_number: 5R01HL090826-02
project_title: Central Nervous System Mechanisms of Obesity Hypertension
administering_ic: NHLBI
award_notice_date: 2009-01-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 090826
program_official: THRASHER, TERRY N
project_start_date: 2008-02-15
project_end_date: 2009-09-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 7258571
contact_pi: STOCKER, SEAN D
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Risk estimates from the Framingham Heart Study indicate that ~75% of essential hypertension in men and 65% of essential hypertension in women is largely attributed to excess body weight and obesity. Convincing evidence from both clinical studies and animal models demonstrates that elevated sympathetic outflow to the kidney and hindlimb vasculature plays a pivotal role in the pathogenesis of obesity-induced hypertension. Despite the important relationship between body weight or adiposity and activation of the sympathetic nervous system little is known regarding the neural pathways and cellular mechanisms that underlie the sustained increase in sympathetic outflow and arterial blood pressure during obesity. The long term goal of our laboratory is to identify the neural pathways and cellular mechanisms that increase sympathetic outflow and blood pressure in obesity. Two afferent signals to the brain postulated to mediate the elevated sympathetic outflow and blood pressure in obesity are hyperinsulinemia and hyperleptinemia. Our working hypothesis is that diet-induced obesity increases circulating insulin and leptin to activate a descending circuit from the arcuate nucleus to the hypothalamic paraventricular nucleus. Subsequent receptor activation in the hypothalamus increases the discharge of sympathetic neurons in the hypothalamic paraventricular nucleus to enhance excitatory drive to the brainstem and spinal cord. This enhanced excitatory drive increases sympathetic outflow and arterial blood pressure. In this application we will use state-or-the-art electrophysiological approaches to identify the central mechanisms that support obesity-induced hypertension. Specific aim 1 will identify the cellular mechanisms within the hypothalamic paraventricular nucleus by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 2 will identify the cellular mechanisms within the rostral ventrolateral medulla by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 3 will identify the mechanisms within the hypothalamic paraventricular nucleus and rostral ventrolateral medulla that support the elevated sympathetic outflow and blood pressure in a rodent model of diet-induced obesity. Our rationale for this project is that identification of the neural pathways and mechanisms that mediate the sympathoexcitatory actions of insulin and leptin and how these pathways ultimately contribute to obesity-induced hypertension will provide a framework for the development of novel therapeutic treatments.

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


application_id: 7569072
project_number: 1U24HL094373-01
project_title: Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies
administering_ic: NHLBI
award_notice_date: 2010-07-30
application_type: 1
activity_code: U24
ic: HL
serial_number: 094373
program_official: LIANG, ISABELLA Y
project_start_date: 2010-08-01
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZHL1 CSR-H (O1)]
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: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant):   
  
Ischemic heart disease causes -600000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately due to methodological problems this enormous investment has not produced any notable clinical application and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded randomized and adequately powered studies using a rigorous design full dose-response analyses optimal statistical methods independent data analysis and statistical Cores histology plasma biomarkers and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse rabbit pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry) thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and thus most likely to be effective in patients the consortium will dramatically advance our ability to rationally translate basic findings into clinical use.   
  
This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large namely the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct reducing infarct size will have a major impact on their morbidity and mortality and thus enormous implications for public health. (End of Abstract)

project_terms:
Academia;Acute myocardial infarction;Address;American;Americas;Animal Model;Basic Science;Blast Cell;Blinded;Carbon Monoxide;Cause of Death;Cessation of life;Clinical;Clinical Trials;Clinical Trials Network;Communities;Comorbidity;Conscious;Doctor of Medicine;Dose;Educational workshop;Ensure;Evaluation;Experimental Models;Failure (biologic function);Family suidae;Funding;Future;Goals;Healthcare;Histology;Individual;Industry;Infarction;Institution;Intervention;Investments;Ischemic Preconditioning;Journals;Laboratories;Letters;Logistics;Mind;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial tissue;National Heart Lung and Blood Institute;Oryctolagus cuniculus;Participant;Patients;Phase;Plasma;Pre-Clinical Model;Probability;Protocols documentation;Publishing;Randomized;Recommendation;Reperfusion Therapy;Reporting;Reproducibility;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Review Committee;Role;Screening procedure;Sodium Nitrite;Statistical Data Interpretation;Statistical Methods;Structure;System;Testing;Therapeutic Intervention;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Work;abstracting;biomarker;clinical application;design;disability;interest;meetings;member;myocardial infarct sizing;novel strategies;operation;outcome forecast;pre-clinical;pre-clinical research;preclinical evaluation;preclinical study;programs;public health medicine (field);research study;response;sildenafil;success;web site;working group


application_id: 7568919
project_number: 5R01CA113735-05
project_title: Development of Nucleolin targeted Anticancer Compounds
administering_ic: NCI
award_notice_date: 2009-02-11
application_type: 5
activity_code: R01
ic: CA
serial_number: 113735
program_official: LEES, ROBERT G
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-03-01
project_abstract:
DESCRIPTION (provided by applicant): GRO26B and GRO29A are G-quartet forming aptamer oligonucleotides that have potent antiproliferative activity against cancer cells in vitro and in vivo. GRO26B has already entered Phase I clinical trials. They are active against a diverse range of tumor types (including lung prostate breast and colon cancers) and are highly selective for malignant cells. The molecular target for these aptamers has been identified as nucleolin a multifunctional phosphoprotein that is highly expressed in the nucleoli and plasma membrane of cancer cells. It is already well established that high levels of nucleolin expression predict rapid tumor growth rate and poor prognosis in many tumor types. Nucleolin is on the surface of tumor cells and not on the surface of normal cells and we have shown that molecules selectively targeting it enter tumor cells preferentially over normal cells. Therefore nucleolin is a cancer selective target with targeted molecules potentially having lower side effects and toxicity by not entering normal cells. We are undertaking an interdisciplinary approach to the discovery of new small molecules targeting nucleolin. Preliminary data indicate that molecules targeting nucleolin (for example GRO26B and small molecules that we have already identified using our approach) can also exhibit growth inhibitory activity against cancer cells while not effecting normal cells. We propose that in understanding how GROs and small molecules bind to nucleolin we can use structure-based drug design to generate new small molecule that have increased efficacy over oligonucleotide-based therapy. Specifically we need to understand the properties and structures of the GROs and how they are related. Using that information we can examine the complexes with nucleolin to identify specific interactions that are favorable. We will target these regions to screen for new compounds that will be subsequently tested for anticancer effects. The significance of this research is that we could establish a new class of low toxicity small molecule anticancer agents targeted to nucleolin.

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


application_id: 7568851
project_number: 5R21DE018177-02
project_title: Analyses of Host-Biofilm Interactions: A Novel Polymicrobial Model
administering_ic: NIDCR
award_notice_date: 2009-02-18
opportunity_number: PA-06-210
application_type: 5
activity_code: R21
ic: DE
serial_number: 018177
program_official: LUNSFORD, DWAYNE
project_start_date: 2008-03-01
project_end_date: 2011-02-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1880406
contact_pi: NOVAK, KAREN F.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis represents the most broadly distributed polymicrobial disease of mankind. The tissue destructive processes that lead to loss of function of periodontal soft tissues and alveolar bone result from a chronic polymicrobial biofilm activation of host inflammatory innate immune and adaptive immune responses in the local tissues. Development of the polymicrobial biofilm is a sequential process that begins with deposition of host and bacterial glycoproteins onto the clean tooth surface. Initial colonization by oral microorganisms occurs next with oral streptococci being the primary early colonizers. This initial colonization by streptococci is followed by increasing proportions of Actinomyces Veillonella and Fusobacterium spp. (middle colonizers) with subsequent colonization predominated by Gram-negative anaerobic bacteria (late colonizers). This shift from a predominance of Gram-positive facultative microorganisms to a microbiota dominated by Gram- negative anaerobic species is manifest clinically by inflammatory changes in the periodontal tissues as the host responds to this microbial challenge. It has been proposed that this multicellular bacterial-host interaction possesses unique features compared to planktonic bacterial infectious challenges; however there is little objective evidence to support this contention. This R21 exploratory/development grant will specifically focus on developing this evidence using a novel polymicrobial biofilm model. The General Hypotheses to be tested are: (1) Oral bacteria in biofilms will elicit different patterns of host responses from gingival epithelial cells; and (2) Host cells will respond differently to bacterial species present as monospecies versus multispecies biofilms. We have developed a novel in vitro biofilm-host cell model system using a rigid gas permeable contact lens material. In Specific Aim 1 we will determine the characteristics of single species and multispecies biofilms created on this material. The biofilms developed in this model system will then be used in Specific Aim 2 to challenge oral epithelial cells allowing us to characterize the patterns of responses elicited in these host cells by the bacterial challenge. In accomplishing these aims we will have developed a novel approach for evaluating host response patterns to planktonic single species biofilm and polymicrobial biofilm challenges. The results obtained will enable us to provide seminal data to enable a further exploration of host responses to biofilms of various compositions and complexities. The bacteria found in dental plaque biofilms interact with tissues supporting the teeth to initiate an inflammatory response. The clinical diseases associated with this inflammatory response are gingivitis and/or periodontitis. However the exact host responses elicited by this interaction have not been determined. We are developing an in vitro model of this interaction to gain a better understanding of the pathologenesis of gingivitis and periodontitis. This understanding is necessary to develop and evaluate new strategies for controlling the destructive features of these chronic inflammatory diseases.

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


application_id: 7568737
project_number: 5R21ES015812-02
project_title: Transplacental Arsenic Induced Hepatic Dysfunction and Vascular Disease
administering_ic: NIEHS
award_notice_date: 2009-03-20
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: ES
serial_number: 015812
program_official: NADADUR, SRIKANTH
project_start_date: 2008-04-01
project_end_date: 2011-03-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of death in the U.S. Chronic arsenic ingestion causes atherosclerosis and is associated with increased mortality from myocardial infarction and stroke. Early life arsenic exposure may play a significant role in development of atherosclerosis in adult life as suggested by reports of infant deaths from myocardial infarction caused by advanced arteriosclerosis in regions where mothers consumed water with high levels of arsenic. Transplacental arsenic exposure can disrupt liver DNA methylation patterns and thus alter liver gene expression. Underlying liver disease is an independent risk factor for atherosclerosis. Hence arsenic exposure induced liver disease may predispose to atherogenesis and widespread exposure to arsenic in drinking water in the U.S. likely contributes to atherogenesis and death from cardiovascular disease. Our working hypothesis is that arsenic exposure disrupts epigenetic control of hepatic gene expression predisposing the liver to inflammation that is an atherogenic trigger resulting in accelerated atherosclerosis in susceptible animals. Preliminary data indicate that atherosclerosis-prone apolipoprotein E knockout (ApoE -/-) mice transplacentally exposed to arsenic in drinking water develop overt vascular disease by 10 weeks of age without high lipid diet and that liver gene expression suggests a pro-inflammatory state. The aims of this exploratory grant application are 1) to refine and to optimize this newly developed model of transplacental arsenic induced atherogenesis by determining arsenic exposure response of arsenic blood levels in pregnant females and fetuses determining exposure/time dependence of atherosclerotic lesion formation (rate and extent of lesion formation) assessing arsenic exposure-response of changes in vascular reactivity and characterizing the nature of arterial lesions (lesion cellularity fibrosis and inflammation) in arsenic exposed mice; 2) explore transplacental arsenic-induced hepatic changes by characterizing liver pathology determining circulating biomarkers of liver dysfunction and test the hypothesis that there is a temporal correlation between hepatic changes and vascular changes. Tissues will be examined at birth and at 10 16 and 24 weeks of age to determine the course of disease and stability of molecular changes induced by in utero arsenic exposure. The goal of the proposed studies is to determine whether there is a threshold level of arsenic exposure necessary to accelerate atherogenesis using the ApoE model. The relevance of this model to human atherosclerosis is that people prenatally exposed to arsenic are likely more susceptible to dietary influences later in life. These studies will provide important information on the mechanisms of arsenic induced atherosclerosis and the role that fetal arsenic exposure plays in disease progression. This model also will be a rich resource for future research on the mechanism of arsenic induced atherosclerosis including determination of the critical stages of development for the arsenic effect and molecular studies of arsenic exposure induced changes in DNA methylation chromatin structure gene expression and genetic imprinting. PUBLIC HEALTH RELEVANCE: Exposure to arsenic drinking water is a major concern in the United States. The effect of early life arsenic exposure on adult disease progression is unknown but potentially very important. This project uses a mouse model of fetal arsenic exposure induced vascular disease to investigate effects of fetal arsenic exposure on liver development that likely cause vascular disease by young adulthood.

project_terms:
Adult;Age;Animal Model;Animals;ApoE knockout mouse;Apolipoprotein E;Applications Grants;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Atherosclerosis;Birth;Blood;Blood Vessels;Cardiovascular Diseases;Cause of Death;Cellular Stress;Cellularity;Cessation of life;Cholesterol;Chromatin Structure;Chronic;DNA Methylation;Data;Dependence;Development;Diet;Digit structure;Disease;Disease Progression;Elderly;Epidemiologic Studies;Epigenetic Process;Exposure to;Fatty acid glycerol esters;Female;Fetus;Fibrosis;Functional disorder;Future;Gangrene;Gene Expression;Genetic;Genomic Imprinting;Goals;Hepatic;Hepatic Tissue;Human;Hyperlipidemia;Infant;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Lesion;Life;Link;Lipids;Liver;Liver Dysfunction;Liver diseases;Modeling;Molecular;Mortality Vital Statistics;Mothers;Mus;Myocardial Infarction;Nature;Pathology;Pattern;Phenocopy;Play;Process;Reporting;Research;Resources;Risk Factors;Role;Staging;Testing;Time;Tissues;United States;Vascular Diseases;Water;Work;arterial lesion;atherogenesis;biomarker;drinking water;fetal;in utero;infant death;interest;mouse model;offspring;pregnant;prenatal;prenatal exposure;programs;public health relevance;response;stroke


application_id: 7564517
project_number: 1R01DA025605-01
project_title: GABA Drugs for Cannabis-Use Disorders: Initial Mechanistic Studies in Humans
administering_ic: NIDA
award_notice_date: 2008-09-12
opportunity_number: PA-07-365
application_type: 1
activity_code: R01
ic: DA
serial_number: 025605
program_official: MONTOYA, IVAN
project_start_date: 2008-09-15
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZDA1 MXH-H (22)]
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_terms:
Admission activity;Agonist;Attenuated;Baclofen;Barbiturates;Behavioral;Benzodiazepine Receptor;Benzodiazepines;Cannabinoids;Cannabis;Cardiovascular system;Clinical Data;Clinical Research;Controlled Clinical Trials;Cues;Data;Dependence;Development;Diagnostic;Diazepam;Disease;Dose;Drug Interactions;Drug Use Disorder;Drug usage;Elevation;Foundations;Future;GABA Receptor;Human;Illicit Drugs;Link;Maintenance;Measures;Mediating;Medication Management;Memory;Neurobiology;Outcome;Patients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Physiological;Physiology;Population;Procedures;Psychomotor Performance;Questionnaires;Rate;Receptor Activation;Relapse;Reporting;Science of neurochemistry;Stimulus;System;Testing;United States;barbituric acid salt;drug discrimination;drug of abuse;gamma-Aminobutyric Acid;inhibitor/antagonist;innovation;memory process;novel;pre-clinical;preclinical study;public health medicine (field);receptor;research study;reuptake;tiagabine


application_id: 7563346
project_number: 1R01DA025591-01
project_title: GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2008-09-12
opportunity_number: PA-07-333
application_type: 1
activity_code: R01
ic: DA
serial_number: 025591
program_official: BOUGH, KRISTOPHER J
project_start_date: 2008-09-15
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZDA1 MXH-H (22)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. ?-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims.  The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference then an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse.  The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information the proposed research will provide basic-science and translational information. First the inclusion of drug self-administration and discrimination measures along with subjective-effect questionnaires will provide information concerning the relationship between the reinforcing discriminative and subjective effects of methamphetamine. Second because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures the proposed research will determine albeit indirectly the extent those findings from preclinical studies generalize to humans. Public Health Relevance: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.

project_terms:
Admission activity;American;Aminobutyric Acid;Aminobutyric Acids;Animals Laboratory;Attenuated;Basic Science;Behavior;Behavioral;Central Nervous System Stimulants;Chromosome Pairing;Clinical;Cocaine;Dependence;Development;Discrimination (Psychology);Dopamine;Dose;Drug Kinetics;Educational process of instructing;Elevation;Foundations;Goals;Great Lakes Region;Human;Institution;Intelligence;Kentucky;Laboratories;Learning;Location;Maintenance;Measures;Mediating;Methamphetamine;Molecular;Nerve;Neurotransmitters;Numbers;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Placebos;Play;Procedures;Psychostimulant dependence;Questionnaires;Range;Relapse;Reporting;Research;Role;Self Administration;Serotonin;Signal Transduction;Stimulus;Synapses;System;Testing;Thinking function;Vesicle;concept;design;dopamine system;drug discrimination;gamma-Aminobutyric Acid;monoamine;noradrenaline transporter;novel;pre-clinical;preclinical study;prevent;public health medicine (field);receptor;research study;reuptake;topiramate;volunteer


application_id: 7560245
project_number: 7U01ES015673-03
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2008-04-11
opportunity_number: RFA-NS-06-004
application_type: 7
activity_code: U01
ic: ES
serial_number: 015673
program_official: HEACOCK, MICHELLE
project_start_date: 2006-09-29
project_end_date: 2011-05-31
study_section: ZNS1-SRB-R(22)
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adenylate Cyclase;Aerosols;Affect;Agreement;Alveolar;Animal Model;Antioxidants;Area;Arts;Basal segment of lung;Blood capillaries;Bradykinin Receptor;Breathing;Buffers;Calcium;Capillary Unspecified;Cell Survival;Cells;Chemical Injury;Chemicals;Chlorine;Class;Cultured Cells;Cyclic AMP;Disruption;Distal;Dose;Endothelial Cells;Epithelial;Epithelial Cells;Exposure to;Family;G alpha q Protein;G-Protein-Coupled Receptors;GTP-Binding Proteins;Gases;Gene Expression;Glutathione;Goals;Hazards Health;Heterotrimeric GTP-Binding Proteins;Homeostasis;Hormones;Human;Industrial Accidents;Infection;Inflammation;Inflammatory;Injury;Inositol;Irritants;Knock-out;Lead;Life;Ligand Binding;Lung;Lung Inflammation;Lung Injury Acute;Measures;Mediating;Mediator of activation protein;Mice Knockout;Modeling;Morbidity - disease rate;Natural Disasters;Neuropeptide Receptor;Neuropeptides;Nose;Numbers;Outcome;Paper;Pathway interactions;Peptides;Phosphodiesterase Inhibitors;Phospholipase;Phospholipase C;Plastics;Platelet Activating Factor;Poisons;Population;Process;Production;Property;Prostaglandins;Proteins;Pulmonary Edema;RNA Small Interfering;Ras/Raf;Research;Research Personnel;Respiratory System;Role;Route;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Solvents;Stimulus;Substance P;Substance P Receptor;Testing;Text;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;United States;Up-Regulation (Physiology);base;cell injury;chemical release;chlorine gas;design;drinking water;established cell line;improved;in vivo;injured;lung injury;mouse model;novel;peptide G;prevent;programs;protective effect;protein function;receptor;receptor coupling;repaired;research study;respiratory;response;surfactant;therapeutic target;toxicant;transcription factor;tripolyphosphate


application_id: 7559564
project_number: 7R03TW007813-03
project_title: Modeling of Hantavirus Reservoirs in Brazil
administering_ic: FIC
award_notice_date: 2009-06-24
opportunity_number: PAR-05-072
application_type: 7
activity_code: R03
ic: TW
serial_number: 007813
program_official: SINA, BARBARA J
project_start_date: 2007-03-20
project_end_date: 2010-12-31
study_section: International and Cooperative Projects - 1 Study Section[ICP1]
contact_pi_person_id: 1871909
contact_pi: JONSSON, COLLEEN B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The parent R01 grant for this proposal "Land Cover Change in the Chaco and Interior Atlantic Forest (IAF) in Paraguay on Hantavirus Ecology " is testing the hypothesis that the rapid anthropogenic land cover change occurring in Paraguay will have a direct impact of ecosystem viability and biodiversity and therefore will affect rodent-hantavirus ecology. From 2003 to present Brazil has reported 670 cases. In the Brazilian Department where we propose the research to take place there were 40 cases (Pincelli et al. 2003). Extension of this project to Brazil will build several important capacities. They include: 1. Approaches and methods in geospatial model building. 2. Approaches and methods in capturing rodents and taking samples from rodents which may harbor possible serious human diseases. 3. Approaches and methods toward general daily work with Hantavirus a BSL3 and isolation of viruses from the Brazilian samples. 4. Training and research opportunities for. Paraguayan scientists at the BSL3 facility in Riberao Preto. The specific aims of the research and capacity building include: Aim 1: To characterize the temporal dynamics of rodent population changes at selected sites in Brazil; Aim 2. To isolate Hantaviruses from the rodents collected in Aim 1 as well as to characterize their prevalence in rodents; Aim 3: To model the relationship between landscape and hantavirus occurrence in human cases in Brazil. Importantly the objectives reached in aims 1 and 2 will permit analyses of the human infections in further depth and this information will be added to the modeling in Aim 3. Currently in Latin America the vast majority of the Hantaviruses that have been identified have not been isolated. Hence physicians and public health workers do not know to what virus their patient was exposed. In Latin America this is an important part of the clinical picture because of the presence of numerous strains of Hantavirus circulating in close or overlapping proximity. To truly understand the impact of the virus on human health further diagnosis of the patient for the virus strain through neutralization assays will be valuable. As in the US Brazil is building BSL3 facilities that can accommodate this work. Isolation of the viruses and the neutralization test requires working with live virus at BSL3. A major effort of this grant will be to transfer the technology to build the BSL3 capacity.

project_terms:
Affect;Antibodies;Applications Grants;Area;Biodiversity;Biological Assay;Blood;Brazil;Cells;Clinical;Data;Databases;Diagnosis;Disease;Ecology;Ecosystem;Environment;Grant;Habitats;Hantavirus;Hantavirus Infections;Health;Human;Incidence;Individual;Infection;Information Systems;Investigation;Latin America;Life;Location;Longitudinal Studies;Maps;Methods;Modeling;Monitor;Movement;Neutralization Tests;Paraguay;Parents;Patients;Phylogenetic Analysis;Physicians;Population;Prevalence;Procedures;Property;Reporting;Reproduction;Reproductive History;Research;Research Personnel;Research Training;Rodent;Sampling;Scientist;Series;Site;Specimen;Technology Transfer;Testing;Time;Training;Virus;Visit;Work;anthropogenesis;base;biosafety level 3 facility;experience;forest;human disease;land cover;multidisciplinary;public health medicine (field);transmission process;viral RNA


application_id: 7559533
project_number: 5R01CA119028-05
project_title: Mechanisms of As-Induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2008-12-11
application_type: 5
activity_code: R01
ic: CA
serial_number: 119028
program_official: POLAND, ALAN P
project_start_date: 2006-02-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-E(02)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-01-01
project_abstract:
DESCRIPTION (provided by applicant): Arsenic (As) is a well-documented human carcinogen. Environmental and occupational exposures to As-containing compounds are major public health issues. Understanding the mechanism of As-induced carcinogenesis is very important for early detection for risk assessment for establishment of an exposure standard and for development of intervention and prevention strategies. While increasing evidence has linked arsenic exposure and generation of reactive oxygen species (ROS) we do not clearly understand the exact nature of the specific reactive species the source and mechanism of ROS generation the sequence of formation of different reactive species and the specific species that are responsible for the arsenic-induced carcinogenesis. The goal of this proposal is to test the hypothesis that As-induced carcinogenesis is mediated by oxidative stress. To test this hypothesis we will: (a) identify the molecular mechanism of As-induced ROS generation in cells with emphasis on 02.- radical generation since this radical is a precursor of other reactive oxygen species; (b) develop and apply an in vivo electron spin resonance (ESR) method for detection and identification of As-induced free radical generation in living animals; (c) determine oxidative stress lipid peroxidation protein oxidation and oxidative DNA damage following As exposure in vivo; and (d) elucidate the role of oxidative stress in Cr(VI)-induced cell transformation and tumorigenesis. We will use As-treated HaCat cells to examine As-induced tumorigenesis in athymic nude mice and investigate the involvement of specific ROS species. We anticipate that As generates ROS which cause activation of NF-KB and activator protein (AP-1) leading to tumorigenesis in nude mice. The methods used in the proposal are multi-disciplinary representing a combination of physical chemical and molecular approaches. The results obtained from this proposal will provide a fundamental understanding concerning the role of ROS in As-induced carcinogenesis.

project_terms:
3-nitrotyrosine;Animal Model;Animals;Antioxidants;Arsenic;Biology;Carcinogens;Cells;Chemicals;Chronic;Confocal Microscopy;DNA Damage;Detection;Development;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental and Occupational Exposure;Exposure to;Free Radicals;Generations;Glutathione Disulfide;Goals;Health;Human;Hydroxyl Radical;Intervention;Kidney;Life;Link;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of urinary bladder;Measures;Mediating;Medicine;Methods;Molecular;Nature;Nude Mice;Oxidative Stress;Play;Post-Translational Protein Processing;Prevention strategy;Protein Overexpression;Proteins;Reaction;Reactive Oxygen Species;Research Personnel;Risk Assessment;Role;Signaling Protein;Skin;Skin Carcinogenesis;Source;Spin Trapping;Superoxide Dismutase;Superoxides;Techniques;Testing;Tumorigenicity;cancer risk;carcinogenesis;catalase;cell injury;cell transformation;chromium hexavalent ion;design;free radical oxygen;glutathione peroxidase;in vivo;inhibitor/antagonist;keratinocyte;oxidation;oxidative DNA damage;programs;public health medicine (field);response;therapy development;tumor;tumorigenesis


application_id: 7559008
project_number: 5R01AI064421-04
project_title: Analyzing and modulating immunoregulatory defects in autoimmune disease.
administering_ic: NIAID
award_notice_date: 2008-12-16
application_type: 5
activity_code: R01
ic: AI
serial_number: 064421
program_official: ESCH, THOMAS R
project_start_date: 2006-01-01
project_end_date: 2010-12-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-01-01
project_abstract:
Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimrnunity.Although the thymus appears to be a major site of CD4+CD25+ T cell development it is stillunclear whether there are also peripheral sites of development. We have found recently thatCD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in theperiphery. Conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells may be a veryimportant mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenanceand a defect in this process could contribute to autoimmune disease development. We havefound that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in thethymus but a significantly lower percentage in the periphery. Furthermore NOD CD4+CD25"Tcells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function stronglysuggesting that NOD mice may have a defect in this conversion process and may therefore beunable to maintain this regulatory population. The central hypothesis of this proposal is thatenhanced conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD micecan prevent diabetes. We will test this hypothesis by studying the mechanisms and defects inconversion in NOD mice determinewhether this process can be restored and whether restorationis associated with amelioration of disease. By understanding the defects in conversion ofCD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice it may be possible todevise strategies to overcome these defects andthereby develop therapies to prevent or treatautoimmune disease.

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


application_id: 7559003
project_number: 5R01AI071047-02
project_title: Adjuvant Functions of Detoxified LPS
administering_ic: NIAID
award_notice_date: 2009-01-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 071047
program_official: LEITNER, WOLFGANG W
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adjuvant;Adoptive Transfer;Agonist;Antibody Formation;Antigens;B-Lymphocytes;Bioterrorism;CD4 Positive T Lymphocytes;CD8B1 gene;Clinical;Clonal Expansion;Communicable Diseases;Data;Detection;Development;Endotoxins;Europe;Event;Glycogen Synthase Kinase 3;Human;Immune response;Immune system;Inflammatory;Knowledge;Lymphoid Cell;Maintenance;Mediating;Memory;Memory B-Lymphocyte;Modeling;Molecular;Mus;Parents;Pathway interactions;Poxviridae;Property;Publishing;Relative (related person);Research Personnel;Role;Science;Signal Pathway;Signal Transduction;Structure;Subunit Vaccines;T memory cell;T-Lymphocyte;TLR4 gene;Testing;Toxic effect;Transgenic Model;United States;Vaccination;Vaccine Adjuvant;Vaccines;Variant;Work;aluminum sulfate;base;cytokine;design;diphosphoryl lipid A;improved;in vivo;interest;macrophage;monocyte;monophosphoryl lipid A;next generation;novel vaccines;prophylactic;public health medicine (field);response;safety testing;success


application_id: 7558916
project_number: 5R01HL082835-02
project_title: The role of Prostaglandin E2 in Angiotensin II-induced vascular disease
administering_ic: NHLBI
award_notice_date: 2009-03-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 082835
program_official: TOLUNAY, ESER
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abdomen;Abdominal Aortic Aneurysm;Agreement;Aneurysm;Angiotensin II;Apolipoprotein E;Applications Grants;Atherosclerosis;Attenuated;Binding (Molecular Function);Biological;Blood Vessels;Cardiovascular Diseases;Cells;Chronic;Coxibs;Data;Development;Dinoprostone;Disease;EP4 receptor;Endothelial Cells;Epoprostenol;Epoprostenol Receptors;Event;Functional disorder;Hematopoietic;Human;In Vitro;Incidence;Inflammation;Inflammation Mediators;Inflammatory;Infusion procedures;Matrix Metalloproteinases;Mediating;Mus;Normal tissue morphology;Pathway interactions;Peritoneal Macrophages;Play;Production;Promotor (Genetics);Prostaglandin H2;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Prostaglandins I;Protein Isoforms;Publishing;Role;Smooth Muscle Myocytes;Staging;Suggestion;Tamoxifen;Testing;Therapeutic;Tissues;Vascular Diseases;abdominal aorta;attenuation;autocrine;cardiovascular risk factor;cyclooxygenase 2;cytokine;in vivo;low density lipoprotein inhibitor;macrophage;paracrine;prostaglandin E synthase;prostaglandin E synthase-1;protective effect;receptor;response


application_id: 7558619
project_number: 7R03AR052904-03
project_title: Lck activity in autoimmune TSAD-deficient mice
administering_ic: NIAMS
award_notice_date: 2008-02-11
opportunity_number: PAR-04-002
application_type: 7
activity_code: R03
ic: AR
serial_number: 052904
program_official: MANCINI, MARIE
project_start_date: 2006-07-01
project_end_date: 2009-06-30
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;Autoimmune Diseases;Autoimmune Process;Binding (Molecular Function);Complex;Development;Event;Goals;Interleukin-2;Laboratories;Lead;Lymphocyte;Lymphocyte Specific Protein Tyrosine Kinase p56(lck);Molecular;Molecular Conformation;Mus;N-terminal;Pathology;Production;Proteins;Regulation;Research;SH3 Domains;Signal Transduction;Signaling Molecule;T-Cell Activation;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Thymocyte Development;Tyrosine Kinase Domain;adapter protein;immunological synapse;in vivo;member;novel;src-Family Kinases


application_id: 7558568
project_number: 5F32CA126294-04
project_title: Identification of Colon Cancer Genes Via Retrotransposon Mutagenesis
administering_ic: NCI
award_notice_date: 2008-09-10
application_type: 5
activity_code: F32
ic: CA
serial_number: 126294
program_official: JAKOWLEW, SONIA B
project_start_date: 2006-09-30
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1-F09-K(20)L]
contact_pi_person_id: 6843229
contact_pi: MADISON, BLAIR BERNARD
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: 2008-09-30
budget_end_date: 2009-04-30
assistance_listing_number: 93.398
project_abstract:
DESCRIPTION (provided by applicant):  Mutations caused by DNA damage in the cell is a major cause of cancer. Familial mutations in colorectal cancer (CRC) account for less than 3% of all CRC cases while other key tumor suppressors or proto-oncogenes remain unidentified. For sporadic CRC pinpointing the causative mutation(s) within a cancer containing many mutations and epigenetic modifications is also incredibly difficult. Thus it is likely that many genetic modifiers and causative mutations remain unidentified. Recent developments of mutagenesis strategies in the mouse now make it possible to rapidly identify causative mutations and modifiers involved in carcinogenesis. The objectives of this proposal are (1) to develop a transgenic mouse model of colorectal cancer through random insertional mutagenesis in the intestinal epithelium and (2) to identify novel cancer modifier genes within a mouse model of CRC. Genes to be identified include novel cancer genes and pathways modifiers of APC/Wnt signaling and synergistic or cooperative mutations. This proposal details a novel forward genetics approach using a transgenic L1 retrotransposon mutagenesis system. Two mutagenic L1 cassettes will be used in this proposal: one containing a small bidirectional splice acceptor gene trap for interruption of gene expression (LOF module) and one containing a constitutive promoter and splice donor for over-expression of possible oncogenes (GOF module). Both transgene cassettes will employ the mouse Vil1 (Villin) promoter. This promoter is unique in its ability to drive specific high-level copy-number dependent expression throughout the entire intestinal epithelium: in stem cells progenitors and differentiated cells. Polyps from a transgenic mouse can be harvested and mutations readily identified by ligation-mediated PCR of genomic DNA or by 3' RACE of RNA. Relevance: This proposal describes a method employing powerful genetic tools developed in the mouse for specifically targeting the intestinal epithelium the tissue where colorectal cancer originates. This approach can potentially identify hundreds of cancer gene mutations in a single mouse as opposed to traditional methods where only one gene is mutated in a single mouse. Thus one can rapidly identify many mutations that have the ability to cause colorectal cancer. This may uncover new mechanisms for how cancer initiates.

project_terms:
Accounting;Cancer Etiology;Cancer Gene Mutation;Cells;Colon Carcinoma;Colorectal Cancer;DNA;DNA Damage;Development;Enhancers;Epigenetic Process;Gene Expression;Genes;Genetic;Genetic Markers;Genomics;Harvest;Interruption;Intestines;Lesion;Ligation;Location;Malignant Neoplasms;Mediating;Methods;Mice Transgenic;Modification;Multipotent Stem Cells;Mus;Mutagenesis;Mutagenesis Insertional;Mutate;Mutation;Numbers;Oncogenes;Oncogenic;Pathway interactions;Polymerase Chain Reaction;Polyps;Promotor (Genetics);Property;Proto-Oncogenes;RNA;RNA Splicing;Race;Retrotransposition;Retrotransposon;Signal Transduction;Stem cells;Structure of intestinal epithelium;Structure of intestinal gland;System;Thinking function;Tissues;Transgenes;Transgenic Organisms;Tumor Suppressor Proteins;adenoma;carcinogenesis;gain of function;loss of function;mouse model;novel;polyposis;progenitor;tool;transgene expression;villin


application_id: 7558559
project_number: 5K23DE015298-04
project_title: Central Pain Processing in Chronic Face Pain:fMRI Study
administering_ic: NIDCR
award_notice_date: 2008-12-17
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015298
program_official: HARDWICK, KEVIN S
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7351795
contact_pi: DE LEEUW, RINSKJE
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal for a K23 "Mentored Patient-Oriented Research Career Development Award" will provide thecandidate with five years of continuous funding to gain a broad knowledge in the design and conduct ofcomplex clinical oral health trials. This training will enhance the research environment of the Orofacial PainCenter and mentoring capacity of the University of Kentucky College of Dentistry. The candidate earned aPhD in General Medicine from the University of Groningen and received three years of postgraduategraduate training in Orofacial Pain at the University of Kentucky. This award would allow the candidate toevolve to an independent investigator and would prepare the candidate to successfully mentor MS and PhDcandidates in orofacial pain research. The training program consists of two phases: a didactic componentemphasizing courses in research design biostatistics data analysis and epidemiology and a researchphase involving a neuroimaging investigation of central pain processing in patients with chronic face pain.Three specific aims are proposed in this training application: Specific Aim 1. To assess the presence of painaugmentation in patients with chronic masticatory myofascial pain; Specific Aim 2. To investigate differencesin location and extent of activation of brain regions involved in trigeminal pain processing between patientswith chronic masticatory muscle pain and pain-free volunteers; and Specific Aim 3. To investigate theinfluence of estrogen level on cerebral activation in response to an acute experimental pain stimulus inpatients with chronic masticatory muscle pain and pain-free volunteers. Dr. Charles Carlson PhD ProfessorDepartments of Psychology and Oral Health Science and research director of the Orofacial Pain Center andDr. Don Gash PhD Alumni Professor and Chair Department of Anatomy and Neurobiology and director ofthe Magnetic Resonance Imaging and Spectroscopy Center will mentor the candidate. There is limitedinformation on cerebral activation in response to stimulation of trigeminal structures in healthy pain-freevolunteers as well as in chronic face pain patients. The available data support that there are importantdifferences in the cerebral processing of pain in chronic pain patients compared to pain-free subjects.Moreover the existing data suggest that in chronic pain conditions the medial pain system the structuresassociated with the processing of the emotional-affective component of pain exhibits altered activity.Additionally there is a lack of information about the influence of estrogen on the central processing of pain.The available data suggest that estrogen may have an inhibitory / anxiolytic effect on the perception of painpossibly by modulating the endogenous opioid system. Because neuroimaging data on this topic are scarceand chronic pain conditions are predominant in women of reproductive age the role of estrogen on painshould be further explored.

project_terms:
Acute;Acute Pain;Affective;Age;Anatomy;Animals;Anterior;Anti-Anxiety Agents;Anxiety;Area;Award;Awareness;Biometry;Brain;Brain region;Burn injury;Burning Mouth Syndrome;Cerebrum;Chronic;Clinical;Complex;Data;Data Analyses;Dentistry;Diagnosis;Doctor of Philosophy;Emotional;Endogenous Opiates;Environment;Epidemiology;Estrogens;Exhibits;Facial Pain;Female;Functional Magnetic Resonance Imaging;Funding;Gonadal Steroid Hormones;Head and neck structure;Human;Hyperalgesia;Investigation;Kentucky;Knowledge;Limbic System;Location;Magnetic Resonance Imaging;Mandible;Masticatory muscles;Measures;Medial;Medicine;Menstruation;Mentored Patient-Oriented Research Career Development Award;Mentors;Monitor;Mouth Diseases;Musculoskeletal Diseases;Musculoskeletal Pain;Myalgia;Neurobiology;Oral health;Orofacial Pain;Pain;Pain Clinics;Pain Research;Pain Threshold;Pain management;Pain-Free;Participant;Patients;Pattern;Perception;Phase;Prefrontal Cortex;Process;Protocols documentation;Psychology;Reporting;Research;Research Design;Research Personnel;Role;Scanning;Sensory;Serum;Signal Transduction;Somatosensory Cortex;Spectrum Analysis;Stimulus;Stress;Structure;System;Temperature;Testing;Thalamic structure;Training;Training Programs;Trigeminal Neuralgia;Trigeminal System;Trigeminal nerve structure;Universities;Woman;base;central pain;chronic pain;cingulate cortex;cold temperature;college;design;experience;health science research;masticatory myalgia;mechanical pressure;neuroimaging;pressure;professor;reproductive;response;volunteer


application_id: 7558546
project_number: 5U10NS053368-04
project_title: Neuroprotection Exploratory Trials in PD (NET-PD)
administering_ic: NINDS
award_notice_date: 2009-02-19
opportunity_number: RFA-NS-05-004
application_type: 5
activity_code: U10
ic: NS
serial_number: 053368
program_official: MOY, CLAUDIA S
project_start_date: 2006-05-17
project_end_date: 2010-11-30
study_section: ZNS1-SRB-K(30)
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Affect;Age;Age of Onset;Anxiety;Area;Autonomic Dysfunction;Back;Basal Nucleus of Meynert;Bradykinesia;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Communities;Corpus striatum structure;County;Deterioration;Diagnosis;Disease;Disease Progression;Dopamine;Double-Blind Method;Enrollment;Environmental Risk Factor;Etiology;Functional disorder;Futility;Gait;Gait abnormality;Genetic;Impaired cognition;Incidence;Individual;Kentucky;Lead;Life Style;Motor;Motor Manifestations;Movement Disorders;Multicenter Trials;Muscle Rigidity;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neuroprotective Agents;Occupations;Ohio;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pigments;Productivity;Request for Applications;Residual state;Rest Tremor;Rural;Signs and Symptoms;Smell Perception;Staging;Substantia nigra structure;Symptoms;Synapses;Testing;Thinking function;Time;Toxic Environmental Substances;Toxin;Universities;West Virginia;career;depression;disability;dopamine system;efficacy testing;executive function;functional disability;locus ceruleus structure;neuropathology;neuroprotection;nigrostriatal system;pars compacta;pilot trial;placebo controlled study;putamen;raphe nuclei;repaired


application_id: 7554619
project_number: 5R21HL089372-02
project_title: Oxidoreductase Activity of the Beta Subunit of Kv Channels
administering_ic: NHLBI
award_notice_date: 2009-01-21
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: HL
serial_number: 089372
program_official: WANG, LAN-HSIANG
project_start_date: 2008-01-15
project_end_date: 2010-12-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 8759282
contact_pi: BARSKI, OLEG A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to define the catalytic properties of the -subunit of the voltage-sensitive potassium channel (Kv). The Kv channels regulate cell excitability and have been shown to play an important role in oxygen-sensing volume regulation memory and learning. The Kv proteins are ancillary proteins that associate with the cytoplasmic domain of Kv channels but no clear physiological function has been assigned to these proteins. Structural and sequence analyses show that Kv proteins are members of the aldo-keto reductase superfamily. Our central hypothesis is that the Kv proteins catalyze the reduction of endogenous carbonyls whereby they impart redox sensitivity to Kv currents. Such regulation may be an important feature of oxygen-sensing or metabolic dependence of Kv currents. To test this hypothesis we will measure the catalytic efficiency of Kv proteins with endogenous substrate series consisting of prostaglandins steroids metabolites of neurotransmitters and lipid peroxidation products. We will also test whether assembly of Kva- complexes enhance enzymatic activity of Kv and determine the sequence and rate-limiting step in its catalytic cycle (Aim 1). To determine whether the endogenous carbonyls utilized by Kv in biochemical experiments are also functionally active we will examine the ability of the most efficient series to alter the voltage-sensitivity and the kinetics of Kva- channels expressed in COS-7 cells (Aim 2). Results of these experiments will allow us to distinguish whether nucleotide binding itself catalytic cycle or binding of ligands which can serve as pharmacologic agents modulate Kv inactivation. Taken together the findings of this study will provide a better understanding of the catalytic and ligand binding properties of Kv and form the basis of a more in-depth project to examine the in vivo role of Kv catalysis and its putative role in regulating surface excitability oxygen-sensing or encoding memory. Results of these studies could also form the basis of developing pharmacological modulators of Kv-mediated changes in Kv current.

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


application_id: 7546867
project_number: 7R01GM059636-08
project_title: Pseudouridine Synthases
administering_ic: NIGMS
award_notice_date: 2008-01-06
application_type: 7
activity_code: R01
ic: GM
serial_number: 059636
program_official: IKEDA, RICHARD A
project_start_date: 1999-08-01
project_end_date: 2008-11-30
study_section: Physical Biochemistry Study Section[PB]
contact_pi_person_id: 1925871
contact_pi: MUELLER, EUGENE G
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-07-31
project_abstract:
DESCRIPTION (provided by applicant): Pseudouridine is the most common post-transcriptional modification of RNA and arises from the isomerization of uridine catalyzed by the pseudouridine synthases. These enzymes fall into four families that share no global sequence similarity but appear homologous on the basis of their tertiary structures. Several pseudouridine synthases are physiologically critical in prokaryotes and eukaryotes including the human enzyme dyskerin the absence of which causes the X-linked disease dyskeratosis congenita. Pseudouridine residues in small nuclear RNA are required for pre-mRNA splicing an essential function in eukaryotes. Since the families of pseudouridine synthases are so highly divergent it remains possible that they proceed by different mechanisms and such differences may eventually be exploited in new classes of antibiotics or provide a better understanding of the disease dyskeratosis congenita. The proposed experiments will elucidate the chemical mechanism followed by two E. coli pseudouridine synthases of different families RluA and TruB which are particularly tractable targets for mechanistic work because they handle small RNA substrates (stem-loop oligonucleotides). RNA containing 5-fluorouridine has been used as an inhibitor and mechanistic probe of the pseudouridine synthases favoring a mechanism involving a Michael addition. Recent results however indicate that TruB is not inhibited by 5-fluorouridine in RNA and that an assumed hydrolysis of a proposed intermediate does not occur leading to doubt concerning the mechanistic conclusions based on earlier studies with the same compound. The proposed experiments will resolve issue concerning 5-fluorouridine in RNA and allow further mechanistic insight. Such insight will also be gained using RNA containing uridine with a 2'-fluoro group similar to the series of remarkably informative experiments using fluorosugars to probe the mechanism of glycosidases. A combination of NMR mass spectrometry site-directed mutagenesis and kinetic analysis supplemented by X-ray crystallography will be employed to examine the effects of the two types of fluorinated RNA as well as site-directed mutagenesis of amino acid residues that appear to play a role in catalysis. Finally synthesized small RNA substrates will be used to examine the substrate specificity of RluA.

project_terms:
5 fluorouridine;Address;Amino Acids;Antibiotics;Anticodon;Behavior;Binding (Molecular Function);Catalysis;Chemicals;Class;Crystallography;Crystallography X-Ray;Disease;Dyskeratosis Congenita;Enzymes;Escherichia coli;Eukaryota;Eukaryotic Cell;Event;Family;Fluorine;Glycoside Hydrolases;Heterogeneous Nuclear RNA;Human;Hydrolysis;Investigation;Kinetics;Link;Methods;Mutagenesis Site-Directed;Oligonucleotides;Physiological;Play;Positioning Attribute;Prokaryotic Cells;Pseudouridine;Pyrimidine;Pyrimidines;RNA;RNA Processing Post-Transcriptional;RNA Splicing;RNA-Protein Interaction;Reaction;Research Personnel;Ribose;Role;Series;Side;Small Nuclear RNA;Small RNA;Specificity;Spectrum Analysis Mass;Structure;Substrate Specificity;Testing;Transfer RNA;Uncertainty;Uridine;Work;base;chemical kinetics;falls;inhibitor/antagonist;insight;mRNA Precursor;programs;research study;stem


application_id: 7545600
project_number: 1F31DA025424-01
project_title: Transdermal Delivery of Hydroxyphenylarachidonylamides
administering_ic: NIDA
award_notice_date: 2008-07-16
application_type: 1
activity_code: F31
ic: DA
serial_number: 025424
program_official: PARK, MOO KWANG
project_start_date: 2008-07-17
project_end_date: 2010-07-16
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 9288396
contact_pi: SWADLEY, COURTNEY LEAH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-17
project_abstract:
DESCRIPTION (provided by applicant):  A patch for transdermal cannabinoid delivery could be therapeutically important in the reduction of chronic pain especially for patients who can't get pain relief from traditional treatments. Addition of a cannabinoid patch to a patient's standard pain-relief regimen could enhance analgesia because this class of drugs works by a different antinociceptive mechanism. Release of endocannabinoids (eCBs) such as anandamide (AEA) occurs in response to injury to relieve pain and inflammation. Inhibitors of eCB degradation mechanisms and transporters such as AM404 have been developed to induce and prolong the effects of the eCBs in situations of injury-induced pain and inflammation. Endocannabinoid and inhibitor compounds are clinically interesting because they initiate therapeutic effects via cannabinoid (CB) receptors without producing the side effects common to traditional cannabinoid agonist compounds such as THC. N-(4- hydroxyphenyl) arachidonoylamide (AM404) has been shown to relieve neuropathic pain and reduce alcohol consumption and anxiety in animals. N-arachidonoyl dopamine (NADA) is an eCB that acts at the CB receptor 1 which is associated with pain and emesis reduction. Transdermal delivery has numerous advantages over other drug delivery methods such as bypassing first-pass metabolism extended controlled drug release and the added ability for patients to self-administer the drug pain-free. NADA and AM404 present a challenge for transdermal delivery because of their high lipophilicity and enzymatic/chemical instability. The goal of this project is to improve the transdermal delivery of the hydroxyphenylarachidonylamides NADA and AM404. We propose to synthesize hydrophilic prodrugs of these compounds to promote their delivery across the skin barrier and possibly increase their stability. The additional phenolic hydroxyl in NADA will allow us to evaluate the effect of disubstituted prodrugs as compared to monosubstituted prodrugs of the AM404 structure. The proposed hydrophilic prodrugs will be useful in investigating quantitative-structure-permeability relationships (QSPR) of transdermal flux used to develop and improve delivery strategies for highly lipophilic compounds. The specific aims for this project are: (1) to study the diffusion and metabolism of NADA and AM404 across the skin barrier (2) to synthesize a series of prodrugs for transdermal flux optimization (3) to measure the penetration/concurrent bioconversion of the prodrugs through human skin in vitro and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo. Correlation of our in vitro data with the in vivo model will aid in developing a QSPR database for transdermal prodrugs.

project_terms:
AM404;Absence of pain sensation;Adverse effects;Agonist;Alcohol consumption;Analgesics;Animals;Anxiety;Blood Circulation;Bypass;Cannabinoids;Cavia;Chemical Structure;Chemicals;Class;Data;Databases;Diffusion;Dopamine;Drug Controls;Drug Delivery Systems;Drug Kinetics;Endocannabinoids;Goals;Heating;Human;Hydrogen Bonding;Hydroxyl Radical;In Vitro;Inflammation;Injury;Knowledge;Measures;Metabolism;Methods;Molecular;Molecular Weight;Mono-S;Pain;Pain-Free;Patients;Penetration;Permeability;Pharmaceutical Preparations;Prodrugs;Property;Protocols Treatment;Rate;Research;Self-Administered;Series;Skin;Solubility;Solvents;Standards of Weights and Measures;Structure;System;Therapeutic Effect;Vomiting;Work;anandamide;cannabinoid receptor;chronic pain;design;hydroxyl group;improved;in vivo;in vivo Model;inhibitor/antagonist;interest;lipophilicity;melting;painful neuropathy;response to injury;tool


application_id: 7544622
project_number: 7R21HL083225-03
project_title: Assessment of Muscle Vascular Disease with Diffuse Light
administering_ic: NHLBI
award_notice_date: 2008-03-20
opportunity_number: PA-03-058
application_type: 7
activity_code: R21
ic: HL
serial_number: 083225
program_official: BUXTON, DENIS B
project_start_date: 2006-02-15
project_end_date: 2010-01-30
study_section: Special Emphasis Panel[ZRG1-CICS(01)Q]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Individuals with chronic critical limb ischemia (CCLI) suffer from microvascular disease that negativelyimpacts the success of interventions for limb salvage. Current diagnostic tools are largely limited toassessing blood flow within large vessels. The ultimate goal of this project is to develop a non-invasiveoptical probe for imaging of microcirculation and tissue metabolism in patients with CCLI. SPECIFIC AIMS:(1) Modify a multi-modal optical instrument for integration with Arterial Spin Labeling MRI. (2) Cross-validation of optical blood flow and MRI perfusion in human muscles. (3) Quantify muscle blood flowoxygenation and oxygen consumption in patients with CCLI and correlate these variables with acceptedvascular testing parameters. RESEARCH DESIGN AND METHODS: The lack of portable noninvasivetechnologies for monitoring of both blood flow and oxygenation in the deep microcirculation has led us todevelop a hybrid optical probe combining for the first time diffuse correlation spectroscopy (DCS) forstudies of tissue blood flow with diffuse reflectance spectroscopy (DRS) for studies of tissue oxygenation.DRS has been validated in a few studies of deep muscle tissues. The same cannot be said for DCS. Theproposed simultaneous MRI/Optical investigation of reactive hyperemia in normal human muscle will validateDCS and explore possible uses of the combined information for accurate analysis of tissue physiology. Forthis purpose a new non-metallic optical probe will be designed and tested to adapt to the MRI. Correlationsof the two simultaneous measurements will be investigated. After validating the DCS flow the firstsimultaneous all-optical measurements of blood flow and oxygenation will be conducted in the patients withCCLI during cuff occlusion or exercise. Multiple hemodymamic indices will be constructed from thesemeasured variables and then be correlated with accepted vascular testing parameters such as the Ankle-Brachial Index or Toe-Brachial Systolic Index. RELEVANCE: Current diagnostic techniques are inadequateto offer necessary information for the patients with chronic critical limb ischemia when determining limbsalvage procedures or the extent of amputation causing a serious health concern. The proposed non-invasive portable and inexpensive optical technology may fill in this gap by providing multiple hemodynamicinformation and by enabling continuous measurements at the bed-side and in.ambulatory care.

project_terms:
Adipose tissue;Age;Amputation;Ankle;Beds;Blood;Blood Vessels;Blood flow;Cardiovascular system;Caring;Chronic;Clinical;Condition;Data;Depth;Deterioration;Diabetes Mellitus;Diabetic Angiopathies;Diagnosis;Diagnostic;Diagnostic Procedure;Diffuse;Disease;Environment;Evaluation;Exercise;Forearm;Functional disorder;Gangrene;Goals;Health;Human;Hybrids;Individual;Intermittent Claudication;Intervention;Invasive;Investigation;Ischemia;Leg;Light;Limb Salvage;Limb Salvage Procedure;Limb structure;Magnetic Resonance Imaging;Measurement;Measures;Medical;Metabolism;Microcirculation;Modality;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Noise;Optical Instrument;Optics;Oxygen;Oxygen Consumption;Patients;Perfusion;Peripheral Vascular Diseases;Pes;Physiology;Population;Purpose;Rate;Rehabilitation therapy;Research;Research Design;Research Personnel;Rest;Side;Skin;Skin Tissue;Spectrum Analysis;Spin Labels;Structure;Techniques;Technology;Testing;Time;Tissues;Toes;Validation;Vascular Diseases;Vascular structure of kidney;Walking;Woman;blood flow measurement;cerebrovascular;claudication;cost;design;diabetic;hemodynamics;imaging probe;improved;indexing;interest;magnetic field;men;perfusion (blood);programs;reactive hyperemia;response;success;tissue oxygenation;tissue phantom;tool


application_id: 7544617
project_number: 3P01AG010836-14S1
project_title: Calcium Regulation in Brain Aging & Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2007-12-31
application_type: 3
activity_code: P01
ic: AG
serial_number: 010836
suffix: S1
program_official: SUNEJA, SANOJ
project_start_date: 1998-12-02
project_end_date: 2009-08-31
study_section: ZAG1-ZIJ-3(M3)
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application is for a renewal of a longstanding program project focused on mechanisms and consequences of brain cell calcium (Ca2+) dysregulation in brain aging and Alzheimer's disease (AD). In prior periods the program project has studied the role of steroid hormones (glucocorticoids estrogen vitamin D) in accelerating or retarding aging-induced changes in Ca2+ channels and Ca2+ homeostasis. The program project has also investigated the roles of reactive oxygen species (ROS) AD-related mutations and mitochondrial dysfunction in Ca+2 dysregulation and neuronal vulnerability. Moreover in the past few years new statistical approaches to gene expression analysis as well as gene profiling of tissue blocks and single cells have been introduced into the program project and revealed much wider alterations of neuronal and glial cell biological processes in hippocampal aging and AD brain than was previously recognized. Particularly notable was an upregulation of S100 family of Ca2+ binding molecules. These recent findings emphasize that the perspectives of the program project should be broadened to encompass studies relating Ca2+ dysregulation to other cell biological pathways including glial/inflammatory processes.    In the next phase therefore it is proposed to bring to bear a wide range of multidisciplinary technical  approaches including Ca2+ imaging single channel recording gene microarray analyses proteomics/protein assays behavioral analyses oxidative stress indexes viral mediated gene transfer and in situ hybridization/immunohistochemistry using animal models of aging/AD and human samples to elucidate interactions between Ca2+ dysregulation steroid modulation gene expression cascades oxidative stress and mitochondrial dysfunction in brain aging and AD. In the next phase new projects cores and experimental designs are proposed that will facilitate multidisciplinary collaboration as well as a broader perspective on interactions among multiple cellular processes. Included among these are cores that will support analyses of inflammatory mechanisms and long-term intervention tests of hypotheses arising from individual projects. The multidisciplinary armamentarium now available to the program project should enable us to elucidate and resolve the major questions related to the roles of Ca2+ dysregulation in cellular aging processes in the brain and AD-related pathology.

project_terms:
Accounting;Address;Affect;Age;Aging;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Behavior;Behavioral Assay;Binding (Molecular Function);Biochemical;Biological;Biological Markers;Biological Process;Brain;Budgets;Buffers;Calcium;Calpain;Cell Aging;Cell Death;Cell physiology;Cells;Cellular Structures;Cognitive;Collaborations;Complex;Data;Development;Disease;Electrophysiology (science);Elevation;Estrogens;Experimental Designs;Family;Fire - disasters;Fruit;Functional disorder;Gene Expression;Gene Transfer;Generations;Genes;Glucocorticoids;Goals;Growth Factor;Hippocampus (Brain);Homeostasis;Human;Image;Imaging Techniques;Immunohistochemistry;Impairment;In Situ Hybridization;Individual;Inflammation;Inflammatory;Intervention;Investigation;Knowledge;Laboratories;Measures;Mediating;Microarray Analysis;Microglia;Mitochondria;Modeling;Molecular;Mus;Mutation;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurons;Nitric Oxide Synthase;Oxidative Phosphorylation;Oxidative Stress;Pathology;Pathway interactions;Pattern;Performance;Phase;Physiological;Physiological Processes;Physiology;Play;Process;Program Research Project Grants;Proteins;Proteomics;Range;Rattus;Reactive Oxygen Species;Receptors Steroid;Regulation;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Second Messenger Systems;Signal Pathway;Signal Transduction;Steroids;Study models;Study Interdisciplinary;Sum;Technology;Testing;Tissues;Up-Regulation (Physiology);Ursidae Family;Viral;Vitamin D;Work;age effect;age related;aging brain;base;brain cell;cell type;cholesterol biosynthesis;design;indexing;interdisciplinary approach;middle age;mitochondrial dysfunction;multicatalytic endopeptidase complex;multidisciplinary;normal aging;programs;research study;response;second messenger;steroid hormone;transgenic model of alzheimer disease;voltage


application_id: 7544491
project_number: 5R01NS040592-09
project_title: Axonal growth and guidance for nervous system repair
administering_ic: NINDS
award_notice_date: 2008-12-01
application_type: 5
activity_code: R01
ic: NS
serial_number: 040592
program_official: KLEITMAN, NAOMI
project_start_date: 2000-03-27
project_end_date: 2009-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(02)M]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-01-01
project_abstract:
DESCRIPTION (provided by applicant): Over 50000 peripheral nerve repair procedures are performed a year due to injury (National Center for Health Statistics 1995). These data do not include nerve injury due to tumor resection or prostatectomies. Even though the peripheral nerves regenerate well only 10 to 20% of patients that undergo surgery to repair traumatic nerve injuries show excellent to very good recovery of function. The high incidence of failed recovery is due to the misrouting of regenerating axons to their targets. This proposal is designed to better understand the potential mechanisms that direct this growth to increase functional recovery in adults. The studies will examine the role strategically expressed neurotrophins and chemorepulsive factors will have on directing the growth of sensory and motor axons into appropriate nerve branches or the spinal cord. All the experiments in this proposal will use bioreabsorbable implants to induce nerve repair and targeted gene expression of guidance factors. The first aim of these experiments will explore the use of the neurotrophins GDNF BDNF and NT-3 to induce the regeneration of sensory axon subsets across a 6mm dorsal root lesion gap and into the spinal cord. Behavioral analysis will examine recovery of mechanoreceptive and proprioceptive responses. The second to forth aim of experiments will use the femoral nerve model to examine peripheral nerve targeting after large excision lesions to that nerve. The femoral nerve contains both sensory and motor axons that normally segregate into a sensory branch (saphenous) and a motor branch (quadriceps femoris). After cut injury regeneration is mostly random in which each branch will contain a mixture of both cutanteous sensory and motor axons. The second aim will be to guide sensory axons into the saphenous branch and not the motor branch. In this study selective neurotrophins that are growth attractive for sensory axons will be expressed in the saphenous nerve and repulsive factors that are specifically inhibitory to sensory axons expressed in the motor branch. The third aim will examine neurotrophins and repulsive factors for the selective guidance of regenerating motor and proprioceptive axons into the motor branch and not the saphenous nerve. The forth aim is designed to incorporate the factors from aim 2 and 3 to optimize target directed regeneration to more normal like patterns. This aim will also develop and test clinically relevant bioreabsorbable nerve cuffs for slow release of guidance factors. This grant proposal is designed to better define the molecular mechanisms that influence axonal regeneration and guidance within the adult PNS with the ultimate goal of directing and organizing regeneration to more appropriate targets while discouraging aberrant connections.

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


application_id: 7544277
project_number: 3R01LM008323-03S1
project_title: Histological Reasoning: Visual Cognition in Microanatomy
administering_ic: NLM
award_notice_date: 2007-12-31
application_type: 3
activity_code: R01
ic: LM
serial_number: 008323
suffix: S1
program_official: SIM, HUA-CHUAN
project_start_date: 2005-02-01
project_end_date: 2009-01-31
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 1911606
contact_pi: PANI, JOHN R
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This project is a multidisciplinary study of cognition in the practice of histology the microanatomy oftissues. Histology is a core course in the biological premedical and medical school curricula andpathologists use its methods to diagnose a variety of medical disorders. Instruction in histology centers onthe recognition of tissues in microscopes. This is a very challenging task that takes years to master. Muchof the basis for this difficulty is that the tissue in microscope slides differs substantially in appearance fromthe whole tissue. As a result ability in histology requires the development of high level skills of visualrecognition and reasoning. This project will investigate the current and optimum methods for gainingexpertise in basic histology through a variety of experimental studies. The specific aims of the proposedresearch are the following: 1) Determine the information for human perceivers in microscope slides.Two studies will generate models of the use of diagnostic information in microscope slides for individualswho have completed the first year course in histology. 2) Assess the importance of visuospatialunderstanding of microanatomy for identification of tissues in microscope slides. An experiment willbe conducted to test the hypothesis that the ability to identify structures and tissues in microscope slides willvary directly with the degree to which people have a clear visuospatial understanding of the microanatomy ofthe whole tissue. 3) Assess the importance of visuospatial understanding of the slice transformationfor identification of tissues in microscope slides. An experiment will be conducted to test the hypothesisthat the ability to identify structures and tissues in microscope slides will vary directly with the degree towhich people have a clear visuospatial understanding of the transformation that relates 3D anatomy to 2Danatomical sections. The results of this research will lead to a detailed understanding of cognition inhistology and to advances in theories of visual symbol systems used in the interpretation of imagesgenerated by human technology (e.g. x-ray mri aerial photographs). This project has the potential togenerate substantial change in the methods for developing skill in histology at both the undergraduate andthe medical school levels. The study of virtual reality methods of learning in conjunction with a rigorousstudy of histological reasoning will lead directly to the development of software that may significantlyaccelerate the development of skill in this challenging and important field.

project_terms:
Accounting;Appearance;Area;Biological;Cognition;Complex;Computer Simulation;Computer Systems;Cues;Data;Development;Diagnosis;Diagnostic;Disease;Educational Curriculum;Evaluation;Generations;Histology;Human;Image;Individual;Information Retrieval;Instruction;Knowledge;Label;Lead;Learning;Maps;Medical;Medical Informatics;Memory;Methods;Microanatomy;Microscope;Modeling;Nature;Participant;Pathologist;Perception;Performance;Problem Solving;Psychology;Purpose;Radar;Research;Research Project Grants;Scans MRI;Schools Medical;Science of Anatomy;Slice;Slide;Structure;System;Technology;Testing;Tissue Model;Tissues;Training;Visual;Visuospatial;Work;X-Ray Computed Tomography;base;extrastriate visual cortex;mental imagery;multidisciplinary;neglect;research study;skills;software development;theories;two-dimensional;virtual reality;visual cognition


application_id: 7541566
project_number: 1R13NS063612-01
project_title: 26th National Neurotrauma Symposium 2008
administering_ic: NINDS
award_notice_date: 2008-06-18
opportunity_number: PA-06-041
application_type: 1
activity_code: R13
ic: NS
serial_number: 063612
program_official: KLEITMAN, NAOMI
project_start_date: 2008-07-01
project_end_date: 2009-05-31
study_section: Special Emphasis Panel[ZNS1 SRB-W (30)]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  We are requesting support for basic science graduate students medical students residents and postdoctoral fellows to participate in the 26th annual National Neurotrauma Symposium to be held July 27-30 2008 in Orlando (Lake Buena Vista) Florida. The National Neurotrauma Symposium is the primary forum for the presentation of current research on the pathophysiology and treatment of central nervous system injury (spinal cord injury traumatic brain injury). The symposium this year is being co-sponsored and organized by the National Neurotrauma Society and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Neurotrauma & Critical Care. The Specific Aims of the symposium are: 1. To provide a forum for the presentation discussion and feedback regarding the most recent findings in Neurotrauma research and to encourage interaction between junior and senior investigators in the field. 2. To encourage the participation and education of students studying in the field of Neurotrauma. The Symposium fosters student participation through large poster sessions student oral open communication sessions student poster competition social mixers student travel awards and subsidized student registration fees. 3. To make the meeting more relevant to clinical neurotrauma researchers to increase the real world neurotrauma knowledge base for basic neurotrauma scientists and thereby enhance basic-clinical interactions and translationally-focused two way collaboration ("Bench to Bedside" and "Bedside to Bench"). 4. To continue to encourage the involvement and advancement of women minority groups and persons with disabilities in Neurotrauma research. The Symposium is the forum for scientific and social activities hosted by Women in Neurotrauma Research the professional society for women in clinical and laboratory Neurotrauma research. 5. To have relevant and thought-provoking presentations by researchers not directly involved in Neurotrauma research. The goal is to foster new ideas and ways of thinking into mainstream Neurotrauma as well as to encourage scientist from other disciplines to engage in Neurotrauma research. The program for the 2008 symposium will feature 38 invited speakers 12 oral presentations by selected student/postdoctoral abstracts 4 poster sessions (two SCI two TBI) with a total of 350 posters and a student poster competition. The symposium will foster basic and translational neurotrauma research that will lead to new techniques for the treatment of patients afflicted with brain and spinal cord injury. PUBLIC HEALTH RELEVANCE: The direct relevance of this project to the public health rests in the exchange of new ideas and debate generated regarding advancing laboratory findings into clinical practice. Students basic scientists clinician scientists and practicing clinicians come together to present and discuss their latest discoveries and advancements in the filed of Neurotrauma. Particular efforts are made to actively engage students to participate and interact with leading basic and clinical scientists.

project_terms:
American;Award;Basic Science;Brain;Clinical;Collaborations;Communication;Congresses;Critical Care;Disabled Persons;Discipline;Educational aspects;Feedback;Fees;Florida;Fostering;Functional disorder;Goals;Injury of central nervous system;Joints;Laboratories;Laboratory Finding;Lead;Mainstreaming (Education);Minority Groups;Neurologic;Oral;Patients;Postdoctoral Fellow;Research;Research Personnel;Rest;Scientist;Societies;Spinal cord injury;Students;Students Medical;Surgeon;Techniques;Thinking function;Traumatic Brain Injury;Travel;Woman;abstracting;bench to bedside;knowledge base;posters;programs;public health medicine (field);social;social competition;symposium


application_id: 7541306
project_number: 1R13NS063606-01
project_title: 14th Annual KSCHIRT Symposium 2008
administering_ic: NINDS
award_notice_date: 2008-06-10
opportunity_number: PA-06-041
application_type: 1
activity_code: R13
ic: NS
serial_number: 063606
program_official: KLEITMAN, NAOMI
project_start_date: 2008-06-15
project_end_date: 2009-05-31
study_section: Special Emphasis Panel[ZNS1 SRB-W (30)]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The Kentucky Spinal Cord & Head Injury Trust (KSCHIRT) Symposium is an annual meeting of neuroscientists clinicians research fellows and graduate and medical students who are involved in research and treatment of patients suffering from the effects of central nervous system (CNS) trauma. The KSCHIRT Symposium is fast becoming a premier annual meeting of the Neurotrauma community. This Symposium provides basic scientists and clinicians a rare opportunity to meet and discuss questions related to the neuropathophysiology of brain and spinal cord injury the latest in neuroprotective strategies as well as mechanisms of recovery. This symposium is unique not only the subject matter covered but the diversity of the attendees. The KSCHIRT Symposium is organized on a biyearly basis by the University of Kentucky Spinal Cord & Brain Injury Research Center (SCoBIRC) or by our sister organization the Kentucky Spinal Cord Injury Research Center at the University of Louisville. The goal of the University of Kentucky SCoBIRC is promote research on injuries to the spinal cord and brain that result in paralysis or other loss of neurological function. The 2008 14th annual KSCHIRT Symposium will focus specifically on the most cutting edge areas of central nervous system injury and repair including the latest breakthroughs in neuroprostheses. The Specific Aims of the 14th annual Kentucky Spinal Cord & Head Injury Trust Symposium are: 1. To provide a forum for the presentation discussion and feedback regarding the most recent findings in Neurotrauma research and to encourage extensive interaction between those new to the field and those with extensive experience of neurotrauma. 2. To have relevant and thought-provoking presentations by researchers not directly involved in Neurotrauma research. The goal is to foster new ideas and ways of thinking into mainstream Neurotrauma as well as to encourage scientist from other disciplines to engage in Neurotrauma research. 3. To encourage participation and education of students that are entering or studying the field of Neurotrauma. The Symposium fosters student participation through poster sessions meet and greets with the speakers and subsidized student registration fees. 4. To encourage the involvement of researchers from women minority groups and persons with disabilities in neurotrauma research. The program for the 2008 symposium will feature 16 lectures and 2 dedicated posters. Their also dinner that is served the first night of the conference with seating that places students and fellows at tables with the speakers. Lunch is also arranged in this fashion.    PUBLIC HEALTH RELEVANCE: The direct relevance of this project to public health rests in the exchange of new ideas and the debate generated regarding advancing laboratory findings into clinical practice. Students basic scientists clinician-scientists and practicing clinicians are brought together to present and discuss their latest discoveries and advancements in the field in the field of Neurotrauma. Particular efforts are made to actively engage students to participate and interact with leading basic scientists and clinicians in the Neurotrauma field of research.

project_terms:
Area;Brain;Brain Injuries;Clinical;Communities;Craniocerebral Trauma;Disabled Persons;Discipline;Educational aspects;Feedback;Fees;Fostering;Goals;Injury;Injury of central nervous system;Kentucky;Laboratory Finding;Mainstreaming (Education);Minority Groups;Nervous System Physiology;Neuraxis;Paralysed;Patients;Principal Investigator;Recovery;Research;Research Personnel;Rest;Scientist;Sister;Spinal Cord;Spinal cord injury;Students;Students Medical;Thinking function;Trauma;Trust;Universities;Woman;base;experience;field study;injury and repair;lectures;neuroprosthesis;posters;programs;public health medicine (field);symposium


application_id: 7539955
project_number: 5R01GM072756-04
project_title: Dissection and Reconstitution of Human Mismatch Repair
administering_ic: NIGMS
award_notice_date: 2008-12-12
application_type: 5
activity_code: R01
ic: GM
serial_number: 072756
program_official: PORTNOY, MATTHEW
project_start_date: 2006-01-01
project_end_date: 2011-12-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-01-01
project_abstract:
The long-term goal of this project is to understand the molecular mechanism of human mismatch repair(MMR) and its impact on human health and disease. The importance of MMR is underscored by the fact thatdefects in MMR genes lead to genomic instability and eventually to cancer predisposition. Despite the factthat the excision-step of the human MMR reaction has been recently reconstituted using purified proteinsincluding MutS alpha MutL alpha EXO1 and RPA many fundamental questions in MMR still remainunanswered. For example how mismatch-provoked excision initiates and terminates and what role MutLalpha plays in MMR are unknown. Through the reconstitution of the 5' nick-directed human MMR reactionwe found that MutL alpha negatively regulates mismatch-provoked EXO1-catalyzed excision and terminatesit immediately upon mismatch removal. Given the dependency of the EXO1-catalyzed mismatch excision onMutS alpha and physical interactions among EXO1 MutS alpha and MutL alpha we hypothesize thatmismatch-provoked excision is precisely regulated through interactions among these proteins. Specifically inthe presence of a mismatch MutS alpha preferentially interacts with EX01 to promote excision; but theremoval of the mismatch by EXO1 allows EXO1 to preferentially interact with MutL alpha which thenterminates the excision. To test this hypothesis a series of EXO1 MutS alpha MutL alpha mutant proteinsthat disrupt the interaction of EXO1 with one Mut protein but not the other will be constructed expressed andpurified. These mutant proteins will be tested in an in vitro reconstitution system for their ability to performmismatch-provoked excision at the initiation and at the termination. Analysis of the excision intermediates ineach reaction will reveal how the interactions among MutS alpha and MutL alpha and EXO1 regulate aparticular step of the excision reaction. Finally to understand how efficiently the MMR system terminatesmismatch-provoked excision the excision termination sites for heteroduplexes with differentsequencecontents and distances separating the mismatch and the strand break will be precisely determined. Inaddition to revealing the molecular mechanism of mismatch-provoked excision this study will provideimportant clues to understand many puzzling phenomena in mlhl null mutants regarding 5' directed MMRmeiotic cell apoptosis and anti-recombination.

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


application_id: 7538931
project_number: 2R42EY017518-02
project_title: Targeting drug delivery nanoparticles to sites of inflammation
administering_ic: NEI
award_notice_date: 2008-09-08
opportunity_number: PA-07-281
application_type: 2
activity_code: R42
ic: EY
serial_number: 017518
program_official: WUJEK, JEROME R
project_start_date: 2006-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1 BDCN-F (12)]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144375263
duns_number: 144375263
fips: US
organization_id: 10002039
organization_name: POTENTIA PHARMACEUTICALS, INC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this Phase II STTR project is to develop a nanoparticle-based drug delivery system for use in the treatment of dry age-related macular degeneration (AMD). AMD is the leading cause of blindness for individuals over fifty-five years of age that live in the industrialized world affecting approximately 10 million people in the US and as many as 30 million worldwide. There are two forms of the disease both of which cause a loss of central vision. Approximately fifteen percent have wet or exudative AMD which causes rapid disabling blindness. The remaining eighty-five percent of patients have dry AMD a less severe form that produces gradual vision loss. At present there are no approved pharmacological agents approved for the treatment of dry AMD. This project seeks study to develop a "smart" poly-lactic glycolic acid (PLGA) nanoparticle drug delivery system that can home to sites of inflammation after intravenous injection. Homing is achieved through a mechanism similar to one used by lymphocytes recognize regions of inflammation. Once there the particles will release a complement inhibitor over a sustained period time. A growing body of research links excessive complement activation with several diseases of aging including AMD. The prototype nanoparticle developed in Phase I is able to selectively bind activated endothelial cells in cell culture. In vivo studies further show that the nanoparticles are able to bind inflamed blood vessels in the eye. In vitro studies showed that they are also able to release a complement inhibitor for periods in excess of 60 days. PUBLIC HEALTH RELEVANCE This application is critically concerned with developing a drug product that can be used to treat nonexudative age-related macular degeneration. There are currently no approved treatments for this disorder making it a major the issue of public health. In the longer term the goal of this work is to develop drug products that can selectively target and treat sites of disease action particularly those associated inflammation and degenerative disease.

project_terms:
Acute;Address;Affect;Age;Age related macular degeneration;Age-Years;Aging;Amino Acids Cyclic;Area;Binding (Molecular Function);Biocompatible;Biodistribution;Blindness;Blood Vessels;Bypass;Chronic;Complement;Complement Activation;Complement Inactivators;Complex;Conjunctival Hemorrhage;Cultured Cells;Cyclic Peptides;Data;Degenerative Disorder;Development;Diagnosis;Disease;Disorder by Site;Drug Delivery Systems;Drug Kinetics;Encapsulated;Endophthalmitis;Endothelial Cells;Environmental Risk Factor;Exudative age-related macular degeneration;Eye;Eye diseases;Formulations Drug;Frequencies (time pattern);Genetic;Goals;Home environment;Homing;In Vitro;Individual;Inflammation;Inflammatory;Injection of therapeutic agent;Invasive;Lead;Legal Blindness;Life;Ligands;Link;Lymphocyte;Nonexudative age-related macular degeneration;Oryctolagus cuniculus;Pain;Pathogenesis;Patients;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Process;Purpose;Research;Risk;Role;Selectins;Site;Small Business Technology Transfer Research;Staging;System;Therapeutic Agents;Time;Toxic effect;Toxicology;Vision;Week;Work;base;concept;day;density;glycolate;in vivo;intravenous injection;nanoparticle;particle;poly (lactic-co-glycolic acid);programs;prototype;public health medicine (field);sialyl Lewis x;trafficking;vitreous floater


application_id: 7538374
project_number: 5R01CA124630-03
project_title: PTTG Role in Ovarian Tumorigenesis and Matastasis
administering_ic: NCI
award_notice_date: 2008-12-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 124630
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2007-03-26
project_end_date: 2011-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-01-01
project_abstract:
Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause ofdeath from gynecologic malignancies in the United States. Molecular mechanisms that initiate and supportovarian tumorigenesis are not well defined. We cloned a novel oncogene "PTTG" also known as securin fromhuman testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional proteinand is highly expressed in many tumors including tumors of ovary. Introduction of PTTG into NIH3T3 andHEK293 cells induces cellular transformation and promotes tumor formation in nude mice suggesting itsstrong oncogenic function. Notably PTTG has been shown to inhibit separation of sister chromatids and toincrease the synthesis and secretion of bFGF VEGF and IL-8 as well as activate the expression of theoncogene c-myc and PI3K/AKT signaling pathway suggesting that the oncogenic activity of PTTG mayinvolve induction of aneuploidy and chromosomal instability increased angiogenesis and production ofgrowth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitroand its deletion in animals (Knockout) results in reduction of tumor development suggesting its importantrole in maintenance of cancer phenotype. The long-term objectives of this application are to understand therole of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti-neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG inovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine theeffect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation progressionand metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis;and iii)to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumorsuppression and metastasis and determine mechanisms that lead to suppression of tumor growth andmetastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovariantumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTGfunction as anti-neoplastic agents. In addition transgenic animal model developed from our studies couldenhance efforts aimed at developing new methods for detection prevention and treatment of ovarian cancer.

project_terms:
5q35.1;AKT Signaling Pathway;Address;Adenoviruses;Aneuploidy;Animal Model;Antineoplastic Agents;Base Sequence;Boxing;Cancer Model;Cause of Death;Cell Proliferation;Cells;Cessation of life;Chromosomal Instability;Chromosome abnormality;Chromosomes;Complementary DNA;Crossbreeding;Cytoplasm;Data;Detection;Developed Countries;Developing Countries;Development;Down-Regulation;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Epithelium;Fetal Kidney;Fetal Liver;Fibroblast Growth Factor 2;Gene Expression;Genes;Genetic;Genetically Engineered Mouse;Genomic Instability;Growth;Gynecologic;Health;Human;IL8 gene;In Vitro;Laboratories;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Messenger RNA;Methods;Modeling;Molecular;Molecular Cloning;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Protein;Nuclear Proteins;Nude Mice;Oncogene Proteins;Oncogenes;Oncogenic;Ovarian;Ovarian Surface Epithelial-Stromal Tumor;Ovary;PI3K/AKT;PTTG1 gene;Phenotype;Preclinical Testing;Prevention;Process;Production;Proline-Rich Domain;Promotor (Genetics);Protein Sequence Analysis;Proteins;Reporting;Research Personnel;Role;Sister Chromatid;Sister Chromatid Exchange;Small Interfering RNA;Staging;Structure;Surface;System;Testis;Time;Transgenic Animals;Transgenic Mice;Tumor Suppression;United States;Vascular Endothelial Growth Factors;Woman;angiogenesis;base;c-myc Genes;cancer diagnosis;cell type;expression vector;gene function;human PTTG1 protein;human tissue;in vivo;indexing;knockout animal;loss of function;malignant breast neoplasm;metaplastic cell transformation;neoplastic;neoplastic cell;novel;ovarian neoplasm;overexpression;pituitary tumor-transforming proteins;programs;small molecule;therapy development;tumor;tumor growth;tumor initiation;tumorigenesis;tumorigenic


application_id: 7538190
project_number: 2R44AI071618-02
project_title: ApoVax104-HPV as a Novel Vaccine for Cervical Cancer
administering_ic: NIAID
award_notice_date: 2008-07-30
opportunity_number: PA-06-134
application_type: 2
activity_code: R44
ic: AI
serial_number: 071618
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2007-07-31
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1 IMM-G (10)]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: SHIRWAN, HAVAL
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
project_abstract:
DESCRIPTION (provided by applicant):  Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. Unlike most cancers cervical cancer is caused by a virus - the human papillomavirus (HPV). Two preventative vaccines against HPV were recently licensed in the United States. Merck & Co. developed a vaccine called Gardasil(tm) and GlaxoSmithKline has developed the vaccine Cervarix(tm). Although both appear to be effective at preventing HPV infection in women neither vaccine protects women already infected with HPV from developing cancer or afflicted with the disease. An estimated 20 million people are infected with HPV and worldwide cervical cancer is the third leading cause of cancer death affecting an estimated 500000 women each year. Consequently a therapeutic approach is still necessary to combat already existing HPV infection and cervical cancer.  
Regardless of significant advances in vaccinology the therapeutic potential of cancer vaccines remains to be realized partly due to an array of evasive and immunosuppressive mechanisms employed by progressing tumors4. Therefore the success of therapeutic vaccines is not only contingent upon their ability to generate new immune responses and/or boost the existing ones but also to overcome immune evasion mechanisms. Therapeutic vaccines based on well-defined universal tumor associated antigens (TAAs) represent an attractive approach because of their practicality as well as targeting broad range of cancer types. However the weak antigenic nature of TAAs combined with possible immune tolerance and evasion mechanisms in cancer patients present major hurdles that require potent adjuvants to achieve therapeutic efficacy.  
To overcome these obstacles ApoImmune has developed a proprietary novel HPV vaccine ApoVax104-HPV that constitutes i) a chimeric molecule containing the extracellular domain of costimulatory 4-1BBL fused C-terminus to core streptavidin (ApoVax104) and ii) biotinylated HPV 16 E7 oncoprotein as a TAA conjugated to the chimeric protein via biotin/streptavidin interaction. In the Phase I SBIR application we demonstrated that ApoVax104 component of the vaccine i) targets conjugated antigens into dendritic cells (DCs) constitutively expressing the 4-1BB receptor and activates DCs for antigen uptake and presentation leading to initiation of adaptive immunity ii) directly works on CD4+ and CD8+ T effector (Teff) cells further augmenting adaptive immunity and most importantly iiii) overcomes the suppressive function of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Therefore the pleiotropic effects of 4-1BBL on innate adaptive and regulatory immunity provides a unique advantage over other vaccine approaches under development or in clinical settings. This notion is supported by our strong data obtained during Phase I SBIR studies demonstrating that vaccination with ApoVax104 with a synthetic peptide representing the dominant CD8+ T cell epitope for HPV E7 oncogene (E749-57) was more effective than 3 benchmark adjuvants (lipopolysaccharide (LPS) Monophosphoryl Lipid A (MPL) and CpG oligonucleotide (CpG) in the generation of primary and long- term T cell memory as well as in the eradication of established E7-expressing TC-1 tumors. In addition vaccination with ApoVax104 resulted in better efficacy and undetectable toxicity as compared an agonistic Ab against 4-1BB receptor currently being pursued for cancer clinical trials. Building on these strong preclinical studies obtained from Phase I the goal of this Phase II SBIR application is to develop a humanized ApoVax104-HPV vaccine containing full length HPV16 E6 and E7 oncoproteins to conform to the requirements of the Food and Drug Administration (FDA) for Phase I clinical trials.  
PUBLIC HEALTH RELEVANCE:  Unlike most cancers cervical cancer is caused by a virus - the human papillomavirus (HPV). Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. An estimated 20 million people are infected with HPV and worldwide cervical cancer is the third leading cause of cancer death affecting an estimated 500000 women each year. The overall goal of this project is to develop a therapeutic cervical cancer vaccine ApoVax104-HPV into a lead commercial product to test in a Phase I clinical trial.

project_terms:
Adjuvant;Affect;Agonist;Animals;Antigens;B-Lymphocytes;Benchmarking;Binding (Molecular Function);Biotechnology;Biotin;C57BL/6 Mouse;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Patient;Cancer Vaccines;Cell Line;Cell physiology;Cells;Cervarix;Cervical cancer vaccine;Cessation of life;Chimeric Proteins;Clinical;Clinical Trials;Clinical Trials Phase I;Clinical Trials Phase II;Data;Dendritic Cells;Development;Disease;Documentation;Dose;Effector Cell;Epitopes;Epitopes T-Lymphocyte;Extracellular Domain;Failure (biologic function);Figs - dietary;Formulations Drug;Gardasil;Generations;Goals;Grant;Guidelines;Health;Homologous Gene;Human;Human Papilloma Virus Vaccine;Human Virus;Human papilloma virus infection;Human papillomavirus 16;Immune;Immune Tolerance;Immune response;Immunity;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Killings;Lead;Length;Licensing;Ligands;Lipopolysaccharides;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Molecular;Monitor;Mus;Nature;Numbers;Oligonucleotides;Oncogene Proteins;Oncogenes;Papillomavirus;Papillomavirus Human;Peptides;Phase;Preparation;Procedures;Process;Production;Protein Isoforms;Proteins;Protocols Treatment;Purpose;Quality Control;Range;Recombinant Proteins;Role;Safety;Signal Transduction;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Specificity;Staining method;Stains;Streptavidin;T memory cell;T-Lymphocyte;Technology;Testing;Therapeutic;Toxic effect;Toxicology;Treatment Efficacy;Tumor Antigens;Tumor Necrosis Factor Receptor;United States;United States Food and Drug Administration;Vaccinated;Vaccination;Vaccines;Vaccines Conjugate;Validation;Woman;Work;base;cancer therapy;cancer type;crosslink;design;in vivo;interest;long term memory;manufacturing process;member;monophosphoryl lipid A;novel;novel therapeutics;novel vaccines;preclinical study;prevent;protein purification;public health medicine (field);quality assurance;receptor;research study;response;success;synthetic peptide;therapeutic vaccine;tumor;uptake;vaccine development;vaccinology


application_id: 7538154
project_number: 1R43AI074176-01A2
project_title: ApoVax104-TB as a Novel Vaccine for Tuberculosis
administering_ic: NIAID
award_notice_date: 2008-08-27
opportunity_number: PA-06-135
application_type: 1
activity_code: R43
ic: AI
serial_number: 074176
suffix: A2
program_official: JACOBS, GAIL G
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1 IMM-K (12)]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant): The objective of this NIAID Advanced STTR Phase I proposal is to combine the strengths of academic investigators from the fields of immunology and animal disease modeling with the resources of ApoImmune Inc. to develop a novel vaccine ApoVax104-TB" targeting both active and latent Tuberculosis (TB) infections. ApoVax104-TB" uses a novel proprietary vaccine based on ApoImmune's chimeric protein consisting of streptavidin and the costimulatory ligand 4-1BBL conjugated with known Mycobacterium tuberculosis T-cell antigens. This vaccine concept bears significant potential as a preventive and therapeutic vaccine against TB since the 4-1BBL component of the vaccine has been shown to induce adaptive (CD4+ and CD8+ T cell responses) and innate (dendritic cells macrophages and NK cells) immunity and overcome various immune evasion mechanisms (CD4+CD25+FoxP3+ Treg cells and clonal anergy). This application proposes to develop a subunit vaccine against TB based on a triple antigen strategy consisting of recombinant Ag85B ESAT-6 and Mpt83 TB proteins. Ag85B and ESAT-6 are expressed by actively growing bacteria and Mpt83 is expressed in non-dividing bacteria thereby targeting both subpopulations in the lung. These antigens will be biotinylated and conjugated to chimeric 4-1BBL via biotin- streptavidin interaction and delivered in vivo specifically to dendritic cells constitutively expressing the 4-1BB receptor. The underlying hypothesis is that 4-1BBL interaction with 4-1BB on dendritic cells will activate these cells for antigen uptake processing and presentation to T cells thereby generating potent adaptive immunity. At a second stage 4-1BBL may directly work on activated CD4+ and CD8+ T cells with upregulated 4-1BB receptor to expand these cells and augment the memory response. At a third stage 4-1BBL may overcome various immune evasion mechanisms such as clonal anergy and CD4+CD25+FoxP3+ Treg cells implicated in persistent TB. These combined effects are expected to result in protective as well as therapeutic effects against TB. This hypothesis is supported by our strong preliminary data demonstrating better efficacy of ApoVax104 than two bench-mark adjuvants Monophosphoryl Lipid A and CpG as components of a therapeutic vaccine against cervical cancer. The efficacy of ApoVax104-TBTM will be tested in preventive and therapeutic settings of TB in an animal model. If proven effective these studies will be followed by a Phase II STTR application to further develop the vaccine for testing in a Phase I clinical trail. The development of a vaccine against TB will have tremendous societal benefits as well as target a global market in the billions of dollars. PUBLIC HEALTH RELEVANCE: This project will establish the necessary fundamental parameters to develop a novel vaccine against tuberculosis (TB). Using ApoImmune's lead vaccine ApoVax104" we will develop a vaccine that will suppress the spread of TB by acting as a preventative as well as a therapeutic vaccine. ApoImmune's novel immunotherapy ApoVax104 TM vaccine is a new innovative approach to treating infectious diseases.

project_terms:
Adjuvant;Animal Disease Models;Animal Model;Antigen Presentation;Antigen Targeting;Antigen-Presenting Cells;Antigens;Bacteria;Binding (Molecular Function);Biotin;C57BL/6 Mouse;CD8B1 gene;Cells;Chimeric Proteins;Chronic;Clinical;Clonal Anergy;Communicable Diseases;Data;Dendritic Cells;Development;Dose;Down-Regulation;Effector Cell;Extracellular Domain;Figs - dietary;Formulations Drug;Generations;Head;Histocompatibility Antigens;Immune;Immune response;Immune system;Immunity;Immunology;Immunotherapy;Infection;Lead;Ligands;Lipopolysaccharides;Lung;Malignant neoplasm of cervix uteri;Marketing;Memory;Mice Knockout;Modeling;Mus;Mycobacterium tuberculosis;N-terminal;National Institute of Allergy and Infectious Disease;Natural Killer Cells;Phase;Preventive;Process;Protein Biochemistry;Proteins;Published Comment;Recombinants;Research Personnel;Resources;Signal Transduction;Small Business Technology Transfer Research;Staging;Standards of Weights and Measures;Streptavidin;Structure;T-Cell Proliferation;T-Lymphocyte;Techniques;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Tuberculosis;Tuberculosis Vaccines;United States Food and Drug Administration;Up-Regulation (Physiology);Upper arm;Ursidae Family;Vaccinated;Vaccination;Vaccines;Vaccines Subunit;Work;base;chemokine;clinical application;concept;crosslink;cytokine;cytotoxicity;design;in vivo;innovation;interest;macrophage;monophosphoryl lipid A;mouse model;novel;novel vaccines;prevent;prophylactic;public health medicine (field);receptor;response;therapeutic vaccine;tumor;uptake;vaccine development;vaccine efficacy;vaccine evaluation


application_id: 7537905
project_number: 2R42HL074579-02
project_title: Stem Cell Graft Engineering to Treat Sickle Cell Disease
administering_ic: NHLBI
award_notice_date: 2008-09-17
opportunity_number: PA-07-281
application_type: 2
activity_code: R42
ic: HL
serial_number: 074579
program_official: MITCHELL, PHYLLIS
project_start_date: 2004-09-23
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1 HEME-D (10)]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140644969
duns_number: 140644969
fips: US
organization_id: 10001459
organization_name: REGENEREX, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-20
budget_end_date: 2009-09-19
project_abstract:
DESCRIPTION (provided by applicant): Sickle Cell Disease (SCD) is a genetic abnormality of red blood cells (RBC) that affects over 70000 people in the United States or approximately 1 in every 500 African-Americans. With current therapies the mortality in the United States is 50% by age 40. SCD is a chronic debilitating disease associated with frequent painful crises acute chest syndrome stroke and renal failure. As a result patients require frequent hospitalizations and experience absenteeism from work. The only cure for SCD to date is hematopoietic stem cell transplant (HSCT). However at present the morbidity and mortality associated with ablative HSCT has limited the widespread application of this approach. Moreover the requirement for a matched donor has limited HSCT to only 17% of candidates. We have developed an approach to engineer a bone marrow graft to avoid the major complications of HSCT: graft-versus-host reactivity (GVHD); graft failure; and the need for perfect matching. Our approach is superior to current therapies because it involves a proprietary process that enriches for patented facilitating cells (FC) and stem cells but removes GVHD-producing cells. In this proposal we will utilize the FCRx product already demonstrated to be effective for treatment of leukemic patients for treatment of patients with SCD. In phase I we successfully developed a reduced-intensity nonmyeloablative conditioning approach that established e20% donor chimerism in two pediatric sickle cell patients with matched sibling donors. We met our defined end point of engraftment with production of normal RBC functionally curing the disease. Both patients tolerated the conditioning very well and remain chimeric and asymptomatic at 529 and 644 post-transplant. Patient #1 is off all immunosuppression and Patient #2 is on low dose monotherapy and will complete tapering of the drug in December 2007. We will develop and market a quality controlled/quality assured FDA-approved bone marrow product (SCD FCRx) to treat individuals with SCD. Our platform technology will be provided to hospital systems worldwide. Such a treatment approach could be expanded to other blood disorders including thalassemia the most commonly inherited genetic disease in the world. The complementary structure and expertise of the company and the University lends itself nicely to this joint effort. The company will continue to develop and execute a strategy to produce and market the product while the University will conduct the early stage clinical trial and process the marrow in its FACT-accredited cell processing facility. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation is the only curative treatment for sickle cell disease (SCD) and thalassemia. However the widespread application of this approach has been limited by a need for perfect HLA matching and the unacceptable toxicity of conditioning. This Phase II STTR project will apply our proprietary facilitating cell/stem cell processing approach to prepare a product called FCRx for the approximately 80% of SCD patients who do not have a suitably matched sibling donor. We successfully demonstrated our approach to functionally cure SCD in Phase I of this project.

project_terms:
Abnormal Red Blood Cell;Absenteeism;Accreditation;Address;Affect;African American;Age;Animal Model;Autoimmune Diseases;B-Lymphocytes;Bone Marrow;Bone Marrow Stem Cell;Bone Marrow Transplantation;Businesses;Canis familiaris;Cell physiology;Cells;Central Nervous System Diseases;Child;Childhood;Chimerism;Chronic;Class;Clinical Trials Phase I;Clinical Trials Phase III;Complication;Condition;Data;Disease;Disease Progression;Donor person;Dose;End Point;Engineering;Engraftment;Enrollment;Erythrocytes;Family;Foundations;Genes;Goals;Graft-vs-Host Disease;Guanosine Monophosphate;Health Personnel;Hematological Disease;Hematopoietic stem cells;Hemoglobinopathies;Hereditary Disease;Hospitalization;Hospitals;Immune;Individual;Industry Healthcare;Inherited;Institutes;Insurance;International;Joints;Kidney Failure;Legal patent;MabCampath;Malignant - descriptor;Marketing;Marrow;Methods;Modeling;Molecular Abnormality;Morbidity - disease rate;Mortality Vital Statistics;Mus;Natural immunosuppression;Organ;Orphan Disease;Pain;Parents;Patients;Peripheral Blood Stem Cell;Personal Satisfaction;Pharmaceutical Preparations;Phase;Positioning Attribute;Process;Production;Protocols documentation;Protocols Treatment;Quality Control;Quality of life;Range;Research;Risk;Role;Safety;Siblings;Sickle Cell;Sickle Cell Anemia;Small Business Technology Transfer Research;Solid;Stem cell transplant;Stem cells;Structure;Symptoms;System;Systemic disease;Technology;Thalassemia;Therapeutic;Therapeutic immunosuppression;Toxic effect;Transfusion;Transplantation;United States;United States Food and Drug Administration;Universities;Weaning;Work;acute chest syndrome;base;conditioning;experience;graft failure;improved;islet;leukemia;mycophenolate mofetil;prevent;progenitor;public health medicine (field);stroke;success


application_id: 7537744
project_number: 2R44HL083586-02A1
project_title: Development of a Counterpulsation Therapy Device
administering_ic: NHLBI
award_notice_date: 2008-08-04
opportunity_number: PA-07-280
application_type: 2
activity_code: R44
ic: HL
serial_number: 083586
suffix: A1
program_official: BALDWIN, TIM
project_start_date: 2006-02-20
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1 SBTS-E (10)]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant):   SCR Inc. (Louisville KY) has developed a long-term implantable counterpulsation device (CPD) to treat heart failure (HF) patients who may be responsive to a milder form of cardiac assist. The CPD is 32-ml stroke volume valveless pneumatically-driven blood sac with a single inflow/outflow cannula. The sac fits ergonomically in a `pacemaker pocket' and the graft is connected to the arterial system by an anastomosis to the subclavian artery. The CPD can be operated by a standard clinical pneumatic drive console (iPulse) or a small wearable pneumatic driver (in development) connected to the sac by a percutaneous air line and timed to ECG. The CPD fills during native heart systole lowering ventricular workload and ejects during diastole augmenting myocardial and end-organ perfusion. In the phase I study the hemodynamic efficacy of the 32-ml CPD was comparable to a standard commercially-available 40-ml IABP in a large animal model (n=10) demonstrating feasibility. In this phase II study the development and testing of the implantable components of the CPD system will be completed to support a future FDA submission. This objective will be accomplished by (1) completing engineering development and surgical procedure (2) demonstrating reliability and hemocompatability and (3) demonstrating long-term safety and biocompatibility of the implantable components of the CPD system. Results of a pivotal Good Laboratory Practices (GLP) study will be completed with a summary report prepared for submission to the Food and Drug Administration (FDA) to request approval for clinical trials. The proposed study leverages the development work of SCR Inc and manufacturing and commercialization resources of Abiomed (Danvers MA). This partnership will be guided by an innovative group of physicians at Jewish Hospital (Louisville KY) and Advocate Christ Medical Center (Oak Lawn IL) and a world class research team in the Cardiovascular Innovation Institute (CII) at the University of Louisville (UofL). Our long- term objective is to successfully introduce the CPD as a viable long-term therapy to treat late NYHA class III and early NYHA class IV HF patients to restore their quality of life and promote myocardial recovery. PUBLIC HEALTH RELEVANCE is developing a long-term counterpulsation device (CPD) to treat early stage heart failure patients. The CPD has been developed for superficial implantation without the need to enter the chest and enables complete patient mobility.

project_terms:
Advocate;Agreement;Air;Anastomosis - action;Animal Model;Blood;Cannulas;Cardiac;Cardiovascular system;Carotid Arteries;Catheters;Chest;Chronic;Class;Clinical;Clinical Trials;Clinical Trials Phase I;Clinical Trials Phase II;Coronary;Counterpulsation;Data;Development;Devices;Diastole;Electrocardiogram;Engineering;Functional disorder;Future;Goals;Heart;Heart failure;Hospitals;Implant;In Vitro;Institutes;Intra-Aortic Balloon Pumping;Jewish follower of religion;Laboratories;Location;Mechanics;Medical center;Modification;Myocardial;Operative Surgical Procedures;Organ;Patients;Perfusion;Phase;Physicians;Quality of life;Recovery;Research;Resources;Safety;Sales;Staging;Standards of Weights and Measures;Stroke Volume;Structure of subclavian artery;Summary Reports;System;Systole;Testing;Thoracic aorta;Time;United States Food and Drug Administration;Universities;Validation;Ventricular;Week;Work;Workload;biomaterial compatibility;commercialization;day;hemodynamics;implantation;in vivo;innovation;pre-clinical;programs;public health medicine (field);research study


application_id: 7537615
project_number: 2R42HL079855-02A1
project_title: New anti-complement therapy to reduce reperfusion injury: Phase II
administering_ic: NHLBI
award_notice_date: 2008-08-29
opportunity_number: PA-07-281
application_type: 2
activity_code: R42
ic: HL
serial_number: 079855
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 2005-05-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1 BST-Z (10)]
contact_pi_person_id: 2129782
contact_pi: MALDONADO, CLAUDIO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Tissue and organ transplantation procedures save and/or improve the lives of hundred of thousands of patients annually in the US. The goal of this research is to develop a local anti-complement therapy for donor organ ex vivo application that will reduce complement-induced injury to the vascular endothelium. An unavoidable consequence of transplantation (allografts or autografts) is ischemia/reperfusion (IR) injury. Studies have shown that IR-induced complement activation leads to the formation of several key inflammatory mediators that alter vascular homeostasis and stimulate leukocyte activation and chemotaxis. After decades of neglect complement has been rediscovered as a potent mediator of inflammation and rejection in organ transplants. In Phase I of this proposal we successfully provided proof-of-concept that our novel therapy reduced complement deposition in vitro after activation of the classical pathway. Our therapy is based on a platform technology that allows the rapid display of protective exogenous proteins on the surface of cells during organ harvest. The goal in Phase II is to prepare the technology for clinical use. This will be accomplished by developing safe and stable lyophilized components which upon reconstitution are perfused into organs ex vivo to effectively reduce locally complement mediated injury in vivo. The technical objectives are: 1) Reduce cost of therapeutic formulations by using the most economical components without compromising anti-complement efficacy. 2) Determine potential toxicity of therapy and demonstrate its efficacy in a kidney rat model of IR. 3) Develop stable lyophilized therapeutic components for storage and demonstrate in vitro that reconstituted components are just as effective as freshly prepared components. 4) Demonstrate in kidney rat models of IR and transplantation that lyophilized products are effective in reducing antigen-independent and antigent-dependent IR injury. If successful these studies will demonstrate the potential clinical value of our therapy in enhancing natural anti-complement defenses in allografts. Our therapy will be applied during routine flushes of donor organs and will achieve therapeutic levels of drug locally without systemic adverse effects. Application of our therapy may extend the donor pool by allowing organ harvest from non-beating heart donors. Our approach is a faster alternative to gene therapy in that proteins can be displayed on the cell membranes in less than 1 hour. The economic implications for this novel therapeutic approach in transplantation are vast not only in terms of the potential benefits to patients but also in reducing health care costs associated with re-operations and complications arising from failed procedures.  
  
Public Health Relevance: The goal of this project is to develop a new targeted therapy that prevents damage to transplanted organs. An unavoidable inherent problem of transplantation is that blood flow during organ harvest must be cutoff and later reestablished during implantation. This process causes the activation of the immune component called the complement system which causes unintended tissue injury that ultimately leads to organ malfunction and failure. Anti-complement agents that are administered systemically have been developed but their use leaves transplant recipients vulnerable to viral and bacterial infections. EndoProtech Inc. is proposing to develop a novel safer anti-complement therapeutic agent that binds to cells of transplanted organs and eliminates systemic circulation of the agent. The therapy is applied during harvest while organs are outside the body before implantation. The objective is to protect tissues from complement-related injury with minimal side effects.

project_terms:
Adverse effects;Allografting;American;Antigens;Bacterial Infections;Binding (Molecular Function);Blood Circulation;Blood Vessels;Blood flow;Carcinogens;Cell Adhesion Molecules;Cell membrane;Cell surface;Cells;Chemotaxis;Clinical;Clinical Trials Phase II;Combined Modality Therapy;Complement;Complement Activation;Coupled;Coupling;Cultured Cells;Deposition;Donor Organ;Economics;Edema;Effectiveness;Endothelial Cells;Endothelium Vascular;Extravasation;Failure (biologic function);Flushing;Formulations Drug;Functional disorder;Goals;Harvest;Health Care Costs;Heart;Homeostasis;Hour;Immune;In Vitro;Incubated;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Ischemia;Kidney;Left;Life;Lipids;Mediating;Mediator of activation protein;Membrane;Metals;Modeling;Operative Surgical Procedures;Organ;Organ Harvestings;Organ Transplantation;Other Agency or Organization;Pathway interactions;Patients;Perfusion;Pharmaceutical Preparations;Phase;Physiological reperfusion;Plasma;Procedures;Process;Proteins;Rattus;Reactive Oxygen Species;Reperfusion Injury;Reperfusion Therapy;Research;System;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Transplantation;Tissues;Toxic effect;Transplant Recipients;Transplantation;Transplantation Autologous;Transplants Cell;Treatment Efficacy;Vesicle;Viral;Virus;analog;base;cell injury;commercialization;complement-control protein Vaccinia virus;concept;cost;gene therapy;genetic regulatory protein;implantation;improved;in vivo;interstitial;leukocyte activation;neglect;novel;novel therapeutics;pre-clinical;prevent;public health medicine (field);reconstitution;therapeutic target


application_id: 7537186
project_number: 5R01NS055228-02
project_title: Multiple circadian oscillators: Regulation of a neuroendocrine rhythm
administering_ic: NINDS
award_notice_date: 2008-10-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 055228
program_official: MITLER, MERRILL
project_start_date: 2007-12-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-D(02)M]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: LEGAN, SANDRA J.
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affective;Aging;Area;Attention;Biological Models;Brain;Brain region;Cardiovascular Diseases;Cell Line;Cells;Circadian Rhythms;Cognitive deficits;Endocrine;Estrous Cycle;Exhibits;Female;Frequencies (time pattern);GABA-A Receptor;Gender;Gene Expression;Generations;Genes;Goals;Gonadotropin Hormone Releasing Hormone;Gonadotropins;Hamsters;Hormones;In Vitro;Individual;Jet Lag Syndrome;Luteinizing Hormone;Measures;Modeling;Molecular;Mood Disorders;Morbidity - disease rate;Mus;Mutate;Mutation;Neuroendocrine Cell;Neurons;Neurosecretory Systems;Output;Pacemakers;Pathway interactions;Pattern;Peripheral;Phase;Phenobarbital;Physiological;Postmenopause;Postpartum Depression;Property;Quality of life;Regulation;Reproduction;Role;Signal Transduction;Site;Syndrome;Time;Tissues;Transfection;Vasopressins;Woman;Work;aged;base;circadian pacemaker;depression;improved;in vivo;male;obesity risk;receptor;shift work;suprachiasmatic nucleus;transmission process


application_id: 7536426
project_number: 5R01HL088989-02
project_title: Role of B cells in host defense against Pneumocystis
administering_ic: NHLBI
award_notice_date: 2008-11-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 088989
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)M]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
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;Goals;HIV;Host Defense;Immune response;Immunoglobulin Class Switching;Immunoglobulin G;Immunologic Deficiency Syndromes;Indium;Individual;Infection;Interleukin-10;Kinetics;Lung;MHC Class II Genes;Memory;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nature;Opportunistic Infections;Patients;Phase;Pneumocystis;Pneumocystis Infections;Pneumocystis carinii Pneumonia;Predisposition;Production;Resistance;Role;SCID Mice;Signal Transduction;T-Cell Proliferation;T-Lymphocyte;TNF gene;TNFRSF5 gene;Time;Transgenic Mice;Vaccine Adjuvant;Viral Load result;cytokine;design;discount;in vitro Assay;in vivo;lymph nodes;memory CD4 T lymphocyte;prevent;research study;response


application_id: 7536011
project_number: 5R01NS050311-05
project_title: Stem Cell Adaptability in Parkinson' Disease
administering_ic: NINDS
award_notice_date: 2008-11-18
opportunity_number: PAS-03-172
application_type: 5
activity_code: R01
ic: NS
serial_number: 050311
program_official: SUTHERLAND, MARGARET L
project_start_date: 2004-12-01
project_end_date: 2010-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Stem Cell Adaptibility in Parkinson's Disease   Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease (PD). Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. Recently it was demonstrated embryonic stem ceils (ESC) could be converted to dopamine neurons in culture and when implanted into animals with experimental Parkinson's disease produced a degree of functional recovery similar to implants of fetal dopamine neurons.  Because dopamine neurons derived from ESC are generated in cultures by manipulating various growth factors it still remains to be determine whether or not ESC-derived dopamine neurons have a similar phenotype as normal developing dopaminergic neurons. Moreover the dynamic microenvironment of the brain particularly the neurotrophic environment may alter the survival function and even the fate of transplanted ESC. The objective of the initial studies will determine whether or not ESC-derived dopamine neurons retain various cellular markers that are critical to the survival and maintenance of developing and mature dopamine neurons. In particular studies will focus on the identification of neurotrophic factors and neurotrophic factor receptors on ESC-derived dopamine neurons that are typically associated with normal dopamine neurons. We will then identify and measure various growth factors within the host brain that may influence the fate of transplanted ESC and assess how these factors change following a degenerative lesion of the nigrostriatal and/or during aging. Studies will be designed to vary the neurotrophic environment of the host brain in order to determine the adaptability of implanted ESC; conditions will be varied using various lesion models and gene therapy techniques to alter the expression of neurotrophic factors. The variable of host age on ESC-derived dopamine neuron adaptability will be studied.

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


application_id: 7535970
project_number: 2R44HL090055-02
project_title: Development of a Personalized Medicine Interface for the Safe and Effective Treat
administering_ic: NHLBI
award_notice_date: 2008-08-26
opportunity_number: PA-07-280
application_type: 2
activity_code: R44
ic: HL
serial_number: 090055
program_official: LINK, REBECCA P
project_start_date: 2007-08-16
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1 GGG-J (10)]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-16
budget_end_date: 2009-07-31
project_abstract:
DESCRIPTION (provided by applicant):  Warfarin is the most commonly used oral anticoagulant medication. Because an individual's proper warfarin dose is difficult to assess most physicians initiate therapy at a standard dose and follow up with an INR blood test to ensure the medicine is working properly. Unfortunately therapeutic warfarin doses vary significantly from patient to patient so that even a standard dose can cause life-threatening hemorrhaging. Genetic and non-genetic factors both influence an individual's warfarin dose requirement and response characteristics and although the importance of pharmacogenetics to warfarin therapy is understood clear guidance for how such information should be applied to patient therapy is woefully absent. The Personalized Medicine Interface (PerMIT) software utility supplies this critical guidance by modeling the dose requirements and response characteristics of individual patients based on their genotypic and physical characteristics. Using state-of-the-art multivariate computations PerMIT conveniently calculates a warfarin maintenance dose estimate and models the influence of repeated dosing on plasma drug concentration. PerMIT provides guidance during the transition from induction to maintenance therapy and limits the potential for misinterpretation of INR measurements by clearly displaying the relationship of the dosing regimen to the progress toward steady-state. The specific aim of Phase I was to develop a computational model that estimates the most appropriate warfarin maintenance dose for an individual accurately estimates the plasma concentration of S-warfarin following each warfarin dose and provides a visual estimate of the time to reach steady state. PGXL Laboratories has accomplished this specific aim with the creation of the graphical patient care interface PerMIT. The specific aim of Phase II is to demonstrate the power of PerMIT in guiding superior clinical management of patients taking warfarin. Three technical objectives will demonstrate that the software functions as intended that it is user friendly and that it is clinically effective: (1) Validate the analytical accuracy of computational algorithms which drive the PerMIT module; (2) Drive design improvements through Usability Testing; (3) Measure the clinical value of PerMIT in a prospective trial of PerMIT-guided therapy versus standard of care. Completion of the above-stated objectives will: (1) confirm that the computational basis of PerMIT is consistent with the state-of-the-art in warfarin dose estimation and plasma concentration modeling (2) assure the highest quality user interface based on a validated approach to Usability Testing and (3) demonstrate the utility of PerMIT for improved efficiency of patient care.  PUBLIC HEALTH RELEVANCE:  Warfarin is the most commonly prescribed oral anticoagulant but managing patients on warfarin is difficult due to variability in patients' response to the medication; indeed adverse reactions to warfarin are second only to insulin in frequency. Inherited differences account for approximately 40% of the variability in warfarin dose response between individuals but clinicians thus far have had no clear and easy methods or tools to help them understand and account for this variability when directing patient therapy. PerMIT:Warfarin provides muchneeded guidance to clinicians throughout the course of warfarin therapy and limits the potential for misinterpretation of blood test results (INR measurements) by clearly displaying the relationship between a patient's dosing regimen and their progress toward stable therapy.

project_terms:
Accident and Emergency department;Accounting;Adverse reactions;Age;Anticoagulants;Arts;Awareness;Blood Clot;Blood Tests;Blood coagulation;CYP2C9 gene;Caring;Characteristics;Clinical;Clinical Management;Computational algorithm;Computer Simulation;Computer software;Data;Development;Dose;Drug usage;Ensure;Event;Frequencies (time pattern);Gender;Genetic;Genotype;Hemorrhage;Hospital Costs;Individual;Inherited;Insulin;Label;Laboratories;Life;Maintenance;Maintenance Therapy;Measurement;Measures;Medicine;Methods;Modeling;Oral;Patient Care;Patient Care Management;Patients;Pharmaceutical Preparations;Pharmacogenetics;Phase;Physicians;Plasma;Protocols Treatment;Risk;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Sodium Warfarin;Standards of Weights and Measures;Test Result;Testing;Therapeutic;Time;Translating;Update;Validation;Visit;Visual;Waran;Warfarin;Weight;Work;base;clinically relevant;design;dosage;follow-up;improved;prospective;public health medicine (field);response;stroke;tool;usability;user-friendly


application_id: 7535963
project_number: 1R21EY018952-01A1
project_title: To produce transgenic mice which express T cell receptors specific for (IRBP).
administering_ic: NEI
award_notice_date: 2008-08-18
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: EY
serial_number: 018952
suffix: A1
program_official: SHEN, GRACE L
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Autoimmune posterior uveitis is a T cell mediated autoimmune disease characterized by mononuclear infiltrate into the retina and irreversible photoreceptor destruction. While the cause is unknown experimental autoimmune uveitis (EAU) can be induced in mice through immunization with interphotoreceptor retinoid binding protein (IRBP). Numerous studies in the EAU field as well as other autoimmune disease models suggest that the primary cause of autoimmune disease is a failure of immune tolerance mechanisms. T cell receptor (TCR) transgenic mice have provided and continue to provide a wealth of important information on mechanisms of tolerance induction as well as mechanisms of autoimmune tissue destruction particularly in the multiple sclerosis and diabetes fields. In this exploratory/developmental research grant application the applicant proposes to develop TCR transgenic mice with specificity for IRBP as a new model for EAU. The applicant has successfully cloned full length cDNAs encoding the alpha and beta chains of the TCR from three IRBP specific T cell clones and is in the process of cloning the receptor genes from two other T cell clones. In the first aim the applicant will generate two lines of transgenic mice from two different T cell clones. In the second aim the applicant will perform the initial characterization of the lines in order to establish them as useful models for EAU. These mice will be made available to the uveitis research community and create valuable new models for uveitis research. Studies using these mice may lead to new therapies for the treatment of uveitis.   
  
PUBLIC HEALTH RELEVANCE:  This project will generate new transgenic mouse models for autoimmune uveitis a severe sight threatening autoimmune disease. Similar mouse models have been produced for multiple sclerosis and diabetes and have been responsible for dramatic advances in those fields. These mice will be made available to the research community and thus foster new research into cures or treatment for autoimmune uveitis.

project_terms:
5-(6)-carboxyfluorescein diacetate succinimidyl ester;Adoptive Transfer;Antigen T Cell Receptor beta Chain;Antigens;Area;Autoantigens;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Backcrossings;Biomedical Research;Breeding;Cell physiology;Cells;Cloning;Communities;Development;Diabetes Mellitus;Disease;Disease model;Effector Cell;Epitopes;Experimental Autoimmune Encephalomyelitis;Exploratory/Developmental Grant;Eye;Failure (biologic function);Fluorescent Dyes;Fostering;Genes;Genes T-Cell Receptor;Goals;Grants Applications;Immune;Immune Tolerance;Immune response;Immunization;In Vitro;Label;Lead;Length;Mediating;Methods;Mice Knockout;Mice Transgenic;Microinjections;Microtus;Modeling;Models Experimental;Mononuclear;Multiple Sclerosis;Mus;Numbers;Pancreas;Peripheral;Photoreceptors;Polymerase Chain Reaction;Population;Pre-Clinical Model;Process;Production;Property;RIII Mouse;Receptor Gene;Research;Research Personnel;Research Project Grants;Retina;Risk;Role;Site;Source;Specificity;Structure of zygote;System;T-Cell Receptor;T-Lymphocyte;Testing;Thymic epithelial cell;Thymus Gland;Tissues;Transfection;Transgenes;Transgenic Organisms;Uveitis;Uveitis Posterior;Vision;alpha-beta T-Cell Receptor;autoimmune uveitis;design;in vivo;interstitial retinol-binding protein;interstitial retinol-binding protein mouse;intravital microscopy;model development;mouse model;novel;public health medicine (field);receptor;receptor expression;research study;success


application_id: 7535500
project_number: 5R01EY012974-07
project_title: The role of costimulatory molecules in uveitis
administering_ic: NEI
award_notice_date: 2008-12-18
application_type: 5
activity_code: R01
ic: EY
serial_number: 012974
program_official: SHEN, GRACE L
project_start_date: 2001-08-01
project_end_date: 2011-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-12-01
project_abstract:
The identification of costimulatory molecules has provided important insights into molecular mechanisms forthe regulation of the immune response andmore importantly into several novel approaches for autoimmuneor tumor immunotherapy. The growing number of known T cell costimulatory pathways together with thedynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatorymolecules regulating responses of naive effector and memory T cells. With the support of the current grantmy laboratory has made significant progress in understanding the role of costimulatory molecules inautoimmune uveitis. However our studies have also raised two important questions: (1) why are effectoruveitogenic T cells more resistant than naive T cells to treatment by costimulatory molecule blockers? (2) Dopathogenic and regulatory T cells rely on different costimulation so that a specific treatment regimen can beidentified to maximally suppress the pathogenic response with a minimal inhibitory effect on regulatory T cellactivation?For human disease immunotherapies that can interfere with an ongoing autoimmune disease are moreimportant than those preventing the development of disease since disease has already started by the time thepatient visits the doctor. Thus the long-term goal of this proposal is to explore therapeutic approachesinhibiting already activated autoreactive effector T cells. We will therefore determine whether CD28/B7costimulatory molecules are crucial for the pathogenic effect of uveitogenic T cells specifically: (1) whethereffector and regulatory T cells use CD28/B7 differently in terms of time and quantity and whether blockade of acombination of costimulatory molecules favors the treatment of ongoing autoimmune disease; (2) whether wecan identify therapeutic regimens that have a limited impact on regulatory T cell activity while inhibitingpathogenic activity; and (3) whether a combined treatment acting on costimulation of autoreactive T cell andocular inflammation can provide better control of ongoing disease. To provide a working model that will allowbetter understanding of the pathogenesis of recurrent uveitis we have established chronic recurrent models inthe rat and mouse. These studies should provide insights into the pathogenic mechanism leading to diseaseprogression and help in the development of supplementary therapies for this devastating disease.

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


application_id: 7534781
project_number: 5R01HL080429-04
project_title: Caspase Mediated Diaphragmatic Dysfunction
administering_ic: NHLBI
award_notice_date: 2008-11-28
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: 2011-11-30
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: 2008-12-01
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;BCL2 gene;Biochemical;Biological Assay;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;Experimental Models;Fiber;Fluorogenic Substrate;Free Radicals;Functional disorder;Gel;Gene Mutation;Generations;Genes;Goals;Heart failure;Image;In Situ;In Vitro;Individual;Infection;Inflammation;Inflammation Mediators;Injection of therapeutic agent;Injury;Investigation;Ischemia;Knock-out;Leg;Ligation;Limb structure;Link;Magnetism;Measurement;Measures;Mediating;Membrane;Modeling;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;Myocardium;Nitric Oxide;Nitric Oxide Synthase;Oranges;Organelles;Pathway interactions;Patients;Pattern;Perforation;Pilot Projects;Play;Pneumonia;Predisposition;Process;Protein Isoforms;Proteins;Proteolysis;Proteomics;Pseudomonas;Recurrence;Relative (related person);Reperfusion Therapy;Reporting;Research Design;Respiratory Failure;Respiratory Muscles;Risk;Role;Sarcolemma;Sepsis;Severities;Skeletal muscle structure;Skin;Spectrin;Superoxides;System;TNF gene;Techniques;Testing;Time;Transgenic Animals;Transgenic Organisms;Ventilator;Virus Diseases;Western Blotting;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;overexpression;protein degradation;protein function;receptor;research study;respiratory;response;theories


application_id: 7533234
project_number: 2R01HL059378-10A1
project_title: Cardiac Metabolism of Enals
administering_ic: NHLBI
award_notice_date: 2008-07-10
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: HL
serial_number: 059378
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2012-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Ablation;Acute myocardial infarction;Affect;Aging;Air;Aldehyde Reductase;Aldehyde dehydrogenase (NAD+);Aldehydes;Asses;Atherosclerosis;Biochemical Pathway;Biochemical Process;Cardiac;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Death;Cell physiology;Characteristics;Coronary;Degradation Pathway;Development;Disease;Endoplasmic Reticulum;Enzyme Inhibition;Enzymes;Food;Functional disorder;Genetic;Glutathione S-Transferase;Heart;Heart Diseases;Heart failure;In Situ;Inflammation;Inflammatory;Injury;Ischemia;Ischemic Preconditioning;Lead;Ligation;Lipid Peroxidation;Lipids;Mediating;Mediator of activation protein;Metabolic Detoxication Drug;Metabolism;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocytes Cardiac;Nature;Neurodegenerative Disorders;Occlusions Coronary;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Phase;Physiological reperfusion;Protein Overexpression;Proteins;Proteolysis;Reaction;Reactive Oxygen Species;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Stress;Structure;Testing;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Organisms;Water;Work;adduct;aldehyde dehydrogenases;base;biological adaptation to stress;heart metabolism;insight;lipid metabolism;oxidation;oxidized lipid;pollutant;prevent;public health medicine (field);response


application_id: 7532965
project_number: 1R21DE019271-01
project_title: In vivo gene silencing in salivary glands
administering_ic: NIDCR
award_notice_date: 2008-08-12
opportunity_number: RFA-DE-08-005
application_type: 1
activity_code: R21
ic: DE
serial_number: 019271
program_official: SHUM, LILLIAN
project_start_date: 2008-08-12
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZDE1 JH (30)]
contact_pi_person_id: 1885630
contact_pi: GORR, SVEN-ULRIK
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to use gene interference to modify the secretory machinery of salivary glands for targeted delivery of therapeutic proteins. To achieve this goal novel lipid-adjuvant complexes will be developed for direct presentation of siRNA to salivary glands. The resultant gene interference is designed to enhance the secretion of therapeutic proteins to the blood stream. Salivary glands are attractive targets for gene therapy protocols since the glands are capable of producing large amounts of secretory proteins and are accessible by non-invasive procedures via the salivary ducts. Retrograde transfusion of DNA constructs into salivary glands has been used to express foreign therapeutic proteins which can be targeted to both oral and systemic diseases. The latter application is limited by the secretory pathways of salivary epithelial cells which are directed 90% to the oral cavity (exocrine secretion). Preliminary data suggest that disruption of exocrine secretion leads to increased endocrine secretion i.e. a shift of secretion from the oral cavity to the blood stream. Thus this application is based on the findings that acidic sulfated proteoglycans and basic proline-rich proteins can regulate protein storage apparently by a pH- dependent mechanism. A low luminal pH appears to also play a role in the polarized secretion of salivary gland proteins. These findings suggest that modulation of the pH of the secretory pathway offers an opportunity to modulate the secretion of therapeutic proteins without changing the structure of those proteins. It is hypothesized that exocrine secretion can be decreased by raising the internal pH of secretory organelles resulting in increased endocrine secretion. This can be accomplished by selectively silencing the genes involved in acidification of secretory organelles. To test this hypothesis the proposed research will address two major goals: 1) develop lipids and adjuvants for efficient transfection of salivary epithelial cells with siRNA and plasmid vectors; and 2) use siRNA to increase endocrine secretion of the model therapeutic protein hGH from salivary glands in vivo. To ensure efficient delivery of the RNAi and gene therapy constructs to salivary glands in vivo novel lipid formulations will be developed and paired with transfection adjuvants. Thus the project will develop a flexible platform technology that can be adapted to the silencing of a variety of genes in salivary glands. Project Narrative: The salivary glands are attractive targets for gene therapy aimed at expressing therapeutic proteins in the circulation. To correctly target these proteins small interfering RNAs will be used to modify the cellular secretion machinery. siRNAs will be introduced with innovative lipid transfection reagents developed specifically for use in salivary glands in vivo.

project_terms:
Address;Adjuvant;Blood;Blood Circulation;Cell secretion;Communities;Complex;DNA;Data;Development;Disruption;Endocrine;Engineering;Ensure;Epithelial Cells;Formulations Drug;Gene Silencing;Genes;Gland;Goals;Invasive;Lipid Chemistry;Lipids;Modeling;Oral;Oral cavity;Organelles;Pathway interactions;Plasmid Cloning Vector;Play;Procedures;Proteins;Proteoglycan;Protocols documentation;RNA Interference;RNA Small Interfering;Reagent;Research;Research Personnel;Role;Salivary;Salivary Glands;Salivary Proteins;Salivary duct structure;Somatropin;Stream;Structure;Sulfates Inorganic;Sulfates Unspecified or Sulfate Ion;Systemic disease;Technology;Testing;Transfection;Transfusion;base;design;gene therapy;improved;in vivo;innovation;novel;proline-rich proteins;secretory protein;targeted delivery;therapeutic protein


application_id: 7532737
project_number: 2R01EY012998-08A1
project_title: Determinants of extraocular muscle function
administering_ic: NEI
award_notice_date: 2008-09-15
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: EY
serial_number: 012998
suffix: A1
program_official: ARAJ, HOUMAM H
project_start_date: 2001-03-01
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (07)]
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academy;Address;Adult;Aerobic;Affect;Age;Aging;American;Biochemical;Biogenesis;Biological Assay;Biology;Boxing;Buffers;Calcium;Cell Respiration;Cells;Characteristics;Child;Chronic progressive external ophthalmoplegia;Clinical;Complex;Condition;Creatine Kinase;Critical Period (Psychology);Data;Dependence;Development;Electron Transport;Eye;Eye Movements;Fatigue;Incidence;Knowledge;Life;Limb structure;Metabolic;Metabolic Pathway;Mitochondria;Mitochondrial Myopathies;Modeling;Motor;Muscle;Muscle Proteins;Muscle function;Muscle of orbit;Myosin ATPase;Neuromuscular Diseases;Ocular Motility Disorders;Pediatrics;Phenotype;Pilot Projects;Predisposition;Property;Protein Isoforms;Proteins;Purpose;Rate;Research Personnel;Resistance;Resolution;Sensory;Skeletal muscle structure;Skeletal system;Stereotyping;Strabismus;System;Testing;Time;Training;Upper arm;Vision;Visual;age related;aged;cell motility;dark rearing;early experience;end of life;experience;oculomotor;postnatal;programs;public health medicine (field);research study;respiratory;response;visual deprivation


application_id: 7532036
project_number: 1R01HD060915-01
project_title: Latexin's role in parsing stem cells
administering_ic: NICHD
award_notice_date: 2008-12-12
opportunity_number: RFA-AG-08-003
application_type: 1
activity_code: R01
ic: HD
serial_number: 060915
program_official: HUANG, TERRY T-K
project_start_date: 2008-12-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-2 (M2)]
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): Juvenile factors that have potential effects on aging are myriad but fall into two broad categories: conscious and unconscious. An example of the former is taking up smoking as a pre-teen or adopting other dangerous lifestyles when young that are known at least on a statistical basis to shorten lifespan. Of course not all conscious decisions have detrimental effects. Many decisions about diet for example could promote healthy aging and a longer lifespan. This application is concerned with the "unconscious" category of factors detectable at early developmental stages that influence either positively or negatively not only overall lifespan but the quality of life with accumulating years. We focus on the number and functional capabilities of adult stem cells and the factors that parse their limited numbers and functional properties over a lifetime. Our underlying hypothesis is that quantitative and qualitative alterations in stem cells influence lifespan and successful aging. We study hematopoietic stem cells as a paradigm adult stem cell population and have shown age-related changes in stem cell number and function in mice. Moreover we have sought genetic determinants of stem cell properties that have an effect during aging. This proposal narrowly focuses on a quantitative trait the number of stem cells at a young age also correlated with lifespan. By utilizing the tools afforded by modern mouse genetics we have identified a quantitative trait gene and its protein product latexin that is important in mammals in parsing stem cells. In this application we propose to investigate the pattern of latexin expression in hematopoietic stem cells during embryonic development and at multiple points during adulthood and correlate these data with quantitative and qualitative parameters of stem cells and organismal longevity. An important tool we will make use of in these studies is latexin knockout mice which we are currently generating. In constitutive knockout animals we will study the effects on stem cells and aging when latexin is absent throughout development and adulthood. In conditional knockout mice we will determine when during development and young adulthood the presence of latexin is critical. Moreover the conditional knockouts will enable us to study the tissues in which latexin's expression is important and when. Lastly we investigate the genetic and epigenetic regulation of latexin expression segmentally at different stages of organismal development and adulthood. Preliminary data demonstrate in specific mouse strains that latexin expression is differentially regulated by both polymorphisms in the promoter and differential methylation of CG dinucleotides comprising a CpG island in the latexin promoter. In aggregate these descriptive and mechanistic studies will provide definitive information on the basic premise that adult stem cells influence aging and in particular the role that latexin plays as a mechanistic factor in this pathway. The median age of the U.S population continues to increase and will accelerate in the upcoming few decades. Healthy aging is thus a national priority especially given the rapidly rising costs of health care. Yet many of the physiological events occurring during development and early in childhood that have serious repercussions on the quality of life later are poorly understood. We believe that the regulation of stem cells and particularly the parsing of these populations chronologically is an important and neglected aspect of this quest. The proposed studies based on firm preliminary results specifically focus on the role of a novel stem cell regulator latexin on the hematopoietic stem cell population in a mammalian species the mouse.

project_terms:
Accounting;Adolescent;Adopted;Age;Aging;Apoptosis;Bone Marrow;C57BL/6 Mouse;Categories;Cell Aging;Cell Count;Cells;Childhood;Chronology;Conscious;CpG Islands;CpG dinucleotide;DNA Damage;Data;Development;Diet;Elderly;Embryo;Embryonic Development;Ensure;Epigenetic Process;Event;Genes;Genetic;Genetic Determinism;Genetic Polymorphism;Health Care Costs;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Knock-out;Knockout Mice;Life;Life Style;Longevity;Mammals;Methylation;Modeling;Mouse Strains;Mus;Organ;PC3.1 antigen;Pathway interactions;Pattern;Physiological;Play;Population;Population Sizes;Promotor (Genetics);Property;Proteins;Quality of life;Reactive Oxygen Species;Regulation;Relative (related person);Role;Smoking;Specificity;Staging;Stem Cell Factor;Stem cells;Teenagers;Tissues;Transgenic Mice;Uncertainty;Unconscious State;adult stem cell;age effect;age related;base;cell age;emerging adult;falls;fetal;functional decline;healthy aging;knockout animal;neglect;novel;progenitor;stem cell population;tool;trait


application_id: 7531673
project_number: 1R21HL091293-01A1
project_title: Regulation of presympathetic RVLM neurons by cannabinoids
administering_ic: NHLBI
award_notice_date: 2008-09-02
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: HL
serial_number: 091293
suffix: A1
program_official: THRASHER, TERRY N
project_start_date: 2008-09-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1 CVS-F (90)]
contact_pi_person_id: 8893817
contact_pi: DERBENEV, ANDREI
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
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this Exploratory/Developmental Research Grant is to discover the effects of endocannabinoids (eCB) in rostral ventrolateral medulla (RVLM) circuits that regulate cardiovascular function. The central nervous system is directly involved in regulation of arterial blood pressure largely through actions of the sympathetic nervous system on renal function and abdominal vasculature. The RVLM is a critical component in the central pathways mediating cardiovascular regulation. Presympathetic RVLM neurons receive inputs from multiple areas of the brain and spinal cord and mediate many cardiovascular reflexes. Hypertension may result from an imbalance between activity of sympathetic vasomotor neurons and those cells that inhibit them. This concept has been described as the "central neuron imbalance" hypothesis of hypertension. Little is known about normal RVLM neuronal regulation. The G protein-coupled cannabinoid type-1 receptor (CB1R) is expressed throughout the CNS including the RVLM. Endogenous cannabinoids (eCB) (e. g. anandamide) act on both CB1R and transient receptor potential vanilloid type 1 (TRPV1) which are also expressed in the RVLM. The function of CB1R and TRPV1 receptors in RVLM is not known. This exploratory study will reveal the site and synaptic mechanisms of eCB actions in RVLM-mediated cardiovascular control which have been elusive until now. A multi-disciplinary approach using immunohistochemistry in vivo renal nerve and arterial blood pressure (ABP) recordings and in vitro patch-clamp recordings of synaptic currents in identified RVLM neurons to test the hypothesis that: 1) CB1R agonists will evoke sympathoexcitation when injected into the RVLM of anesthetized rats by decreasing GABAergic synaptic activity to presympathetic RVLM kidney-related neurons. 2) TRPV1 agonists will evoke sympathoinhibition when injected into the RVLM of anesthetized rats. Exploring these mechanisms will provide important insights about understanding the cellular mechanisms of cannabinoid actions on RVLM. This approach will also have clinical implications by providing direct evidence about the regulation of ABP by cannabinoids and therefore offer novel therapeutic strategies in the treatment of hypertension. PUBLIC HEALTH RELEVANCE: This study will reveal the site and effect of cannabinoids on a brainstem area involved in blood pressure control. Cannabinoid actions in the brainstem can have important clinical implications for the treatment of such medical conditions as hypertension.

project_terms:
Abdomen;Agonist;Area;Autonomic nervous system;Blood Pressure;Brain;Brain Stem;Cannabinoids;Capsaicin;Cardiovascular Physiology;Cardiovascular system;Cells;Clinical;Condition;Data;Development;Endocannabinoids;G-Protein-Coupled Receptors;GTP-Binding Proteins;Glutamates;Goals;Hypertension;Immunohistochemistry;In Vitro;Kidney;Localized;Measures;Mediating;Medical;Microinjections;Microscopy Confocal;Nerve;Neuraxis;Neurons;Pathway interactions;Play;Rattus;Receptor Activation;Reflex action;Regulation;Renal function;Research Project Grants;Role;Site;Spinal Cord;Structure of medulla of kidney;Sympathetic Nervous System;Synapses;Testing;Vanilloid;Vasomotor;anandamide;blood pressure regulation;cannabinoid receptor;concept;hypertension treatment;in vivo;insight;novel therapeutics;patch clamp;public health medicine (field);receptor;research study;response


application_id: 7531640
project_number: 1R21CA127052-01A1
project_title: Coleus forskohlii extract: melanization and UV protection by a natural product
administering_ic: NCI
award_notice_date: 2008-05-28
opportunity_number: PA-06-400
application_type: 1
activity_code: R21
ic: CA
serial_number: 127052
suffix: A1
program_official: UMAR, ASAD
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):   
  
Fairness of skin correlates with diminished epidermal expression of eumelanin the brown/black pigment responsible for dark complexion. Instead there is preferential expression of pheomelanin a sulfated blonde/red melanin species that is soluble and has poor UV-blocking abilities. Persons with high levels of pheomelanin and low levels of eumelanin in the skin have little basal protection from UV radiation and therefore suffer the highest incidence of UV-mediated skin damage and skin cancer. To delineate the relationship between UV exposure and pigmentation and develop novel pigment-based UV protective strategies we have developed a mouse model of "humanized skin" with inducible pigmentation. Like in humans the fair-skinned phenotype in our animal model is caused by defective signaling in melanocytes by the melanocortin-1 receptor (MC1R) a protein that mediates adenylate cyclase activation and cAMP generation when bound by its natural ligand melanocyte stimulating hormone (MSH). Similar to fair- skinned humans who tend to burn rather than tan after sunlight exposure our fair-skinned animals demonstrate heightened UV sensitivity and failure to tan adaptively. Using this novel mouse model we study melanin induction by forskolin a labdane diterpenoid that directly activates adenylate cyclase and promotes intracellular accumulation of cAMP. By topically applying root extract from the C. forskohlii plant (the natural source of forskolin) to the skin we can induce the production of UV-protective eumelanin by chemically circumventing the defective cAMP signaling associated with the mutant MC1R. Using our animal model we will directly modulate cAMP signaling and melanin levels to clarify the protective effects of C. forskohlii extract against UV-mediated skin damage. We hypothesize that pharmacologic up- regulation of cAMP in the skin will protect against UV-mediated damage by promoting eumelanin synthesis and by enhancing the repair of UV-induced DNA photolesions. To address our hypothesis we propose three specific aims: i) Characterize the role of MC1R function in UV-mediated oxidative damage and determine whether pharmacologic replacement of MC1R function protects against oxidative UV injury; ii) Delineate the impact of MC1R function in the repair of UV-induced DNA lesions; and iii) Determine whether molecular bypass of MC1R function by cAMP up-regulation enhances repair following UV exposure. Our goal is to develop the novel approach of UV protection by sunless tanning based on topical administration of this root extract or small molecule derivatives. Our research strategy will provide a substantial foundation on which we can develop UV-protective strategies to prevent rather than treat skin cancer. PUBLIC HEALTH RELEVANCE: Our goals are to (1) understand how UV irradiation damages skin of different pigment types; (2) devise natural pigment-based strategies that protect against UV-mediated skin damage; and (3) effectively prevent skin cancer. Using unique transgenic mice that mimic human skin we will measure DNA damage and repair in UV- exposed skin and explore mitigation of this damage and enhancement of repair. Our proposed research includes both in vivo and in vitro analyses of UV effects in whole skin and in melanocytes derived from our animal model respectively.

project_terms:
Address;Adenylate Cyclase;Affect;Animal Model;Animals;Binding (Molecular Function);Biological Factors;Biological Models;Biology;Breeding;Burn injury;Bypass;Coleus forskohli;Cyclic AMP;DNA;DNA Repair;DNA lesion;Data;Disruption;Diterpenes;Failure (biologic function);Forskolin;Foundations;Free Radical Formation;Functional disorder;Generations;Goals;Human;In Vitro;Incidence;Individual;Injury;Investigation;Labdanes;Ligands;Location;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Mice Transgenic;Modeling;Molecular;Mus;Nucleotides;Pathway interactions;Persons;Phenotype;Pigmentation physiologic function;Pigments;Plant Roots;Plants;Polymorphism Genetic;Prevention of Skin Cancer;Production;Proteins;Receptor Signaling;Receptor Melanocortin Type 1;Relative (related person);Repairs Base Excision;Reporting;Research;Role;Science of Anatomy;Signal Transduction;Skin;Skin Cancer;Skin tanning;Source;Sulfates Inorganic;Sulfates Unspecified or Sulfate Ion;Sunlight;System;Testing;Thymine Dimers;Topical application;Transcriptional Activation;UV Radiation Exposure;UV induced;UV induced DNA damage;UV protection;UV sensitive;Ultraviolet Rays;Up-Regulation (Physiology);Variant;Wild Type Mouse;alpha-Melanocyte stimulating hormone;base;congenic;eumelanin;in vivo;labdane;loss of function;melanocyte;melanoma;mimicry;mouse model;mutant;novel;novel strategies;pheomelanin;photolesion;prevent;protective effect;public health medicine (field);receptor function;repaired;response;small molecule;ultraviolet damage;ultraviolet irradiation;ultraviolet lesions


application_id: 7531323
project_number: 1R03AI076714-01A1
project_title: PAR2 Bronchopulmonary Sensory Nerve and Pathogenesis of Asthma
administering_ic: NIAID
award_notice_date: 2008-06-26
opportunity_number: PA-06-180
application_type: 1
activity_code: R03
ic: AI
serial_number: 076714
suffix: A1
program_official: DONG, GANG
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 8579171
contact_pi: GU, QIHAI
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
project_abstract:
DESCRIPTION (provided by applicant): Protease-activated receptor-2 (PAR2) is expressed in various cells in the airways and lungs. Increasing evidence has suggested that activation of PAR2 contributes to airway inflammation and airway hyperresponsiveness the prominent features of many respiratory diseases including asthma. The mechanism underlying the potent actions of PAR2 in the airways and lungs remains to be elucidated; and an involvement of neurogenic mechanisms caused by the activation of bronchopulmonary sensory nerves particularly C-fiber afferents has been recently suggested. The long-range goal of this research project is to elucidate the mechanism that how the interaction between PAR2 and bronchopulmonary C-fibers is involved in the pathogenesis of asthma. Airway acidification occurs in asthmatic patients and affects airway functions by numerous pathways. One prominent consequence of acidification in the airways is the stimulation of bronchopulmonary C- fibers. The primary objective of this R03 pilot proposal is to investigate the effect of PAR2 activation on the acid stress-induced bronchopulmonary C-fiber responses. Our hypothesis is that when PAR2 is activated by endogenous (e.g. mast cell tryptase and trypsin-like proteases) or exogenous (e.g. airborne allergens) agonists the airway acidification-induced changes in airway functions may be amplified and collectively contributes to the disease process of asthma. Two specific aims have been proposed: 1) to determine the effect of PAR2 activation on vagal bronchopulmonary C-fiber responses to acid stress and to investigate the underlying cellular mechanisms; and 2) to determine the involvement of bronchopulmonary C-fibers in the PAR2 activation-induced airway hyperresponsiveness to acid stress and to differentiate the relative contributions of cholinergic reflex and tachykininergic mechanisms. The in-vivo respiratory recording and in-vitro whole-cell patch-clamping will be carried out in the proposed studies. The results obtained from this proposal should improve our understanding of the pathogenic role of the interaction between PAR2 and bronchopulmonary sensory nerves and offer novel therapeutic strategies for the treatment of airway inflammatory diseases such as asthma.   
  
PUBLIC HEALTH RELEVANCE: A decrease in airway luminal pH occurs in asthmatic patients and has diverse effect on airway functions. A receptor called protease-activated receptor-2 is known to play an important role in the pathogenesis of asthma. The proposed project will investigate how activation of this receptor regulates the pulmonary sensory nerve responses to low pH in the airways and how these interactions will affect the disease process of asthma.

project_terms:
Affect;Agonist;Airway Obstruction;Asthma;C Fiber;Cells;Cholinergic Agents;Chronic;Development;Disease;Endopeptidases;Goals;Immune;In Vitro;Inflammatory;Knowledge;Liquid substance;Lung;Lung diseases;Nervous system structure;Neuroimmunomodulation;Neuropeptides;Pathogenesis;Pathway interactions;Peptide Hydrolases;Play;Process;Range;Receptor Activation;Receptor PAR-2;Recurrence;Reflex action;Relative (related person);Research Project Grants;Role;Signal Transduction;Trypsin;Tryptase;acid stress;afferent nerve;airborne allergen;airway hyperresponsiveness;airway inflammation;asthmatic patient;base;cholinergic;cytokine;improved;in vivo;neurotrophic factor;novel therapeutics;patch clamp;public health medicine (field);receptor;respiratory;response


application_id: 7531028
project_number: 5R01EY017131-02
project_title: Proteomic Analysis of Retinal Ganglion Cell Death in Glaucoma
administering_ic: NEI
award_notice_date: 2008-11-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 017131
program_official: AGARWAL, NEERAJ
project_start_date: 2007-12-01
project_end_date: 2010-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6803489
contact_pi: TEZEL, GULGUN
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Only through a better understanding of the pathogenic mechanisms of glaucoma will improved and innovative treatments evolve. Preliminary studies using different series of in vitro and in vivo experiments as well as histopathological studies using human donor eyes have provided evidence that alterations in protein expression protein protein interactions post translational protein modifications and proteolytic cleavage change the protein complement of retinal ganglion cells (RGCs) during glaucomatous neurodegeneration with important implications in pathogenic mechanisms. The proposed experiments in this application are based on the hypothesis that an innovative analytical approach using the proteomics technology can identify time dependent alterations in the RGC protein complement on a large scale which characterize precise mechanisms of the RGC response to injury from initial insult to execution of cell death in glaucoma. The specific aims that will address this hypothesis include the identification of alterations in the RGC protein expression and post translational protein modifications during the course of glaucomatous neurodegeneration in an experimental rat model of chronic pressure induced glaucoma. Time dependent alterations of the RGC proteome such as up regulation or down regulation of protein expression will be quantitatively evaluated by comparing the proteomic datasets between ocular hypertensive and control eyes using RGC protein samples obtained at different time points by pooling from rat eyes matched for intraocular pressure (IOP) exposure and axon loss. Relationship between the differential protein expression and the level of IOP exposure and axon loss will be statistically determined. To improve the sensitivity of the detection identification and relative quantification of protein expression complementary proteomic approaches will be utilized which will include 2D PAGE based and gel free techniques using mass spectrometry. Oxidatively modified RGC proteins will be identified through 2D oxylot analysis and phosphorylated RGC proteins and their interacting proteins in enriched phosphoprotein complexes will be identified through complementary approaches of the targeted proteomics. Parallel experiments will also determine cellular localization of the identified proteins using immunohistochemistry. In addition to histological sections obtained from ocular hypertensive and control rat eyes glaucomatous and normal retinas obtained from human donor eyes will also be utilized to better validate the relevance of new findings to human disease. These studies should provide comprehensive information about the cellular mechanisms associated with RGC death at the protein level thereby offering biomarkers and novel treatment targets for neuroprotective interventions in glaucoma a leading cause of blindness. The information obtained from these studies is also expected to be useful in multiple disciplines to characterize pathogenic processes of various other neurodegenerative diseases leading to RGC death.   
In glaucoma a specific type of nerve cells the retinal ganglion cells progressively die leading to gradual loss of visual function. Since the current treatment of this blinding disease is not sufficient to prevent disease progression additional treatment strategies need to be developed to protect these cells in glaucomatous eyes. As a requirement to accomplish this goal this project aims to identify the precise mechanisms associated with the nerve cell death in glaucoma using a powerful technology in animal experiments as well as performing experiments utilizing human donor eyes. These studies are expected to provide comprehensive information about the nerve cell death process thereby allowing new treatment possibilities for 3 million Americans suffering from glaucoma.

project_terms:
Address;American;Animal Experiments;Axon;Blindness;Cell Death;Cell Death Process;Cells;Chronic;Complement;Complex;Data Set;Detection;Discipline;Disease;Disease Progression;Down-Regulation;Eye;Gel;Glaucoma;Goals;Human;Immunohistochemistry;In Vitro;Intervention;Mass Spectrum Analysis;Modeling;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Ocular Hypertension;Phosphoproteins;Physiologic Intraocular Pressure;Post-Translational Protein Processing;Process;Proteins;Proteome;Proteomics;Rattus;Relative (related person);Retina;Retinal Ganglion Cells;Sampling;Series;Techniques;Technology;Time;Two-Dimensional Polyacrylamide Gel Electrophoresis;Up-Regulation (Physiology);Vision;base;biomarker;human disease;improved;in vivo;innovation;novel;pressure;prevent;protein expression;protein protein interaction;research study;response to injury;treatment strategy


application_id: 7530065
project_number: 1R03AG029304-01A2
project_title: Dynamics of Sleep Fragmentation in the Elderly
administering_ic: NIA
award_notice_date: 2008-07-17
opportunity_number: PA-06-180
application_type: 1
activity_code: R03
ic: AG
serial_number: 029304
suffix: A2
program_official: SUNEJA, SANOJ
project_start_date: 2008-08-01
project_end_date: 2010-06-30
study_section: Cardiovascular and Sleep Epidemiology Study Section[CASE]
contact_pi_person_id: 1918429
contact_pi: BRUCE, EUGENE N
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Aging is associated with major changes in the structure and quality of sleep. Older subjects experience decreased sleep efficiency increased numbers of arousals and awakenings and sleep fragmentation which may well play a pivotal role in both the daytime sleepiness and the age-associated decline in neurocognitive function in the elderly. This application develops and tests an integrative hypothesis that relates arousals to the occurrence of transient EEG events indicative of subthreshold arousals and sleep consolidations. By applying this integrative framework to both middle-aged (40-49 yrs) and elderly (70-79 yrs) Caucasian and African-American men and women we expect to generate novel insights into the causes of sleep fragmentation in the elderly. Preliminary results show that Sample Entropy of the C3A2 EEG signal varies systematically with sleep state being highest in Wake and lowest in stage 3-4 and that this variation is age-dependent. Thus a conceptual model of temporal fluctuations of depth of sleep within a sleep state and a novel measure of depth of sleep EEG entropy (a measure of irregularity) are proposed. A core principle of the model is that depth of sleep is continuously graded. Three hypotheses derived from this model will be tested: (1) EEG entropy fluctuates in a given sleep state and arousals are more likely when entropy transiently increases; (2) in a given sleep state fluctuations of EEG entropy with time (which reflect short-lived events in the EEG such as microarousals and bursts of delta waves) are not entirely random; rather they also reflect the slow decay of the effects of prior events that perturbed the depth of sleep; and (3) the time course of decay of the effects of past sleep-disturbing events is slower in elderly than in middle- aged subjects; this factor contributes to the increased number of arousals in the elderly by prolonging the period of increased susceptibility to a subsequent sleep disturbance. This Small Research Grant will utilize existing data from the NHLBI-supported Sleep Heart Health Study (polysomnograms from >6400 subjects are available).  PUBLIC HEALTH RELEVANCE: We expect that the proposed studies will develop and validate a novel framework for understanding the time-varying relationship of transient EEG events to arousals and their increase with aging. Additionally Sample Entropy of EEG signals may find utility as a measure of depth of sleep for evaluating the effects of therapies. The goal of this study is to understand why the elderly awaken more frequently at night than younger individuals. To accomplish this objective we will analyze electroencephalogram (EEG) recordings obtained from middle-aged and elderly subjects while they are asleep to enhance our understanding of the changes that occur in these EEGs immediately before subjects wake up.

project_terms:
Accounting;Address;Adult;African American;Age;Aging;Arousal;Categories;Caucasians;Caucasoid Race;Circadian Rhythms;Clinical;Complex;Data;Data Analyses;Depth;Development;Disruption;Distant;Elderly;Electroencephalogram;Entropy;Evaluation;Event;Figs - dietary;Foundations;Frequencies (time pattern);Future;Gender;Goals;Grants Applications;Health;Heart;Homeostasis;Incidence;Individual;Kale - dietary;Life;Measures;Methods;Modeling;Nature;Neurocognitive;Numbers;Pattern;Play;Predisposition;Prevalence;Race;Rate;Relative (related person);Reporting;Research Project Grants;Resolution;Role;Sampling;Signal Transduction;Sleep;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Staging;Standards of Weights and Measures;Stimulus;Structure;Testing;Time;Variant;Woman;age effect;age related;base;clinically significant;concept;experience;indexing;insight;men;middle age;neuromechanism;novel;public health medicine (field);relating to nervous system;sleep regulation;time use


application_id: 7529996
project_number: 1R01DE019243-01
project_title: Mathematical Model of Parotid Acinar Differentiation
administering_ic: NIDCR
award_notice_date: 2008-09-16
opportunity_number: RFA-DE-08-001
application_type: 1
activity_code: R01
ic: DE
serial_number: 019243
program_official: SHUM, LILLIAN
project_start_date: 2008-09-16
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZDE1 RW (17)]
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: REMPALA, GRZEGORZ A
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_terms:
Acinar Cell;Address;Algorithms;American;Antigens Differentiation;Biological Response Modifier Therapy;Biology;Blotting Western;Cell Differentiation process;Computing Methodologies;Confidence Intervals;Coupled;Data;Development;Embryo;Equation;Foundations;Functional disorder;Gene Expression;Gene Proteins;Gene Targeting;Gene Transfer;Genes;Genomics;Goals;Histologic;Immunohistochemistry;Infant Newborn;MicroRNAs;Microarray Analysis;Modeling;Models Statistical;Molecular;Muscle;Natural regeneration;Neurons;Oral;Output;Parotid Gland;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Procedures;Process;Publications;RNA;RNA Small Interfering;Radiation therapy;Rattus;Regulation;Regulatory Pathway;Research;Reverse Transcriptase Polymerase Chain Reaction;Salivary;Salivary Glands;Serous;Signal Pathway;Signal Transduction;Sjogren's Syndrome;Source;Standards of Weights and Measures;Symptoms;Syndrome;Syndromes Radiation;System;Systems Biology;Testing;Time;Tissues;Transfection;Validation;Variant;Work;Xerostomia;cell type;expectation;gene therapy;laser capture microdissection;mathematical model;network models;new technology;parotid cell;predictive modeling;prototype;research study;response;restoration;salivary acinar cell;salivary cell;transcription factor


application_id: 7529978
project_number: 1R21CA131688-01A1
project_title: Predicting Non-Sentinel Node Metastasis in Breast Cancer Patients
administering_ic: NCI
award_notice_date: 2008-06-20
opportunity_number: PA-07-022
application_type: 1
activity_code: R21
ic: CA
serial_number: 131688
suffix: A1
program_official: LIVELY, TRACY LUGO
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 7874100
contact_pi: CHAGPAR, ANEES B
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Sentinel lymph node (SLN) biopsy is a minimally invasive means of accurately staging the axilla in breast cancer patients. While finding negative SLNs avoids axillary lymph node dissection (ALND) the finding of micrometastasis in the SLN mandates a completion ALND. Up to 80% of all SLN-positive patients will have no further disease in the axilla. There is a significant gap in our current knowledge in predicting which SLN- positive patients have a low likelihood of non-SLN metastasis and can therefore avoid ALND. A novel intra- operative RT-PCR based assay (GeneSearch(r)) for detecting SLN micrometastases has been shown to correlate with SLN tumor burden in breast cancer patients. The potential utility of this new technology in predicting which patients will not have further disease in their non-SLNs has not been investigated. Developing a robust clinical prediction rule for non-SLN status using these data will fill this gap in our knowledge and provide timely conclusions which will have a direct impact on patient care. In order to achieve this over-arching objective we propose the following specific aims: (1) To determine the impact of quantitative cycle time values of the GeneSearch(r) assay on non-SLN status using both bivariate and multivariable logistic regression analyses and (2) to create and validate (using bootstrap techniques) a clinical prediction rule to predict non-SLN status in SLN-positive patients using preoperatively- and intraoperatively-available clinicopathologic factors including data obtained from the GeneSearch(r) assay. We hypothesize that the quantitative RT-PCR cycle time for both mammoglobin (MMG) and cytokeratin 19 (CK19) as evaluated as continuous values using the GeneSearch(r) assay will be significantly associated with non-SLN metastasis on bivariate analyses. In addition the cycle time for these markers will predict non-SLN metastasis independent of other factors. We hypothesize that a valid clinical prediction rule can be created using preoperatively- and intraoperatively-available clinicopathologic factors including data obtained from the GeneSearch(r) assay that will identify a subset of patients in whom the likelihood of non-SLN metastasis is = 5%. It is anticipated that the addition of data from the GeneSearch(r) assay will significantly improve the ability to predict this group of patients over the use of clinicopathologic factors alone. The creation and validation of a robust clinical prediction rule that incorporates novel molecular data to identify a subgroup of patients at low risk of having non-SLN metastasis will fill a significant gap in our current knowledge and will reduce unnecessary morbidity of ALND helping to meet the NCI's Challenge of eliminating suffering due to cancer by 2015. PUBLIC HEALTH RELEVANCE: Up to 80% of breast cancer patients who have minimal disease in their first draining (sentinel) lymph nodes will have no further disease in their axilla. However currently there is no accurate means of predicting which patients will not have residual disease and therefore all patients who have a tumor deposit = 0.2 mm in their sentinel lymph nodes will have the remaining lymph nodes removed -- a procedure that is associated with considerable morbidity. We seek to create and validate a clinical prediction rule incorporating novel molecular data to identify a subgroup of patients at low risk of having non-SLN metastasis thereby filling a significant gap in our current knowledge and reducing unnecessary morbidity for breast cancer patients.

project_terms:
Axilla;Axillary Lymph Node Dissection;Biological Assay;Breast;Cancer Patient;Clinical;Clinical Trials;Data;Decision Making;Deposition;Disease;Excision;Invasive;Keratin-19;Knowledge;Logistics;Malignant Neoplasms;Malignant neoplasm of breast;Micrometastasis;Molecular;Morbidity - disease rate;Negative Axillary Lymph Node;Negative Finding;Negative Lymph Node;Neoplasm Metastasis;Nomograms;Numbers;Pathology;Patient Care;Patients;Polymerase Chain Reaction;Procedures;Regression Analysis;Reverse Transcriptase Polymerase Chain Reaction;Risk;Sentinel Lymph Node;Sentinel Lymph Node Biopsy;Staging;Standards of Weights and Measures;Subgroup;Surgical Management;Techniques;Technology;Time;Translating;Tumor Burden;Tumors Residual;Validation;base;improved;lymph nodes;new technology;novel;public health medicine (field);success;tumor


application_id: 7527641
project_number: 1R01AG027258-01A2
project_title: Telomeric dysfunction and the premature aging and cancer-prone disease Werner syn
administering_ic: NIA
award_notice_date: 2008-07-28
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AG
serial_number: 027258
suffix: A2
program_official: CHATTERJI, MINKI
project_start_date: 2008-08-01
project_end_date: 2012-06-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 7034221
contact_pi: ORREN, DAVID KEITH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Affect;Age;Aging;Apoptosis;Apoptotic;Atherosclerosis;Back;Binding (Molecular Function);Biochemical;Cataract;Cell Aging;Cell Death;Cell division;Cells;Characteristics;Chromosomal Instability;Chromosomes;Chronic;Cisplatin;Condition;DNA;DNA Damage;DNA Structure;DNA lesion;Development;Diabetes Mellitus;Disease;Disease regression;Dose;Ensure;Enzymes;Exonuclease;Fibroblasts;Frequencies (time pattern);Functional disorder;Genes;Genome;Genome Stability;Hereditary Disease;Human;Hypertension;Individual;Investigation;Kinetics;Knowledge;Laboratories;Length;Life;Link;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Metabolism;Methods;Modeling;Monitor;Normal Cell;Osteoporosis;Oxidative Stress;Pathway interactions;Patients;Phenotype;Play;Premature aging syndrome;Process;Proteins;Reaction;Recombination Genetic;Research;Resolution;Role;Solid;Structure;Study models;TERF1 gene;Telomerase;Telomere Maintenance;Telomeric Repeat Binding Protein 2;Time;Tissues;WRN gene;WRN protein human;Werner Syndrome;Work;age related;early onset;helicase;loss of function;normal aging;nuclease;prevent;public health medicine (field);research study;senescence;telomere;tumor progression


application_id: 7527245
project_number: 2R01GM050388-15
project_title: Role of Lipid Phosphatases in Cholesterol and Triglyceride Synthesis
administering_ic: NIGMS
award_notice_date: 2008-09-01
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: GM
serial_number: 050388
program_official: IKEDA, RICHARD A
project_start_date: 1994-08-01
project_end_date: 2012-06-30
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
12-diacylglycerol;Acid Phosphatidic;Address;Adipose tissue;Amplifiers;Anabolism;Basic Science;Behavior;Binding (Molecular Function);Biochemical;Biochemistry;Biological;Biological Assay;Body fat;Calories;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Nucleus;Cell model;Cells;Cerebrovascular Disorders;Cholesterol;Cholesterol Synthesis Inhibition;Cholesterol Dietary;Class;Clinical Management;Condition;Country;Data;Deposition;Desire for food;Detergents;Development;Diet;Diet Modification;Diglycerides;Diphosphates;Disease;Drug Delivery Systems;Effectiveness;Elevation;Endoplasmic Reticulum;Enzymatic Biochemistry;Enzymes;Equilibrium;Excretory function;Exhibits;Farnesol;Funding;Gene Family;Genes;Genetic;Glycerophospholipids;Goals;In Vitro;Intervention;Intracellular Membranes;Knowledge;Lecithin;Lipids;Lipoproteins;Localized;Malignant Neoplasms;Mediating;Membrane;Membrane Lipids;Membrane Proteins;Metabolic;Metabolic Diseases;Metabolism;Molecular;Molecular and Cellular Biology;Mono-S;Morbidity - disease rate;Mortality Vital Statistics;Nuclear Envelope;Obesity;Output;Pathway interactions;Peripheral;Pharmaceutical Preparations;Phosphates Isoprenoid;Phosphatidate Phosphatase;Phospholipids;Phosphoric Monoester Hydrolases;Physical activity;Play;Positioning Attribute;Prevalence;Process;Process of absorption;Protein Isoforms;Protein Isoprenylation;Proteins;Range;Regulation;Research;Research Project Grants;Role;Signal Transduction;Source;Specific qualifier value;Sphingolipids;Sterols;System;Techniques;Testing;Triglycerides;Viral Vector;Work;Yeasts;base;cardiovascular risk factor;energy balance;enzyme activity;enzyme pathway;geranylgeraniol;human disease;hypercholesterolemia;improved;inorganic phosphate;insight;isoprenoid;lipid metabolism;lipine;member;membrane model;mevalonate;mouse model;novel;obesity management;obesity treatment;phosphate ester;preference;programs;prospective;public health medicine (field);success;therapeutic target;therapy development


application_id: 7527090
project_number: 2R01EY012354-09A1
project_title: Isolation of congenital stationary night blindness genes
administering_ic: NEI
award_notice_date: 2008-09-01
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: EY
serial_number: 012354
suffix: A1
program_official: MARIANI, ANDREW P
project_start_date: 1999-02-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 CB-G (90)]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Binding (Molecular Function);Biochemical;Blindness;Brain;Calcium Channel;Candidate Disease Gene;Cations;Cells;Chromosome Pairing;Class;Complex;Defect;Dendrites;Disease;Electroretinography;Elements;Extracellular Matrix Proteins;Family;Family member;Feedback;Funding;Genes;Glutamate Receptor;Glutamates;Goals;Grant;Human;Hybrids;Immunoprecipitation;Individual;Lateral;Lead;Leucine-Rich Repeat;Ligands;Light;Link;Mediating;Mice Knockout;Mice Mutant Strains;Molecular;Mus;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Numbers;Pathway interactions;Phosphatidylinositol 45-Diphosphate;Photoreceptors;Property;Proteins;Proteoglycan;Receptors Metabotropic Glutamate;Retina;Retinal;Retinal Cone;Rods (Retina);Role;Signal Transduction;Site;Spectrum Analysis Mass;Standards of Weights and Measures;Structure;Structure-Activity Relationship;Synapses;Synaptic Transmission;Vision;Yeasts;blind;extracellular;ganglion cell;glycosylation;horizontal cell;in vivo;intracellular protein transport;member;mouse model;mutant;neurotransmitter release;patch clamp;postsynaptic;presynaptic;protein transport;public health medicine (field);research study;response;transmission process


application_id: 7527007
project_number: 1R01CA131059-01A1
project_title: Novel Modular Vascular Patterning Assay for HTS
administering_ic: NCI
award_notice_date: 2008-07-01
opportunity_number: PA-07-320
application_type: 1
activity_code: R01
ic: CA
serial_number: 131059
suffix: A1
program_official: LI, JERRY
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 1881039
contact_pi: MOHAN, ROYCE
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The vascular endothelial cells lining blood vessels in humans are one of the principle sites that become involved in inflammatory and proliferative responses to a diverse array of human diseases. Microvascular homeostasis is thus a vital component of human health; its inappropriate activation in response to inflammatory and angiogenic stimuli can become a pathogenic component fueling the growth and spread of cancers and contributing to debilitating arthritis age-related macular degeneration and multiple organ failure associated with underlying diseases such as diabetes. On the other hand impaired angiogenesis is also equally pathogenic and afflicts its victims by slowing down wound healing and contributing to heart diseases and stroke. Collectively given the complexity of the angiogenesis signaling system these major burdens of human health that arise from dysregulation of blood vessel growth need to be addressed by a more concerted effort in drug discovery. Biological assays that model the processes of angiogenic diseases can assist the process of drug discovery and disease target identification. However currently few assays represent the complexity of the diseased microvasculature as they typically focus on one pathogenic mechanism/pathway. With this in mind we propose to continue the development of a high content high throughput screening (HC-HTS) vascular patterning assay which we have recently validated as drug screening tool through a previously funded NIH Roadmap Initiative R21 grant. In this R01 proposal we plan to extend the scale and scope of the three dimensional endothelial cell sprouting assay (3D-ECSA) to promote its adoption for the HTS paradigm. Our innovative approaches bring in 1) modern automated robotic systems that allow us to improve efficiency and standardize production of spheroids 2) high content image analysis software to use with 3D-ECSA under HTS conditions and 3) development of a pilot scale chemical library focused on the immunoproteosome as a chemical enabling tool towards validation of the 3D-ECSA. The successful accomplishments of these goals will not only afford us a valuable tool for large scale biology but will help bring forward a technology advancement to identify new classes of chemical probes of protein function and drug leads for life saving therapeutics.

project_terms:
3-Dimensional;Address;Adoption;Age related macular degeneration;Arthritis;Biological;Biological Assay;Biology;Blood Vessels;Cardiovascular Diseases;Cell Line;Characteristics;Chemicals;Class;Complex;Computer software;Condition;Controlled Study;Development;Diabetes Mellitus;Differentiation and Growth;Disease;Diversity Library;Drug Evaluation Preclinical;Endothelial Cells;Funding;Goals;Grant;Growth;Growth Factor;Hand;Health;Heart Diseases;Homeostasis;Human;Hyperglycemia;Hypoxia;Image;Image Analysis;Impaired wound healing;Individual;Inflammatory;Lead;Life;Malignant Neoplasms;Manuals;Mind;Modeling;Multicellular Process;Multiple Organ Failure;Numbers;Optics;Pathway interactions;Pattern;Pharmaceutical Preparations;Principal Investigator;Process;Production;Quality Control;Research;Robotics;Running;Screening procedure;Signal Transduction;Simulate;Site;Stimulus;System;Technology;Therapeutic;United States Food and Drug Administration;United States National Institutes of Health;Validation;Vascular Endothelial Cell;Wound Healing;angiogenesis;drug discovery;high throughput screening;human disease;improved;innovation;novel;programs;protein function;prototype;response;small molecule libraries;stroke;tool


application_id: 7525871
project_number: 2R01CA091901-06A1
project_title: Novel Aureolic Acid-Type Antitumor Agents
administering_ic: NCI
award_notice_date: 2008-07-28
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: CA
serial_number: 091901
suffix: A1
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2013-05-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adverse effects;Anabolism;Antineoplastic Agents;Arthritis;Biochemical;Biological Factors;Cancer Cell Growth;Chromomycin A3;Chromomycins;DNA;Depth;Disease;Engineering;Enzymes;Funding;Generations;Goals;Hypercalcemia;In Vitro;Investigation;Lead;Methods;Oxidoreductase;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Plicamycin;Process;Production;Property;Proteins;Proto-Oncogenes;Refractory;Research;Research Project Grants;Role;SRC gene;Signal Transduction Pathway;Specificity;Substrate Specificity;Therapeutic Index;Toxic effect;Work;analog;anticancer activity;antitumor agent;c-myc Genes;chemotherapy;chromomycin;combinatorial;crosslink;design;desire;enzyme mechanism;follow-up;glycosyltransferase;improved;in vivo;interest;nervous system disorder;novel;olivomycin A;polyketide synthase;protein structure;public health medicine (field);research study;sugar;tool;tumor


application_id: 7525462
project_number: 1R01CA118434-01A2
project_title: Biochemical Mechanisms of Se Anticancer Activity in Lung
administering_ic: NCI
award_notice_date: 2008-08-29
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 118434
suffix: A2
program_official: PERLOFF, MARJORIE
project_start_date: 2008-09-01
project_end_date: 2012-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
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
project_terms:
Adhesions;Anabolism;Antineoplastic Agents;Apoptosis;Biochemical;Biochemical Pathway;Biochemistry;Biological Availability;Biological Markers;Blood;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cancer cell line;Cell Cycle Arrest;Cell Death;Cell Proliferation;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chemotaxis;Citric Acid Cycle;Class;Clinical Trials;Complex;Cultured Cells;Data;Dependence;Detection;Development;Diagnostic;Dietary Supplements;Elements;Figs - dietary;Formulations Drug;Functional disorder;G-Protein-Coupled Receptors;Gene Expression;Gene Expression Profiling;Glycolysis;Growth;Histocompatibility Testing;Human;Laboratories;Lead;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Metabolism;Mice Knockout;Modification;Molecular;Molecular Profiling;Mus;Nature;Neoplasm Metastasis;Numbers;Organ;Oxidation-Reduction;Pathway interactions;Patients;Pattern;Pentosephosphate Pathway;Plasma;Play;Polyamines;Process;Property;Prostate;Protein Processing Post-Translational;Proteins;Proteomics;Range;Regulation;Regulatory Pathway;Research;Role;Science;Selenium;Selenium Compounds;Selenomethionine;Site;Small cell carcinoma of lung;System;Testing;Tissues;Trace Elements;Validation;Work;anticancer activity;anticancer treatment;base;cancer cell;cancer prevention;cell growth;cell motility;chemokine;immunodeficient mouse model;in vivo;lipid metabolism;lymph nodes;metabolomics;methylselenic acid;migration;mouse model;neoplastic cell;nucleotide metabolism;protein expression;public health medicine (field);response;thioredoxin reductase;tool;transcriptomics;tumor;urea cycle


application_id: 7524957
project_number: 1R01HL090749-01A1
project_title: Myocardial Stiffness in Diastolic Heart Failure
administering_ic: NHLBI
award_notice_date: 2008-08-04
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 090749
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 2008-09-01
project_end_date: 2013-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Actins;Affect;Age;Aging;American;Animal Model;Animals;Biochemical;Calcium;Cardiac;Cardiovascular Diseases;Categories;Catheters;Cessation of life;Characteristics;Clinical;Clinical Treatment;Collagen;Computer Simulation;Condition;Control Animal;Control Groups;Data;Diagnosis;Diastole;Diastolic heart failure;Diet;Diet Fat-Restricted;Disease;EFRAC;Elastin;Elderly;Elements;Etiology;Extracellular Matrix;Failure (biologic function);Fatty acid glycerol esters;Figs - dietary;Filament;Functional disorder;Future;Gene Expression;Head;Health Care Costs;Heart;Heart failure;Histological Techniques;Individual;Intermediate Filaments;Kinetics;Left ventricular structure;Measurement;Measures;Mechanics;Methods;Modeling;Molecular;Molecular Profiling;Muscle Cells;Myocardial;Myocardium;Myosin ATPase;Myosin Heavy Chains;Obesity;Overweight;Patients;Physiological;Preparation;Pressure- physical agent;Principal Investigator;Property;Protein Isoforms;Proteins;Range;Rat-1;Rats Inbred F344;Rats Sprague-Dawley;Rattus;Relative (related person);Research;Research Project Grants;Resistance;Sampling;Scientist;Simulate;Stretching;Sum;Symptoms;Takeda brand of pioglitazone hydrochloride;Techniques;Testing;Therapeutic;Tissues;Ventricular;Ventricular Function;Weight;Work;age related;aged;connectin;crosslink;feeding;gel electrophoresis;in vivo;mathematical model;older patient;particle;public health medicine (field);research study;sensor;simulation


application_id: 7524287
project_number: 2R01CA060872-11
project_title: Mechanism of Apoptosis and Inhibition of Tumor Progression and Metastasis by Par-
administering_ic: NCI
award_notice_date: 2008-07-01
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: CA
serial_number: 060872
program_official: SALNIKOW, KONSTANTIN
project_start_date: 1995-09-30
project_end_date: 2013-04-30
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
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
project_terms:
Address;Adenocarcinoma;Amino Acids;Animals;Apoptosis;Apoptotic;Binding (Molecular Function);Blotting Western;Bone Marrow Transplantation;Brefeldin A;Cancer Model;Cell Nucleus;Cell Survival;Cell membrane;Cells;Cessation of life;Control Animal;Culture Media Conditioned;Cyclic AMP-Dependent Protein Kinases;Data;Dependence;Disease regression;Distant Metastasis;Endoplasmic Reticulum;Exposure to;Frequencies (time pattern);Funding;Golgi Apparatus;Growth;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Lesion;Leucine Zippers;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mice Transgenic;Morphologic artifacts;Mus;NF-kappa B;Neoplasm Metastasis;Normal Cell;PAWR gene;PAWR protein;Pathway interactions;Phosphorylation;Plasmids;Prostate;Prostatic;Prostatic Intraepithelial Neoplasias;Prostatic Neoplasms;Proteins;RNA Interference;Range;Receptor Signaling;Receptors Cell Surface;Recombinants;Research;Science;Signal Pathway;Spleen;Stromal Cells;TNFSF10 gene;Tertiary Protein Structure;Testing;Therapeutic;Thinking function;Transfection;Transgenes;Transgenic Animals;Transgenic Organisms;Vertebrates;base;cancer cell;clinically relevant;extracellular;glucose-regulated proteins;in vivo;inhibitor/antagonist;insight;intravenous injection;neutralizing antibody;novel;prevent;public health medicine (field);tumor;tumor growth;tumor progression


application_id: 7522736
project_number: 7R01EB007556-02
project_title: Fabricated Microvascular Networks
administering_ic: NIBIB
award_notice_date: 2007-11-21
opportunity_number: PAR-06-504
application_type: 7
activity_code: R01
ic: EB
serial_number: 007556
program_official: HUNZIKER, ROSEMARIE
project_start_date: 2007-07-12
project_end_date: 2011-04-30
study_section: ZEB1-OSR-C(M1)S
contact_pi_person_id: 1915922
contact_pi: HOYING, JAMES B
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Fabricated Microvascular Networks. The importance of an effective vascular supply for tissue health is universally accepted. In developing strategies to build vasculatures for tissue engineering and other therapeutic applications it is important to recognize that foremost the new vasculature must quickly provide sufficient blood flow to the target tissue to preserve cell viability. We have found that new microvessels formed in vitro can begin to carry blood within the first days following implantation. However flow patterns are atypical and likely ineffective at establishing normoxia until many days later. The delay is primarily due to a lack of organization within the network at the time of implantation and the time needed to develop new mature inflow and outflow pathways. We hypothesize that pre-determining an appropriate network organization prior to implantation would reduce the amount of time needed for the new microvasculature to effectively perfuse a tissue. We have established generic technologies utilizing a direct-write tissue printing tool for patterning and organizing tissue components for tissue engineering applications. We propose to implement this technology to design and fabricate pre-patterned 3-dimensional microvascular networks with pre-existing inflow and outflow pathways. Also we will use an in vitro intravascular-perfusion bioreactor system to establish flow through the networks to further organize and mature the microvascular networks prior to implantation. Computational modeling and physiological analyses serve to direct design strategies and characterize the architectures and functionality of the fabricated vasculatures both in vitro and in vivo. In addition to providing an enabling technology platform for assembling pre-determined microvascular networks this work will provide a foundation from which to explore the importance of network architectures in vascular function.

project_terms:
3-Dimensional;Adipose tissue;Architecture;Bioreactors;Blood;Blood Vessels;Blood flow;Caliber;Cell Death;Cell Survival;Cells;Computer Architectures;Computer Simulation;Condition;Data;Effectiveness;Elements;Engineering;Foundations;Generic Drugs;Health;Hypoxia;Image;Implant;In Vitro;Indium;Lead;Liquid substance;Mechanics;Methods;Modeling;Molds;Pathway interactions;Pattern;Perfusion;Phenotype;Physiological;Physiology;Printing;Process;Protocols documentation;Research;Structure;System;Technology;Testing;Therapeutic;Three-dimensional analysis;Time;Tissue Engineering;Tissues;Vascular blood supply;Work;Writing;day;design;implantation;in vivo;indexing;insight;lithography;research study;scaffold;tool


application_id: 7522576
project_number: 1R21NS060033-01A2
project_title: Role of Olig3 in cerebellar and precerebellar development
administering_ic: NINDS
award_notice_date: 2008-05-27
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: NS
serial_number: 060033
suffix: A2
program_official: RIDDLE, ROBERT D
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Neurogenesis and Cell Fate Study Section[NCF]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
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_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this application is to understand the molecular control of neuronal specification and differentiation in the cerebellum. The cerebellum is a midbrain-hindbrain structure that participates in coordination of motor function and higher cognition function. Abnormal cerebellar development can lead to neurological diseases such as autism and medulloblastoma. Although the morphogenesis of cerebellum has been well studied in the past century little is known about the molecular mechanisms that control the fate specification and differentiation of the cerebellar neurons and their associated precerebellar neurons located in the brainstem. Recent studies have demonstrated that transcription factors of the bHLH family are important regulators of the proliferation fate specification and differentiation of cerebellar neurons and precerebellar neurons. In this application we propose to study the functional role of Olig3 bHLH factor in the development of cerebellar and precerebellar neurons. During early neural development Olig3 is highly expressed in the rhombic lips of the hindbrain the dorsal neural progenitor cells that give rise to both cerebellar neurons and precerebellar neurons. The pattern of Olig3 expression leads us to hypothesize that it functions to regulate the development of cerebellar system. In this pilot application two specific aims are proposed to test this hypothesis and further define its role in the fate specification proliferation migration or differentiation of cerebellar and precerebellar neurons. The first aim of the proposal is to characterize the mutational effects of Olig3 on the specification and differentiation of cerebellar nd precerebellar neurons. The second aim is to investigate possible changes in the identity and migration of rhombic lips cells in Olig3 mutant embryos using the Cre-loxP mediated genetic labeling methods.   
PUBLIC HEALTH RELEVANCE: The proposed studies will provide important insights into the molecular regulation of neuronal specification proliferation and differentiation in the developing cerebellar system. Knowledge obtained from this study can help us understand the molecular mechanisms underlying cerebellum disorders and medulloblastoma and provide cues for therapeutic treatment of these neurological diseases.

project_terms:
Affect;Animals;Autistic Disorder;Brain Stem;Cell Nucleus;Cells;Cerebellum;Cognition;Cues;Development;Disease;Dorsal;Embryo;Family;Fiber;Genes;Genetic;Goals;Immunohistochemistry;In Situ;Inferior;Knowledge;Label;Lead;Lip structure;Maps;Mediating;Methods;Midbrain structure;Molecular;Morphogenesis;Motor;Movement;Mutation;Neurons;Numbers;Olives - dietary;Pattern;Personal Satisfaction;Phenotype;Principal Investigator;RNA;Regulation;Role;Structure;System;Testing;Therapeutic;hindbrain;insight;medulloblastoma;migration;mossy fiber;mutant;nerve stem cell;nervous system disorder;neurodevelopment;progenitor;programs;public health medicine (field);relating to nervous system;transcription factor


application_id: 7522335
project_number: 2U01DA016205-06
project_title: Central States Criminal Justice Drug Abuse Center
administering_ic: NIDA
award_notice_date: 2008-08-21
opportunity_number: RFA-DA-08-002
application_type: 2
activity_code: U01
ic: DA
serial_number: 016205
program_official: LIBERMAN, AKIVA M
project_start_date: 2002-09-30
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZDA1 MXS-M (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:
Caring;Communities;Continuity of Patient Care;Data;Data Analyses;Drug abuse;Drug usage;Evidence based intervention;Grants Applications;Guidelines;Justice Criminal;Kentucky;Knowledge;Letters;Manuscripts;National Institute of Drug Abuse;Numbers;Organizational Change;Prisoner;Protocols documentation;Publications;Publishing;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Rural;Safety;Study Outcome;Substance abuse problem;System;Universities;Vision;Woman;concept;design;innovation;interest;offender;parolee;public health medicine (field);success;treatment organization


application_id: 7515485
project_number: 1R15GM085749-01
project_title: Analysis of Polyhydroxyalkanoate Inclusion Biogenesis
administering_ic: NIGMS
award_notice_date: 2008-06-30
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 085749
program_official: ANDERSON, JAMES J
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The general goal of this research is  
to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis. Polyhydroxyalkanoates (PHAs) are bacterial polymers that are synthesized in inclusions when carbon levels are high and another essential nutrient such as nitrogen is limited. There is considerable commercial interest in PHAs because they comprise a family of polyesters that can be formed into plastics that are biodegradable. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an  
outer envelope that is the thickness of a membrane bilayer a middle network layer and an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic  
membrane as an envelope. The goal of this research is to prove or disprove this supposition. The specific aims of the research are: 1) definitively prove periplasmic localization of PhaP via fluorescence localization and Western blot analyses of subcellular fractions 2) demonstrate that the inclusion envelope is derived from the cytoplasmic membrane by proteomic analysis and 3) characterize proteins that bind transiently and permanently to PhaP in hopes of elucidating the mechanism of inclusion biogenesis. Ultimately the goal of the research is to enlarge our knowledge of inclusion  
biogenesis to the point that this process can be controlled and utilized for medical applications. For instance it could be envisioned that instead of polymer being inserted into the inclusion bioactive compounds could be inserted making the inclusion into a drug delivery vehicle. Morehead State University has recently embarked upon a process whereby undergraduate research is emphasized and faculty members are encouraged to become teacher/scholars. Significant resources have been allocated to this goal. This project supports this mission and will enhance the research environment at MSU by providing undergraduate students with numerous opportunities to learn the fundamentals of biomedical research while conducting research that will enlarge our knowledge of prokaryotic processes. PUBLIC HEALTH RELEVANCE:  Using atomic force microscopy we have resolved the structural arrangement of polyhydroxyalkanoate inclusions and this has led to a preliminary model for inclusion biogenesis. The purpose of this research is to test this preliminary model in hopes of adapting the strategy of biogenesis for medical applications in which inclusions could be used as drug delivery vehicles.

project_terms:
Bacteria;Biogenesis;Biomedical Research;Blotting Western;Carbon;Cell membrane;Cytoplasm;Data;Drug Delivery Systems;Electron Microscopy;Environment;Faculty;Family;Fluorescence;Genetic;Goals;Knowledge;Learning;Ligands;Medical;Membrane;Microscopy Atomic Force;Mission;Modeling;Molecular;Molecular Genetics;Movement;Nitrogen;Nutrient;Plastics;Polyesters;Polymers;Process;Protein Binding;Proteins;Proteomics;Purpose;Research;Resources;Scaffolding Protein;Solid;Sorting - Cell Movement;Structure;Students;Subcellular Fractions;Surface;Testing;Thick;Tissues;Universities;interest;member;periplasm;programs;public health medicine (field);receptor;teacher

public_health_relevance:
Using atomic force microscopy we have resolved the structural arrangement ofpolyhydroxyalkanoate inclusions and this has led to a preliminary model for inclusionbiogenesis. The purpose of this research is to test this preliminary model in hopes ofadapting the strategy of biogenesis for medical applications in which inclusions could beused as drug delivery vehicles.


application_id: 7514945
project_number: 5P01ES011860-05
project_title: Inhalation Core
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 9002
contact_pi_person_id: 1867518
contact_pi: POSTLETHWAIT, EDWARD M
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Acrolein;Animals;Arts;Back;Biological;Blood;Breathing;Butadiene;Chemicals;Collection;Condition;Data;Freezing;Health;Human Resources;Inhalation Exposure;Killings;Life;Medical;Monitor;Safety;Sampling;Shipping;Ships;Texas;Tissues;Universities;Urine;Week;animal resource;day;research study


application_id: 7514928
project_number: 5P01ES011860-05
project_title: Bioanalytical Core
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 9001
contact_pi_person_id: 1957095
contact_pi: PIERCE, WILLIAM M
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Aldehydes;Biochemical;Cardiac;Chromatography High Pressure Liquid;Chromatography Mass;Enzymes;Gas Chromatography;Individual;Proteins;Proteomics;Purpose;Spectrometry;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spectrum Analysis Mass;Techniques;adduct


application_id: 7514927
project_number: 5P01ES011860-05
project_title: Administrative Core
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 5001
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Administrator;Aldehydes;Animals;Blood;Breathing;Businesses;Cardiology;Daily;Data;Databases;Histology;Individual;Internet;Maintenance;Manuscripts;Monitor;Mus;Pathologist;Reporting;Schedule;Sentinel;Shipping;Ships;Site;Toxic effect;animal tissue;programs;repository;research study


application_id: 7514926
project_number: 5P01ES011860-05
project_title: Role of Environmental Aldehydes in Acute and Chronic Cardiac Dysfunction
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 0004
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Acrolein;Acute;Affect;Aldehydes;Apolipoprotein E;Area;Arrhythmia;Atherosclerosis;Biochemical;Calcium;Cardiac;Cardiology;Cardiomyopathies;Cardiomyopathy Dilated;Cardiotoxicity;Characteristics;Chronic;Cities;Clinical;Collaborations;Complex;Condition;Contractile Proteins;Coupling;Data;Depressed mood;Development;Doctor of Medicine;Doctor of Philosophy;Environment;Environmental Pollutants;Environmental Risk Factor;Etiology;Exposure to;Functional disorder;Glutathione S-Transferase;Goals;Hand;Health Sciences;Heart Diseases;Heart failure;Hypertrophy;In Vitro;Infarction;Inflammation;Inflammatory;Injury;Investigation;Ischemia;Ischemic Preconditioning;Left;Left Ventricular Remodeling;Light;Link;Measures;Mediating;Medicine;Mental Depression;Metabolism;Mice Knockout;Microfilaments;Modification;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial dysfunction;Myocytes Cardiac;NF-kappa B;NOS3 protein human;Names;Occupational Medicine;Oxidative Stress;Pathologic;Patient Care;Performance;Phenotype;Physiological reperfusion;Play;Pressure- physical agent;Principal Investigator;Protein Kinase C;Reperfusion Therapy;Research;Research Personnel;Resources;Role;Severities;Signal Transduction;Specific qualifier value;Stress;Testing;Texas;Universities;Ventricular;Ventricular Function Left;Ventricular Remodeling;Yang;base;cytokine;design;exposed human population;hypercholesterolemia;in vivo;insight;programs;protein kinase C epsilon;public health medicine (field);research study;response;trans-2-hexenal;transcription factor


application_id: 7514925
project_number: 5P01ES011860-05
project_title: Role of Platelet Activation and Vascular Pathology in Aldehyde Toxicity
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 0003
contact_pi_person_id: 1879365
contact_pi: D'SOUZA, STANLEY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Acrolein;Acute;Adhesions;Adhesiveness;Adhesives;Affect;Agonist;Aldehydes;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Blood Cells;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell Adhesion Molecules;Cells;Cities;Coagulation Process;Collaborations;Deposition;Doctor of Medicine;Doctor of Philosophy;Eating;Endothelium;Environment;Environmental Pollutants;Enzymes;Event;Fibrinogen;Food;Fossil Fuels;Functional disorder;Glutathione S-Transferase;Health Sciences;Hexenal;Human;Individual;Instruction;Integrins;Intercellular adhesion molecule 1;Jewish follower of religion;Lead;Lesion;Link;Lipoproteins;Measures;Metabolic;Metabolism;Mice Knockout;Mus;Myocardial Infarction;Names;Oxidoreductase;P-Selectin;Pathology;Pathway interactions;Platelet Activation;Platelet aggregation;Preparation;Principal Investigator;Process;Proteins;Research;Research Personnel;Resources;Risk;Role;Series;Signal Transduction;Specific qualifier value;Techniques;Testing;Thrombosis;Toxic Environmental Substances;Toxic effect;Universities;Up-Regulation (Physiology);adduct;cardiovascular disorder risk;cell motility;inhibitor/antagonist;injured;monocyte;pollutant;programs;receptor;research study;response to injury;stroke;trans-2-hexenal


application_id: 7514918
project_number: 5P01ES011860-05
project_title: Atherogenic Effects of Environmental Aldehydes
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 0002
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Abdominal aorta structure;Acrolein;Adhesiveness;Affect;Aldehydes;Animals;Apolipoprotein E;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Breathing;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cause of Death;Cell Adhesion Molecules;Cellularity;Cholesterol;Chronic;Collaborations;Deposition;Depth;Development;Disease;Doctor of Philosophy;Eating;Endothelium Vascular;Environmental Exposure;Enzymes;Excision;Exposure to;Future;Goals;Growth;Hexenal;High Density Lipoproteins;Human;In Situ;Infiltration;Intercellular adhesion molecule 1;Investigation;Lead;Lecithin;Lesion;Light;Lipids;Lipoproteins;Measures;Mediating;Metabolism;Mice Knockout;Modification;Molecular;Mus;Muscle Smooth Vascular;Myocytes Smooth Muscle;NF-kappa B;Oral;Organ;Oxidation-Reduction;Peripheral;Plant Roots;Predisposition;Process;Rate;Research Personnel;Risk;Series;Serum;Severities;Site;Smc1l1 protein mouse;Smc1l2 protein mouse;Staging;Sulfhydryl Compounds;T-Lymphocyte;TP53 gene;Testing;Tissues;Toxic effect;Transferase;Vascular Cell Adhesion Molecule-1;Vascular remodeling;Very low density lipoprotein;Work;activating transcription factor;adduct;arterial stiffness;atherogenesis;base;cardiovascular risk factor;cell growth;design;macrophage;particle;pollutant;programs;research study;trans-2-hexenal;transcription factor;vascular inflammation


application_id: 7514916
project_number: 5P01ES011860-05
project_title: Aldehyde Metabolism and Cardiovascular Disease
administering_ic: NIEHS
application_type: 5
activity_code: P01
ic: ES
serial_number: 011860
project_start_date: 2007-09-01
project_end_date: 2008-06-30
study_section: ZES1-SET-A(P7)
subproject_number: 0001
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-01
budget_end_date: 2008-06-30
project_terms:
Ablation;Acetylcysteine;Acrolein;Affect;Aldehyde Reductase;Aldehyde dehydrogenase (NAD+);Aldehydes;Autoimmune Responses;Biochemical Pathway;Blood;Breathing;Cardiac;Cardiovascular Diseases;Cardiovascular system;Chronic;Collaborations;Cytochrome P450;Deposition;Doctor of Philosophy;Endothelial Cells;Enzymes;Functional disorder;Future;Genetic;Glutathione;Glutathione S-Transferase;Goals;Hepatic;Hexenal;Individual;Inflammation;Injury;Kidney;Lead;Lipoproteins;Measures;Mediating;Metabolic;Metabolic Detoxication Drug;Metabolism;Mice Knockout;Modeling;Mus;Myocytes Smooth Muscle;Oxidoreductase;Pathway interactions;Platelet Activation;Population;Predisposition;Protein Isoforms;Proteins;Relative (related person);Relaxation;Research Personnel;Risk;Risks Relative;Role;Route;Serum;Site;Testing;Tissues;Toxic effect;Toxicokinetics;Up-Regulation (Physiology);Urine;adduct;aldehyde dehydrogenases;base;cardiovascular injury;design;prevent;programs;response;trans-2-hexenal


application_id: 7514742
project_number: 7R01HL074289-05
project_title: Mechanisms of lung injury following autologous BMT
administering_ic: NHLBI
award_notice_date: 2007-12-26
application_type: 7
activity_code: R01
ic: HL
serial_number: 074289
program_official: PEAVY, HANNAH H
project_start_date: 2003-08-01
project_end_date: 2009-07-31
study_section: Lung Biology and Pathology Study Section[LBPA]
contact_pi_person_id: 1863574
contact_pi: FOLZ, RODNEY J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-12-26
project_abstract:
DESCRIPTION (provided by applicant): Lung toxicity following high dose chemotherapy (HDC) and bone marrow transplantation (BMT) or hematopoietic stem cell support develops in up to 70% of patients with the most severe form of toxicity termed idiopathic pneumonia syndrome (IPS) accounting for up to 40% of non-graft versus host disease related deaths.  We have described a lung toxicity syndrome that occurs following HDC and autologous bone marrow transplant (autoBMT) that we termed delayed pulmonary toxicity syndrome (DPTS).  DPTS may be an early form of IPS is a risk factor for increased mortality and manifests as an interstitial pneumonitis no sooner than 4 to 6 weeks following autoBMT (mean onset 11 weeks).  To begin to better understand its pathogenesis we developed a novel HDCIautoBMT mouse model of lung toxicity that shows remarkable similarity to the human condition.  Based on clinical and bronchoalveolar lavage studies of patients undergoing HDC/autoBMT and our mouse model we hypothesize three specific mechanisms the development of DPTS.  First HDC induces an intense oxidative stress resulting in both lung tissue injury and increases in monocyte chemo attractant protein-1 (MCP-1).  Second in response primarily to MCP-1 (and MIP-1a) pulmonary inflammatory cells are recruited into the lung which possess antigen presenting cells (APC) features and may further stimulate a T cell lymphocyte response.  Finally fibroblast growth factors like FGF-2 initiate a lung repair and fibrotic response.  We plan to test these hypotheses by utilizing mouse strains that 1) overexpress and under express (knockout) antioxidant enzymes 2) overexpress MCP-1 and 3) are deficient in CCR2.  Additional studies designed to characterize the pulmonary inflammatory cells determine their activation status and their ability to stimulate T cells will be performed.  Finally we plan to identify BALF growth factors responsible for the development of restrictive lung.  This proposal should provide new insights into the pathophysiology of lung injury following autologous bone marrow transplant and provide the basis for future clinical studies to prevent or treat this serious pulmonary complication.

project_terms:
acute disease /disorder;antigen presentation;antigen presenting cell;antioxidants;autologous transplantation;bone marrow transplantation;chemotherapy;fibroblast growth factor;flow cytometry;gene targeting;genetically modified animals;glutathione;inflammation;kinase inhibitor;laboratory mouse;leukocyte activation /transformation;lung injury;lymphocyte;macrophage;monocyte chemoattractant protein 1;oxidative stress;pathologic process;phenotype;protein purification


application_id: 7514586
project_number: 7R01AG029623-02
project_title: Role of TWEAK in Skeletal Muscle Metabolism
administering_ic: NIA
award_notice_date: 2007-10-31
application_type: 7
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2012-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-11-01
project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Actins;Adverse effects;Affect;Age;Aging;Anabolism;Antigens Differentiation;Apoptosis;Apoptosis Promoter;Appendix;Area;Attenuated;Bacteria;Binding (Molecular Function);Biological;Body Weight;Cachexia;Catabolism;Cell physiology;Cells;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complication;Condition;Cultured Cells;Cystic Fibrosis;Cytoplasmic Tail;DNA Complementary;Data;Development;Dexamethasone;Diabetes Mellitus;Disease;Disruption;Dominant-Negative Mutation;Endotoxins;Equilibrium;Etiology;Event;Exhibits;Family;Fiber;Fibroblast Growth Factor;Future;Genes;Grant;Growth;HIV;Heart failure;Hypersensitivity;Immobilization;In Vitro;Inflammation;Inflammatory;Interleukin-6;Knock-out;Lead;Ligand Binding;Ligand Binding Domain;Maintenance;Malignant Neoplasms;Mediating;Medical;Mice Knockout;Mice Transgenic;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Development;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Myoblasts;Myogenic Regulatory Factors;Myogenin;Natural Killer Cells;Natural regeneration;Numbers;Outcome;Pathway interactions;Peptides;Phenotype;Physiological;Play;Prevention;Principal Investigator;Process;Production;Protein Overexpression;Proteins;Publishing;RNA Small Interfering;Recombinants;Regulation;Reporting;Research Personnel;Role;Screening procedure;Sepsis;Signal Pathway;Skeletal muscle structure;Skeletal system;Somatomedins;Space Flight;Starvation;Stimulus;Study Section;Survival Rate;Syndrome;Techniques;Testing;Therapeutic;Transgenic Organisms;Tropomyosin;Troponin;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-Beta;Two-Hybrid System Techniques;Weight;Work;Yeasts;angiogenesis;base;cDNA Library;caspase;cell growth;cytokine;functional status;gene function;health related quality of life;in vivo;insight;knockout animal;mouse model;muscle metabolism;neutralizing antibody;novel;prevent;programs;protein degradation;receptor;research study;response;size;success;therapy development;tumor growth;wasting;yeast two hybrid system


application_id: 7514522
project_number: 2R01CA073599-09A1
project_title: Redox Regulation of Tumor Suppression by MnSOD
administering_ic: NCI
award_notice_date: 2008-06-10
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: CA
serial_number: 073599
suffix: A1
program_official: POLAND, ALAN P
project_start_date: 1998-09-01
project_end_date: 2013-07-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
910-Dimethyl-12-benzanthracene;Acetates;Affect;Anthracenes;Antioxidants;Apoptosis;Biochemical;Cancer Etiology;Carcinogens;Cell Fractionation;Chemicals;Coupled;Development;Enzymes;Exposure to;Funding;Gene Targeting;Genes;Goals;Health;Human;Immunoprecipitation;Incidence;Injury;Intervention;Knock-out;Knowledge;Learning;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Mice Knockout;Microscopy Confocal;Mitochondria;Modeling;Molecular Biology;Mus;Nuclear;Oxidation-Reduction;Oxidative Stress;Papilloma;Phase;Predisposition;Prevention of Skin Cancer;Process;Promoters Tumor;Protein Overexpression;Protein p53;Radiation;Radiation Other;Range;Regulation;Research;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Neoplasms;Skin Papilloma;Skin Tissue;Staging;Superoxide Dismutase;TP53 gene;Testing;Tetradecanoylphorbol Acetate;Time;Transcription Factor AP-1;Transcription Genetic;Tumor Suppression;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;Wild Type Mouse;anthracene;base;carcinogenesis;cell growth;chemical carcinogen;concept;design;insight;irradiation;mimetics;novel;nucleophosmin;prevent;prototype;public health medicine (field);research study;tumor


application_id: 7513994
project_number: 1R21AG032567-01
project_title: Role of p62 in Protein Aggregation and Neurodegeneration in ALS
administering_ic: NIA
award_notice_date: 2008-08-19
opportunity_number: RFA-AG-08-001
application_type: 1
activity_code: R21
ic: AG
serial_number: 032567
program_official: ST HILLAIRE-CLARKE, CORYSE
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-5 (M1)]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Protein aggregates containing mutant copper-zinc superoxide dismutase (SOD1) are a hallmark of familial amyotrophic lateral sclerosis (ALS Lou Gehrig's disease) an age-related neurodegenerative disease. Conformational differences between wild-type (WT) and mutant SOD1 proteins have been demonstrated by many in vitro studies using a variety of biophysical techniques but in vivo details of the aggregation process remain to be defined. It is also unclear whether protein aggregates are toxic or beneficial. P62/Sequestome 1 (referred as p62 in this proposal) is a multifunctional protein involved in both of the two major protein degradation mechanisms ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. We recently reported that the endogenous mouse p62 levels significantly increased prior to the disease onset in G93A SOD1 transgenic mice. In addition p62 was co-localized with mutant SOD1 and ubiquitin in the protein aggregates in spinal motor neurons in G93A SOD1 transgenic mice. We have established collaboration with Dr. Marie Wooten at Auburn University who is the leading scientist studying p62 in signaling cascades and who will provide the p62 knockout mice for the study. The long term goal of this collaborative project is to understand the role of p62 in protein aggregation caused by ALS-linked SOD1 mutants and motor neuron degeneration in ALS. The innovative aspect of this project is that the role of p62 in the ALS etiology is largely undefined. The central hypothesis to be tested in the project is that p62 can recognize misfolded mutant SOD1 and that p62 can ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteins to the ubiquitin-proteasome system (UPS) and/or autophagy. Our preliminary studies demonstrate that p62 specifically recognizes mutant SOD1 and the ubiquitin-association (UBA) domain of p62 is not essential to such interaction. Our results also show that p62 enhances the formation of aggresome-like inclusion of mutant SOD1 but had little effect on WT SOD1. Recent results from other groups showed that p62 can directly bind to autophagy effector protein Atg8/LC3 and that the formation of autophagy was increased in the G93A SOD1 transgenic mice. These data strongly support the central hypothesis. Three specific aims are designed to determine the mechanisms by which p62 recognizes mutant SOD1 the downstream pathways activated by such interaction and the functional role of p62 in neuronal degeneration. Aim 1 is to map the domains of p62 essential for recognizing and interacting with mutant SOD1. Aim 2 is to determine whether and how p62 mediates the autophagy activation induced by mutant SOD1. Aim 3 is to study how p62 influences protein aggregation and ALS disease progression in vivo using p62 KO mice. The results from this study will provide invaluable insights into the role of p62 in protein aggregation and neurodegeneration in ALS which will result in better understanding of ALS etiology and potential discovery of new therapeutic target for ALS treatment. Project Narrative This collaborative project between Dr. Zhu at University of Kentucky and Dr. Wooten at Auburn University is to understand the role of p62 in mutant SOD1 induced protein aggregation and motor neuron degeneration in amyotrophic lateral sclerosis (ALS) an age-related neurodegenerative disease. The innovative aspect of this project is that the role of p62 in the ALS etiology is largely undefined. P62 is a multifunctional protein involved in both of the two major protein degradation mechanisms ubiquitin-proteasome system (UPS) and autophagy- lysosome pathway. The central hypotheses to be tested in the project are that p62 can recognize misfolded mutant SOD1 and that p62 can ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteins to UPS and/or autophagy. We have obtained substantial amount of preliminary data that strongly support these hypotheses. Three specific aims are designed to further characterize the molecular details regarding the role of p62 in protein homeostasis (degradation and aggregation) and neuronal survival in ALS. Aim 1 is to map the domains of p62 essential for recognizing and interacting with mutant SOD1. Aim 2 is to determine whether and how p62 mediates the autophagy activation induced by mutant SOD1. Aim 3 is to study how p62 influences protein aggregation and ALS disease progression in vivo using p62 KO mice. The results from this study will provide invaluable insights into the role of p62 in protein aggregation and neurodegeneration in ALS which will result in better understanding of ALS etiology and potential discovery of new therapeutic target for ALS treatment.

project_terms:
Address;Amyotrophic Lateral Sclerosis;Animal Model;Autophagocytosis;Autophagosome;Binding (Molecular Function);Blotting Western;Cessation of life;Collaborations;Cultured Cells;Data;Disease Progression;Electrons;Etiology;Familial Amyotrophic Lateral Sclerosis;Goals;Homeostasis;In Vitro;Kentucky;Length;Link;Localized;Lysosomes;Mediating;Mice Knockout;Mice Transgenic;Microscopic;Molecular;Motor;Motor Neurons;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Onset of illness;Pathway interactions;Polyubiquitin;Precipitation;Process;Protein Overexpression;Proteins;Reporting;Role;Scientist;Series;Signal Transduction;Spinal;System;Techniques;Testing;Time;Tissues;Toxic effect;Transgenic Animals;Ubiquitin;Ubiquitination;Universities;age related;copper zinc superoxide dismutase;design;domain mapping;in vivo;innovation;insight;motor neuron degeneration;multicatalytic endopeptidase complex;mutant;neuronal survival;novel therapeutics;protein aggregate;protein aggregation;protein degradation;protein misfolding;therapeutic target


application_id: 7511251
project_number: 1R03HD058850-01
project_title: Academic-Community Coalition for a School-based Obesity Prevention/Treatment Prog
administering_ic: NICHD
award_notice_date: 2008-07-18
opportunity_number: PA-06-416
application_type: 1
activity_code: R03
ic: HD
serial_number: 058850
program_official: HAVERKOS, LYNNE
project_start_date: 2008-08-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZHD1 DSR-M (HB)]
contact_pi_person_id: 8535924
contact_pi: PERMAN, JAY 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky College of Medicine proposes a pilot study to test the feasibility of a school-based program for the prevention and treatment of childhood obesity. The prevalence of childhood obesity has increased dramatically in the United States along with a host of obesity-related diseases. The human and economic costs of this epidemic and related illnesses are enormous and left unchecked they threaten to overwhelm the health care system of this country. Unfortunately there are relatively few studies that both document success in obesity prevention and treatment in children and identify "best practices" suitable for export to other communities and neighborhoods. Initial data from our earlier pilot program at a local elementary school demonstrated a significant improvement in Body Mass Index (BMI) endpoints after only six months of a universal intervention program consisting of physical activity nutrition instruction and behavioral modification. Therefore we propose to test the overall hypothesis that a coalition of academic and community partners can develop and implement a school-based obesity prevention and treatment program that is effective affordable scalable and sustainable. The study design is a parallel-group randomized controlled trial to compare an obesity prevention and treatment program consisting of tiered interventions of escalating intensity with conventional school programs and curricula. Cross-group contamination is minimized by designating an entire elementary school as the intervention group compared with a control elementary school of similar demographic characteristics and student profiles. Specific aim 1 will evaluate the effectiveness of module 1 (universal prevention) interventions aimed at the entire enrollment of the intervention school. They include daily in-class physical activities and nutritional instruction elimination of food rewards and improvements in the school menu. Specific aim 2 will evaluate the efficacy of module 2 (Jumpin' Jaguars program) interventions that are targeted to and tailored for children who are at risk or already overweight/obese (i.e. BMI = 85 percent) and at greatest risk for weight-related illnesses. This module includes individualized strategies to enhance physical activity nutritional education behavioral modification and caregiver involvement and participation. The outcomes for both intervention modules are weight height calculated BMI BMI percentile weight status category and will be obtained every 6-month for two years. We anticipate that the significant improvement in BMI endpoints in module 1 (universal) interventions seen in our earlier pilot will be maintained and extended after the two years of this study. We expect the trend in improvement in BMI endpoints in module 2 interventions (Jumpin' Jaguars) seen in our 6-month earlier pilot will reach significance with the two-year duration of this study. The coalition of academic and community partners enables the leveraging of personnel and material resources such that our program is affordable scalable and sustainable. Programs with these characteristics represent the future for the prevention of childhood obesity in this country. Project Narrative: Since childhood obesity and related illnesses have reached epidemic proportions in the United States effective programs for the prevention and treatment of obesity in children and adolescents are critical for the future health and well-being of the citizens of this nation. In this research application the University Of Kentucky College Of Medicine proposes to test the efficacy of a school-based childhood obesity prevention and treatment program that is built on a coalition of academic and community partners. This program has a high likelihood of identifying "best practices" that are both affordable and scalable and therefore transferable to other communities across the Commonwealth and nation.

project_terms:
Accounting;Address;Adolescent;Age;Behavior Therapy;Body mass index;Cardiovascular Diseases;Caregivers;Categories;Centers for Disease Control and Prevention (U.S.);Characteristics;Child;Childhood;Class;Communities;Country;County;Daily;Data;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Disease;Economic Burden;Economics;Educational Curriculum;Educational aspects;Effectiveness;End Point;Enrollment;Epidemic;Family;Food;Future;Gender;Growth;Health;Healthcare Systems;Height;Human;Human Resources;Instruction;Intervention;Kentucky;Left;Life;Life Expectancy;Malignant Neoplasms;Medical;Medicine;Neighborhoods;Nutritional;Obesity;Obesity associated disease;Orthopedics;Outcome;Overweight;Panthera onca;Personal Satisfaction;Physical activity;Pilot Projects;Population;Prevalence;Prevention;Prevention intervention;Prevention program;Probability;Quality of life;Randomized Controlled Trials;Range;Rate;Research;Research Design;Resources;Rewards;Risk;Schools;Science of nutrition;Sleep Apnea Syndromes;Students;Support Child;Testing;Underrepresented Minority;United States;Universities;Weight;Youth;base;college;cost;design;elementary school;intervention program;obesity prevention;obesity treatment;programs;self esteem;success;treatment program;trend;universal prevention


application_id: 7509433
project_number: 1R03CA135123-01
project_title: SNARE-Mediated Exocytosis in Migration of Pancreatic Cancer Cells
administering_ic: NCI
award_notice_date: 2008-06-11
opportunity_number: PA-06-314
application_type: 1
activity_code: R03
ic: CA
serial_number: 135123
program_official: AULT, GRACE S
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1 ONC-U (92)]
contact_pi_person_id: 9084705
contact_pi: HU, CHUAN
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): Pancreatic cancer is the fourth leading cause of cancer death in the United States. Metastasis - the spreading of cancer from a primary site to distant organs is responsible for 90 percent of the deaths from pancreatic cancer. A fundamental event in metastasis is the migration of cancer cells. Accumulating evidence indicates that intracellular vesicle trafficking plays an important role in cell migration. In migrating cells plasma membrane components and cell adhesion receptors such as integrins are transported by vesicles and exocytosed at the cell front or leading edge. However it is not known what proteins drive polarized exocytosis and how exocytosis is modulated in cancer metastasis. Studies using model systems has demonstrated that pairing of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins on vesicles (v-SNAREs) and SNARE proteins on target membrane (t-SNAREs) mediates intracellular vesicle fusion events including exocytosis. Our preliminary studies indicate that SNARE proteins are actively involved in cell migration. The hypothesis is that SNARE proteins mediate polarized exocytosis in migration of pancreatic cancer cells. Using cell-based assays two Specific Aims will be pursued: 1) Define the function of endocytic v-SNAREs in migration of pancreatic cancer cells; 2) Identify v-SNAREs that mediate the recycling of ?1 integrins to the cell surface. The long-term goal is to elucidate how the SNARE fusion machinery interacts with signal transduction cascades to regulate migration and metastasis of pancreatic cancer cells. Accomplishing the specific aims will deepen our understanding of polarized exocytosis in cell migration and will likely provide potential targets for therapeutic strategies that target motility of pancreatic cancer cells. PUBLIC HEALTH RELEVANCE: Cancer metastasis is still not well understood at the molecular level and current therapies are ineffective in preventing metastasis. Inhibiting the migration of cancer cells is a promising strategy to overcome metastasis. The proposed work will enhance our understanding of the most fundamental event in metastasis - migration of cancer cells.

project_terms:
Biological Assay;Biological Models;Blood Vessel Tissue;Cancer Etiology;Cell Adhesion;Cell membrane;Cell surface;Cells;Cessation of life;Cytoplasmic Tail;Diagnosis;Disease;Distant;Endocytosis;Event;Exocytosis;Goals;In-Migration;Integrins;Life;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Membrane;Metastatic to;Molecular;Mortality Vital Statistics;N-ethylmaleimide-sensitive protein;Nature;Neoplasm Metastasis;Organ;Pathway interactions;Patients;Play;Proteins;RNA Small Interfering;Recycling;Research;Role;SNAP receptor;Signal Transduction;Site;Transport Vesicles;Travel;United States;Vesicle;Work;adhesion receptor;base;cancer cell;cell motility;cellubrevin;cellular imaging;migration;mutant;novel;prevent;public health medicine (field);receptor;target SNARE proteins;therapeutic target;trafficking;vesicular SNARE proteins


application_id: 7509060
project_number: 2R01DE015254-06A1
project_title: Pattern Recognition of P. gingivalis Virulence Factors
administering_ic: NIDCR
award_notice_date: 2008-07-23
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: DE
serial_number: 015254
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-07-01
project_end_date: 2013-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Innate immunity plays a central role in infection-driven inflammatory conditions including periodontitis which is one of the most common chronic disorders of infectious origin in humans. However successful microbial pathogens such as the periodontopathogen Porphyromonas gingivalis have evolved mechanisms which proactively manipulate the innate immune response. Subversion of innate immunity may additionally undermine the overall host defense since the innate immune response plays an instructive role in adaptive immunity. This research proposal has been designed to investigate and elucidate molecular mechanisms whereby P. gingivalis modifies innate immune signaling pathways leading to increased virulence and persistence within the host. Although innate recognition and signaling in response to P. gingivalis is primarily mediated by the Toll-like receptor 2 (TLR2)-centered pattern recognition apparatus preliminary studies indicate that this periodontal pathogen instigates the association of the chemokine receptor CXCR4 with TLR2 resulting in cross-talk and altered signaling downstream of TLR2. On the basis of additional preliminary evidence the overall hypothesis is that P. gingivalis through its cell surface fimbriae exploits CXCR4 and manipulates TLR2 intracellular signaling in ways that suppress the proinflammatory/antimicrobial pathway but enhance a distinct proadhesive pathway; both of these activities have the potential to increase the survival capacity of the pathogen thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. In vitro immunological approaches using transfected cell lines or primary macrophages will elucidate the mechanistic basis of TLR2/CXCR4 cross-talk which is hypothesized to involve the cAMP-dependent protein kinase A. Moreover the biological significance of the putative exploitation of CXCR4 by P. gingivalis will be investigated using a mouse periodontitis model in which a CXCR4 antagonist (AMD3100) is expected to suppress P. gingivalis virulence. The long-term objective of investigating CXCR4-dependent mechanisms whereby P. gingivalis manipulates TLR2 signaling is to identify effective antagonists for redirecting the innate response to benefit the host. The fight against HIV and AIDS has produced a number of drugs including CXCR4 antagonists which are available for investigation in other formidable diseases where CXCR4 may play a pathophysiological role. Such CXCR4 antagonists may find therapeutic application in human periodontitis.   
  
PUBLIC HEALTH RELEVANCE: Periodontitis is one of the most common chronic disorders of infectious origin in humans and is also associated with systemic diseases such as atherosclerosis. This research proposal presents evidence that the periodontal pathogen P. gingivalis exploits a host receptor namely CXCR4 for undermining host defense and promoting its virulence. We believe that CXCR4 antagonists may find therapeutic application in human periodontitis and in this context; we will test a CXCR4 antagonist (AMD3100) for its ability to inhibit P. gingivalis-induced periodontitis in a mouse model.

project_terms:
1-Phosphatidylinositol 3-Kinase;AMD3100;Acquired Immunodeficiency Syndrome;Adhesives;Alveolar Bone Loss;Atherosclerosis;Biological;Biological Response Modifiers;CD14 gene;CXCR4 Signaling Pathway;CXCR4 gene;Cell Line;Cell surface;Chronic Disease;Complex;Condition;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease;Exhibits;Fimbria of hippocampus;Fluorescence Resonance Energy Transfer;Funding;HIV;Host Defense;Human;Immune;Immune response;Immunity;Immunity Natural;In Vitro;Infection;Inflammation;Inflammatory;Integrins;Investigation;Mediating;Microbe;Modeling;Molecular;Mus;Numbers;Oral cavity;Pathway interactions;Pattern Recognition;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Peritonitis;Pharmaceutical Preparations;Pilum;Play;Porphyromonas gingivalis;Proteins;Publishing;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Standards of Weights and Measures;Structure;Systemic disease;Testing;Therapeutic;Toll-Like Receptor 2;Toll-like receptors;Virulence;Virulence Factors;Virulent;Work;antimicrobial;base;bone loss;chemokine receptor;concept;cytohesin-1;design;fight against;fimbrillin;in vivo;macrophage;microbial;microbicide;mouse model;mutant;novel;pathogen;periodontopathogen;prevent;public health medicine (field);receptor;response


application_id: 7508763
project_number: 1R21EY019113-01
project_title: Zeb1 and epithelial-mesenchymal balance in the eye
administering_ic: NEI
award_notice_date: 2008-07-21
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: EY
serial_number: 019113
program_official: MARIANI, ANDREW P
project_start_date: 2008-08-01
project_end_date: 2010-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Overexpression of zinc finger homeodomain 1 (Zeb1) triggers epithelial-mesenchymal transition (EMT) by repressing key epithelial specialization genes including E-cadherin. By contrast mutation of Zeb1 leads to mesenchymal-epithelial transition with ectopic expression of epithelial genes. Mutation of Zeb1 in patients is linked to epithelization of corneal endothelium and posterior polymorphous corneal dystrophy (PPCD). Mice null for Zeb1 exhibit PPCD characteristics late in embryogenesis whereas such pathologic changes are delayed until adulthood in heterozygous mice. Overexpression of Zeb1 occurs in dedifferentiation of retinal pigment epithelial (RPE) cells an EMT characterized by ectopic proliferation loss of pigment and transition to fibroblastic morphology. Such RPE dedifferentiation contributes to proliferative vitreoretinopathy the major complication in retinal detachment. Heterozygous mutation of Zeb1 prevents RPE dedifferentiation. We propose a series of experiments to begin examining the molecular basis for Zeb1 function in regulating epithelial-mesenchymal balance in eye cells. PUBLIC HEALTH RELEVANCE: Epithelial vs. mesenchymal balance is crucial for normal tissue formation in development and this balance is disrupted in eye diseases such as posterior corneal dystrophies and proliferative vitreoretinopathy. We provide evidence that the zinc finger E-box binding homeodomain1 (Zeb1) is important in regulating epithelial-mesenchymal balance in corneal endothelium and retinal pigmented epithelium.

project_terms:
Back;Binding (Molecular Function);Boxing;Cells;Characteristics;Complication;Corneal Endothelium;Corneal dystrophy;Development;E-Cadherin;Ectopic Expression;Embryonic Development;Epithelial;Equilibrium;Exhibits;Eye;Eye diseases;Gene Expression;Genes;Human;Link;Mesenchymal;Mice Knockout;Mice Mutant Strains;Molecular;Morphology;Mus;Mutation;Normal tissue morphology;Pathologic;Patients;Phenotype;Pigments;Principal Investigator;Protein Overexpression;Repression;Retinal Detachment;Retinal Pigments;Role;Series;Specific qualifier value;Structure of retinal pigment epithelium;Transcription Genetic;Vitreoretinopathy Proliferative;Zinc Fingers;base;epithelial to mesenchymal transition;homeodomain;in vivo;prevent;programs;public health medicine (field);research study;transcription factor


application_id: 7506455
project_number: 1R01DA025100-01
project_title: High-activity mutants of cocaine esterase for treatment of drug addiction
administering_ic: NIDA
award_notice_date: 2008-08-11
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DA
serial_number: 025100
program_official: SHIH, MING L
project_start_date: 2008-08-15
project_end_date: 2013-06-30
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: LANDRY, DONALD W;WOODS, JAMES H
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Addiction Drug;Adverse effects;Arts;Behavioral;Catalysis;Cocaine;Computational Technique;Coupled;Dependences Cocaine;Dose;Enzymes;Evaluation;Free Energy;Hybrids;Hydrolysis;In Vitro;Investigation;Lead;Mechanics;Metabolism;Modeling;Molecular;Mutagenesis Site-Directed;Numbers;Overdose;Performance;Pharmaceutical Preparations;Preclinical Testing;Process;Protocols documentation;Reaction;Rodent Model;Roentgen Rays;Structure;Testing;Toxic effect;addiction;base;cocaine esterase;computer studies;design;esterase;immunogenicity;improved;in vivo;models and simulation;molecular dynamics;molecular modeling;mutant;novel;preclinical study;prevent;protein expression;public health medicine (field);quantum;response;therapeutic effectiveness;three dimensional structure


application_id: 7505230
project_number: 1R01GM085231-01
project_title: Role of SR-BI in LPS detoxification
administering_ic: NIGMS
award_notice_date: 2008-08-04
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: GM
serial_number: 085231
program_official: DUNSMORE, SARAH
project_start_date: 2008-08-06
project_end_date: 2013-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Americas;Animals;Antibodies;Bacteria;Bacterial Infections;Binding (Molecular Function);Biological Assay;Bone Marrow;Bone Marrow Transplantation;CD14 Antigen;Cause of Death;Cecum;Cells;Cessation of life;Chinese Hamster Ovary Cell;Co-Immunoprecipitations;Complex;Cross-Over Studies;Death Rate;Disease;End Point;Excision;Functional disorder;HDL cholesteryl ester;HDL receptor;Hepatic;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Hypotension;Infection;Inflammatory;Intervention;Label;Ligation;Lipopolysaccharides;Liver;Living Costs;Mediating;Metabolic Detoxication Drug;Mice Knockout;Mice Transgenic;Modeling;Molecular;Mus;Mutate;Organ;Play;Predisposition;Process;Proteins;Puncture procedure;Purpose;Reaction;Relative (related person);Reporting;Role;SR-BI receptor;Sepsis;Septic Shock;Serum;TLR4 gene;Techniques;Tissues;Toxic effect;Transplantation;Wild Type Mouse;Work;cell type;cytokine;in vivo;macrophage;mutant;novel;novel strategies;prevent;public health medicine (field);receptor;receptor binding;response;scavenger receptor;septic;uptake


application_id: 7504971
project_number: 1P20NR010679-01
project_title: Admin Core
administering_ic: NINR
application_type: 1
activity_code: P20
ic: NR
serial_number: 010679
project_start_date: 2007-09-29
project_end_date: 2012-06-30
study_section: ZNR1-REV-B(04)R
subproject_number: 9003
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-09-29
budget_end_date: 2008-06-30
project_abstract:
Virtually all cardiovascular and most pulmonary diseases are chronic in nature and require complex andlife-long self-management. Current statistics elaborating the impact of chronic cardiovascular and pulmonaryconditions ' illustrate the importance of targeting self-management research specifically to cardiovascular andpulmonary diseases. Chronic cardiac or pulmonary diseases comprise 3 of the top 4 causes of death (i.e.heart disease cancers stroke and chronic lower respiratory diseases). Worldwide cardiovascular disease(CVD) is the most common cause of death and morbidity and in most developed countries is the single largesthealthcare expenditure.2'3 At least one in three Americans lives with chronic CVD; this percentage increaseswith age and ultimately one in two dies of CVD usually after living years with the challenge of engaging inself-management of the chronic condition.2'3 The World Health Organization (WHO) estimates thatchronic lower respiratory diseases share 4th and 5th places with HIV/AIDS as causes of deathworldwide. There were more than 3 million deaths worldwide from chronic obstructive pulmonary disease in2005 which corresponds to 5% of all deaths globally. As with CVD most patients with chronic lowerrespiratory diseases live years with the associated self-management challenges. As people accumulate CVDand pulmonary risk factors develop chronic CVD and pulmonary illnesses or grow older the process of selfmanagementbecomes exponentially more complex demanding and time-consuming. In fact it is preciselywhen people could benefit most from self-management that self-management efforts fail are abandoned orare not even attempted.4"15 thus research aimed at improving self-management skills and efforts should havea measurable impact on the public and personal burden from cardiac and pulmonary conditions.16"In order to address this significant problem we propose to establish an exploratory research center theCenter for Biobehavioral Research on Self-Management of Cardiopulmonary Disease at the University ofKentucky College of Nursing (UKCON). The short-term goal of the Center is to provide both new andexperienced investigators with the support and resources necessary to conduct pilot/feasibility work usingbiobehavioral measures to investigate self-management related to cardiopulmonary conditions. The long-termgoal of the Center is to facilitate faculty use of data from these studies to develop sustained interdisciplinaryprograms of self-management research and to support more established investigators in the continuationexpansion or redirection of current research programs. The Center will be composed of an Administrative Corethat oversees the Center and the two additional Cores: 1) Self-Management Pilot/Feasibility and BiobehavioralOutcomes Core; and 2) Research Program Development Data Analysis and Dissemination Core. The specificaims for the Center are listed below. Strategies for achieving these aims and associated evaluation criteria areoutlined in the Evaluation section.1. Develop the research infrastructure at the UKCON to promote and support research on processesinterventions and outcomes of self-management of cardiovascular and pulmonary diseases byestablishing an exploratory research Center for Biobehavioral Research on Self-Management ofCardiopulmonary Disease.2. Expand the quality and quantity of self-management research projects using biobehavioralmethods by centralizing methodological resources.3. Expand the number of nurse investigators doing interdisciplinary self-management research bysupporting interdisciplinary exchange and linkages.4. Contribute to the scientific foundation for self-management by promotion and dissemination ofsystematic investigations of self-management processes interventions and outcomes.5. Plan for and develop sustainability of interdisciplinary self-management research programs bybuilding active and growing partnerships inside and outside of the University of Kentucky.Given existing research strengths in the UKCON our initial pilot/feasibility studies will focus on improvingself-management in patients with heart failure. However the focus will expand to improvement of selfmanagementof other cardiopulmonary conditions. We will publish calls once the Center is funded forpilot/feasibility studies in all areas of CVD and pulmonary disease self-management.The initial focus on heart failure self-management interventions will be innovative in that each studyproposes a different self-management skill target and focuses on a different process or processes. The projectproposed by Dr. Chung will target a full range of heart failure self-management skills and will focus on the roleof family members as partners in the self-management process who can either help or hinder the process.Dr. Peden's proposal focuses on depression a major co-morbidity in heart failure that markedly impairs heartfailure self-management20'21 using a cognitive restructuring intervention to manage depression and enhancepatient's self-management skills. Dr. Welsh's project will include a test of a theory-based intervention aimed atimproving one particularly intractable behavior among patients with heart failure following a low-sodium diet.Because fluid overload related to sodium diet nonadherence is thought to be one of the major proximatecauses of rehospitalization in patients with heart failure improvement of self-management in this one areacould have a substantial impact on rehospitalization outcomes.22'23Research Base for Self-Management. There are 5 separate ongoing R01's at the UKCON directly related toself-management. Dr. Debra Moseris PI on one NIH NINRR01 and site PI on two other NIH NINRROIs. Dr.Terry Lennie is PI on one NIH NINR R01; and Dr. Ellen Hahn is PI on a NIH NHLBI R01 (see biosketches fordetails of these 5 grants). The R01 s encompass the range of self-management from the individual (Drs. Moserand Lennie's 4 grants that address self-management in patients with heart failure or CVD) to the community(Dr. Hahn's R01 that addresses the impact of state-wide smoke-free policy development on smokingcessation) levels as defined by the WHO (see Evaluation section for definition).

project_terms:
AIDS/HIV problem;Address;Adherence (attribute);Age;American;Area;Behavior;Cardiac;Cardiopulmonary;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Classification;Cognitive;Collaborations;Communities;Complex;Condition;Consultations;Cor pulmonale;Data;Data Analyses;Developed Countries;Developing Countries;Development;Diet;Diet Sodium-Restricted;Discipline of Nursing;Evaluation;Expenditure;Faculty;Family member;Feasibility Studies;Fluid overload;Foundations;Funding;Goals;Grant;Guidelines;Healthcare;Heart Diseases;Heart failure;Individual;Intervention;Investigation;Kentucky;Life;Lung;Lung diseases;Malignant Neoplasms;Measurable;Measures;Mental Depression;Methods;Monitor;Morbidity - disease rate;Nature;Numbers;Nurses;Outcome;Patients;Policy Developments;Policy Development;Preparation;Process;Productivity;Program Development;Publishing;Range;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Risk Factors;Role;Science of Statistics;Self Management;Site;Smoke;Sodium;Support of Research;Testing;Thinking function;Time;United States National Institutes of Health;Universities;Work;World Health Organization;base;biobehavior;chronic stroke;college;dissemination research;experience;improved;innovation;programs;skills;smoking cessation;theories


application_id: 7504300
project_number: 1R01DA025032-01
project_title: Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies
administering_ic: NIDA
award_notice_date: 2008-12-29
opportunity_number: PA-07-333
application_type: 1
activity_code: R01
ic: DA
serial_number: 025032
program_official: OVERSBY, STEVEN
project_start_date: 2009-01-01
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZDA1 MXH-H (20)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Admission activity;Agonist;American;Attenuated;Behavior;Behavioral;Behavioral Mechanisms;Cardiovascular system;Clinical;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Dependence;Dextroamphetamine;Dose;Educational process of instructing;Engineering;Epidemiology;Goals;Great Lakes Region;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Laboratory Procedures;Laboratory Study;Learning;Location;Maintenance;Mediating;Methadone;Methamphetamine;Methods;Modeling;Nicotine;Opiate Addiction;Pharmaceutical Preparations;Pharmacotherapy;Placebos;Procedures;Psychostimulant dependence;Questionnaires;Recording of previous events;Relapse;Replacement Therapy;Reporting;Research;Safety;Self Administration;Signal Transduction;Stimulus;Testing;Uncertainty;bench to bedside;clinical effect;clinical efficacy;design;disorder later incidence prevention;drug abstinence;drug discrimination;effective therapy;indexing;methamphetamine abuse;nicotine replacement;novel;preclinical study;prevent;public health medicine (field);public health relevance;research study;volunteer


application_id: 7503457
project_number: 5R01AA016959-02
project_title: Ethanol alteration of the neurogenic niche
administering_ic: NIAAA
award_notice_date: 2008-08-13
opportunity_number: PA-05-074
application_type: 5
activity_code: R01
ic: AA
serial_number: 016959
program_official: NORONHA, ANTONIO
project_start_date: 2007-09-30
project_end_date: 2012-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Address;Adult;Alcohol abuse;Alcoholic Intoxication;Alcoholism;Alcohols;American;Anti-Inflammatory Agents;Anti-inflammatory;Autopsy;Autoradiography;Behavior;Behavioral;Biological Assay;Brain;Brain Injuries;Brain Mass;Cell Death;Cell Proliferation;Cells;Cellular Morphology;Chronic;Cognition;Cognitive deficits;Data;Dependence;Diagnostic;Environment;Enzymes;Ethanol;Event;Future;Goals;Grant;Growth Factor;Hippocampus (Brain);Image;Immunohistochemistry;Impaired cognition;In Situ Hybridization;Intention;Laboratories;Lead;Link;Microglia;Modeling;Morphology;Natural regeneration;Nerve Degeneration;Neuroglia;Neuroprotective Agents;Outcome;Pathway interactions;Pharmacotherapy;Phenotype;Population;Proliferating;Recovery;Recruitment (Neurology);Recruitment Activity;Regulation;Research Personnel;Role;Site;Stem cells;Structure;Testing;Week;Work;alcohol abstinence;alcohol abuse therapy;alcohol exposure;alcohol use disorder;binge drinking;cognitive function;cytokine;cytotoxicity;macrophage;nerve stem cell;neurogenesis;neuroprotection;novel;novel strategies;novel therapeutics;preconditioning;prevent;problem drinker;public health medicine (field);receptor;relating to nervous system;repaired;response;stem;therapeutic target


application_id: 7503007
project_number: 1R56DK075892-01A1
project_title: Targeting TLR/CLR to enhance immunoregulation and prevent or treat diabetes.
administering_ic: NIDDK
award_notice_date: 2007-09-29
opportunity_number: PA-07-070
application_type: 1
activity_code: R56
ic: DK
serial_number: 075892
suffix: A1
program_official: SPAIN, LISA M
project_start_date: 2007-09-30
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1-IMM-K(02)M]
contact_pi_person_id: 7770672
contact_pi: ALARD, PASCALE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
AbstractDefects in antigen presenting cell (APC) function and immunoregulation underlie thedevelopment of type I diabetes in NOD mice and humans. Studies have shown thatCD4+CD25+ regulatory T cell function is reduced in NOD mice and diabetic patients. Ourpreliminary studies suggest the defect resides in the ability of NOD APC to activateCD4+CD25+ regulatory T cells rather than in the CD4+CD25+ regulatory T cellsthemselves. We hypothesize that a defect in the APC compartment in NOD mice mayresult in deficient regulatory T cell activation and may contribute to diabetesdevelopment. Infection or treatment with a number of different types of microorganismsincluding lactobacillus and M. tuberculosis prevent or delay diabetes in NOD mice.Interestingly microorganisms can evade the immune response by inducing tolerancethrough the targeting of Toll-like receptors (TLR) and/or C-type lectin receptors (CLR)expressed by APC. For this reason we propose that the microorganisms that preventdiabetes act on NOD APC via TLR and/or CLR enabling the APC to activate/induceregulatory T cells. The objective of the present proposal is to determine whetherTLR/CLR ligands can enhance NOD APC ability to activate regulatory cells and preventor treat diabetes. In Aim 1 we will analyze the defect in NOD APC. In Aim 2 we willevaluate the mechanisms by which Lactobacilli prevent disease in NOD mice. In Aim 3we will examine whether TLR2 and/or CLR ligands that have been associated withtolerance induction can enhance NOD APC activation of CD4+CD25+ regulatory T cellsand prevent disease in mice. The results of these experiments should provide a basisfor the development of novel strategies for the treatment of diabetes.

project_terms:
Address;Adoptive Transfer;Antigen-Presenting Cells;Autoimmune Diseases;Biological Assay;Cell physiology;Cells;Data;Defect;Development;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Disease;Emulsions;Exhibits;Freund's Adjuvant;Goals;Human;Immune response;Immunization;In Vitro;Infection;Infectious Agent;Injection of therapeutic agent;Lactobacillus;Lectin Receptors;Ligands;Mediating;Mice Congenic;Mice Inbred NOD;Microspheres;Molecular;Mus;Mycobacterium tuberculosis;Non obese;Numbers;Oils;Patients;Play;Polymerase Chain Reaction;Receptors C Type Lectin;Regulation;Resistance;Role;Signal Pathway;Surface;T-Cell Activation;T-Lymphocyte;TLR2 gene;Testing;Time;Toll-like receptors;abstracting;base;cytokine;diabetic;genetic analysis;immunoregulation;in vivo;microorganism;novel strategies;prevent;research study


application_id: 7502596
project_number: 5R01NS058382-02
project_title: Cellular Nucleic Acid Binding Protein (CNBP) in Aging and Disease
administering_ic: NINDS
award_notice_date: 2008-03-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 058382
program_official: REFOLO, LORENZO
project_start_date: 2007-09-30
project_end_date: 2012-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
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:
Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein Precursor;Amyloid deposition;Animal Model;Automobile Driving;Binding Proteins;Binding Sites;Biochemical;Biological;Biological Models;Brain;Cell Culture System;Cell physiology;Cells;Cultured Cells;Data;Degenerative Disorder;Deposition;Development;Disease;Drug Industry;Enzymes;Event;Foundations;Future;Generations;Genes;Genetic;Health;Human;In Vitro;Introns;Investigation;Knowledge;Lead;Link;Mediator of activation protein;Muscular Dystrophies;Myopathy;Myositis Inclusion Body;Myotonic Dystrophy;Nucleotides;Pathogenesis;Pathology;Peptides;Peripheral;Process;Protein Binding;Protein Overexpression;Proteins;RNA;RNA Messenger;RNA-Binding Proteins;Rate;Regulation;Role;Site;Skeletal system;Staging;Testing;Therapeutic;Title;ZNF9 protein human;age related;base;beta-site APP cleaving enzyme 1;beta-site APP cleaving enzyme 2;design;improved;in vivo;inhibitor/antagonist;insight;knock-down;mouse model;normal aging;novel;secretase


application_id: 7502391
project_number: 3R01EY014701-04S1
project_title: GABAc Receptors & Mouse Retinal Ganglion Cell Responses
administering_ic: NEI
award_notice_date: 2007-09-30
application_type: 3
activity_code: R01
ic: EY
serial_number: 014701
suffix: S1
program_official: MARIANI, ANDREW P
project_start_date: 2004-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
at bhetop of each _ _ _ _ __ _ RESEARCH GRANTTABLE OF CONTENTS Page NumbersFace Page .................................................................................................................................................. 1Description

project_terms:
Agonist;Biological Models;Cells;Cellular Morphology;Class;Complement;Data;Depth;Evaluation;Eye;Face;Feedback;Felis catus;Goldfish;In Vitro;Individual;Knowledge;Light;Mediating;Mice Knockout;Morphology;Mus;Nerve Fibers;Numbers;Optic Nerve;Oryctolagus cuniculus;Physiological;Play;Preparation;Primates;Property;Relative (related person);Reporting;Research Project Grants;Retina;Retinal;Retinal Ganglion Cells;Role;Salamander;Sampling;Shapes;Specificity;Structure;Systems Analysis;Thinking function;Vision;Visual;defined contribution;in vivo;interest;receptor;response;retinal adaptation;theories;visual receptive field


application_id: 7501380
project_number: 5R36DA024127-02
project_title: Separate and Combined Effects of Progesterone and Triazolam in Healthy Women
administering_ic: NIDA
award_notice_date: 2008-08-20
opportunity_number: PAR-06-476
application_type: 5
activity_code: R36
ic: DA
serial_number: 024127
program_official: WETHERINGTON, CORA LEE
project_start_date: 2007-09-30
project_end_date: 2010-02-28
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
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): There is accumulating evidence from many directions indicating that gender plays a critical role in drug abuse. Biological factors including gonadal sex hormones contribute in a significant although incompletely understood manner to gender differences in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example GABAA receptor function is positively modulated by both progesterone and many sedative drugs including the benzodiazepines. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines. The first proposed study will utilize a within-subject design to examine the separate and combined effects of a range of doses of micronized sublingual progesterone (0 50 150 and 250) and oral triazolam (0.00 0.12 and 0.25 mg/70 kg) on the subjective psychomotor and physiological effects of healthy premenopausal women under conditions of low circulating sex hormones. The second study also a withinsubject design will examine the effect of progesterone pretreatment on the discriminative stimulus effects of triazolam (0.00 0.06 0.12 and 0.25 mg/70 kg) in healthy premenopausal women also under conditions of low circulating sex hormones. The progesterone dose to be tested will be determined based on the results of the initial study (i.e. the dose inactive in isolation that engenders the most robust potentiation of triazolam effects). The proposed studies will help to clarify the manner in which the ovarian hormone progesterone modulates the behavioral effects of the sedative drug triazolam. In addition these studies will establish a foundation for additional studies designed to further elucidate mechanisms associated with progesterone modulation of benzodiazepine effects thereby further informing gender differences in health and behavior. As such these studies will contribute towards the development of gender-specific intervention and/or prevention strategies and health management approaches.

project_terms:
Adult;Affect;Behavioral;Benzodiazepines;Biological;Biological Factors;Blood;Cardiovascular system;Chemosensitization;Clinical Research;Condition;Dependence;Development;Dose;Drug Modulation;Drug abuse;Estradiol;Female;Foundations;Gender;Gonadal Steroid Hormones;Health;Health behavior;Health Reproductive;Hormonal;Hormones;In Vitro;Individual;Intervention;Mediating;Menstrual cycle;Nervous System Physiology;Neuraxis;Neurons;Oral;Ovarian Steroid Hormone;Ovarian hormone;Peripheral Nervous System;Pharmaceutical Preparations;Phase;Physiological;Plasma;Play;Premenopause;Prevention;Prevention strategy;Progesterone;Psychomotor Performance;Psychotropic Drugs;Purpose;Range;Research Design;Role;Sex Characteristics;Steroids;Stimulus;Testing;Time;Triazolam;Woman;base;design;drug of abuse;in vivo;men;non-genomic;pre-clinical;receptor;receptor function;sedative;steroid hormone


application_id: 7500046
project_number: 5R21EY017869-02
project_title: Ocular defects caused by TCF8/Zfhx1a mutations
administering_ic: NEI
award_notice_date: 2008-09-01
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: EY
serial_number: 017869
program_official: CHIN, HEMIN R
project_start_date: 2007-09-30
project_end_date: 2010-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this work is to define the mechanisms that lead to the development of tissues in the anterior segment of the eye and the hyaloid vasculature. Persistent Hyperplastic Primary Vitreous (PHPV or PFV) is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress and generates secondary glaucoma cataracts retinal detachment and intravitreal hemorrhage. There is no clear understanding of the overlapping molecular pathways responsible for regression of the primary vitreous. Our preliminary studies indicate that targeted mutation of the Zfhx1a gene in mice causes an ocular defect similar to PHPV and including defects of the cornea and metaplasia at the iridocorneal angle. This is surprising because it indicates that Zfhx1a is a critical step in a regulatory pathway essential for eye development. This is supported by the recent identification of Zfhx1a mutations in Posterior Polymorphous Corneal Dystrophy-3 (PPCD3) families. We propose to define the ocular developmental defects in Zfhx1a-null embryos and identify the relevant molecular pathway(s). Our overall hypothesis for these studies is that Zfhx1a regulates a novel critical step in BMP-mediated oculogenesis. Specific Aim #1 will characterize the developmental defects of the eye in Zfhx1a-mutant mice. We will define the extent and timing of PHPV in Zfhx1a-null and Zfhx1a-het mice and characterize associated defects of the cornea and iris. We will define the cell type(s) within the vitreous and cornea that are involved in the ocular defects and investigate changes in proliferation rate and apoptosis. We will use immunohistochemistry to investigate changes in expression of potential downstream genes involved in vascularization or regression. In Specific Aim #2 we will use genetic crosses to define the relevant signaling pathways. Together these experiments will define the critical role for Zfhx1a in development of the anterior eye and provide a foundation and genetic tools for future studies on how the Zfhx1a pathway is integrated with other signaling pathways. The long-term goal of this work is to define signaling pathways and cytokine-based therapies for treatment of congenital eye defects including PHPV and PPCD-3. The overall long term goal of this research is to define major molecular signaling pathways required for regression of the fetal hyaloid vasculature and genesis of the cornea. Defining the molecular mechanisms that contribute to ocular diseases in humans is a significant goal. Identification of multiple signaling pathways that direct the regression of hyaloid vasculature should allow a therapeutic approach to the treatment of Persistent Hyperplastic Primary Vitreous (PHPV) by intraocular injection. PHPV is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress. A number of clinical findings are frequently associated with PHPV including microphthalmos glaucoma shallowing of the anterior chamber corneal opacity congenital cataract coloboma and retinal degeneration (11-13). Even mild cases are associated with amblyopia. A very early therapeutic treatment is needed to prevent later secondary defects. This directly relates to the National Eye Institute program's goal to investigate the development of the visual system.

project_terms:
Amblyopia;Anterior;Anterior chamber of eye structure;Anterior eyeball segment structure;Apoptosis;Cataract;Characteristics;Clinical;Coloboma;Cornea;Corneal Endothelium;Corneal Opacity;Corneal dystrophy;Crosses Genetic;Defect;Development;Disease;Disease regression;Embryo;Endothelial Cells;Epithelial;Eye;Eye Development;Failure (biologic function);Family;Foundations;Future;Gene Targeting;Genes;Genetic;Glaucoma;Goals;Hemorrhage;Human;Hyperplasia;Immunohistochemistry;Injection of therapeutic agent;Iris (Eye);Lead;Mediating;Metaplasia;Mice Knockout;Mice Mutant Strains;Microphthalmos;Molecular;Mus;Mutation;National Eye Institute;Numbers;Pathway interactions;Physiological;Proteins;Rate;Regulatory Pathway;Research;Retinal Degeneration;Retinal Detachment;Role;Signal Pathway;Signal Transduction;Therapeutic;Time;Tissues;Vascularization;Work;base;cell type;congenital cataract;cytokine;fetal;in vivo;insight;lens;novel;prevent;programs;repaired;research study;tool;transcription factor;vision development


application_id: 7498625
project_number: 1R01DK081324-01
project_title: An Intergenerational CBPR Intervention to Reduce Appalachian Health Disparities
administering_ic: NIDDK
award_notice_date: 2008-08-21
opportunity_number: PAR-07-379
application_type: 1
activity_code: R01
ic: DK
serial_number: 081324
program_official: HUNTER, CHRISTINE
project_start_date: 2008-09-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 RPHB-K (50)]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Appalachian Region;Behavior;Behavioral Risk Factor Surveillance System;Body Weight decreased;Cardiovascular system;Cause of Death;Cessation of life;Characteristics;Chronic Disease;Class;Communities;Condition;Dancing;Data;Death Rate;Development;Diabetes Mellitus;Diet;Diet good;Dietary intake;Educational workshop;Effectiveness of Interventions;Ensure;Equipment and supply inventories;Evaluation;Exercise;Goals;Health;Health care facility;Heart Diseases;Institution;Intake;Intervention;Interview;Kentucky;Life;Linguistics;Malignant Neoplasms;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Nutritionist;Obesity;Overweight;Participant;Phase;Physical activity;Population;Process;Protocols documentation;Protocols Treatment;Psychologist;Questionnaires;Randomized;Rate;Reporting;Research;Research Personnel;Research Project Grants;Risk Factors;Rural;Solutions;Structure;Testing;Tomography Spiral Computed;Training;Translational Research;Visit;Weight;Work;Youth;base;burden of illness;community based participatory research;cooking;design;energy balance;ethnographic method;fruits and vegetables;health disparity;improved;innovation;instrument;intergenerational;member;motivational enhancement therapy;prevent;public health medicine (field);sedentary


application_id: 7498472
project_number: 5R21DK079293-02
project_title: Transgenic mouse models of hepatitis C virus replication
administering_ic: NIDDK
award_notice_date: 2008-09-08
opportunity_number: PA-06-295
application_type: 5
activity_code: R21
ic: DK
serial_number: 079293
program_official: DOO, EDWARD
project_start_date: 2007-09-30
project_end_date: 2010-08-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a common cause of chronic hepatitis infecting approximately 4 million people in the United States and 170 million people worldwide. The vast majority of HCV-infected individuals develop chronic hepatitis C which can progress to fibrosis cirrhosis and hepatocellular carcinoma. The study of the molecular mechanisms of HCV replication and hepatocarcinogenesis has been hampered by the lack of a small animal model of HCV replication and infection. Currently chimpanzee is the only reliable animal susceptible to productive HCV infection and replication. However the application of chimpanzee model is restricted by its limited resource and high maintenance cost. Our ability to develop alternative small animal models for HCV replication is constrained by the narrow host range of HCV infection. Recently we have made significant advances in genetic studies of HCV replication and development of small murine models of HCV replication and infection. We have demonstrated that HCV RNA derived from a chromosomally integrated HCV cDNA resulted in robust production of infectious HCV. More importantly we have found that HCV RNA replicated efficiently in the mouse embryo fibroblasts (MEFs). These advances allow us to hypothesize that the cDNA-derived HCV RNA can replicate efficiently in transgenic mice. The overall goal of this application is to develop transgenic mouse models for HCV RNA replication and to demonstrate HCV RNA replication in transgenic mice. Thus we will develop multiple transgenic mouse lines that contain the cDNAs of a subgenomic and full-length HCV RNAs and a reversible tetracycline-controlled transcriptional activator (rtTA) and suppressor (tTS). Transcriptional expression of HCV RNA is under the control of a tetracycline-responsive promoter. HCV RNA replication in transgenic mice will be determined by multidiscipline approaches and will be validated by the use of HCV protease inhibitors and mouse interferons. Development of animal models that recapitulate HCV RNA replication disease development and progression and hepatocarcinogenesis will facilitate the determination of the roles and molecular mechanisms of host and viral factors in HCV replication pathogenesis and carcinogenesis. Moreover the availability of transgenic HCV models will accelerate the discovery and development of prophylactic and therapeutic antiviral drugs and vaccines against HCV infection and thereby prevent HCC development.

project_terms:
Albumins;Animal Model;Animals;Antiviral Agents;Apolipoprotein E;Catalytic RNA;Chronic;Cirrhosis;Cultured Cells;Cytomegalovirus;DNA Polymerase II;DNA Complementary;Detection;Developed Countries;Developing Countries;Development;Disease;Doxycycline;Embryo;Fibroblasts;Fibrosis;Foundations;Frequencies (time pattern);Genes;Genetic;Genome;Genotype;Goals;Hepatitis C;Hepatitis C virus;Hepatitis C Chronic;Hepatitis Delta Virus;Hepatitis Chronic;Hepatocarcinogenesis;Hepatocyte;Individual;Infection;Infectious hepatitides;Interferons;Length;Liver;Maintenance;Malignant Neoplasms;Mice Transgenic;Modeling;Molecular;Mortality Vital Statistics;Mus;Pan Genus;Pan troglodytes;Pathogenesis;Polymerase;Prevalence;Primary carcinoma of the liver cells;Production;Promotor (Genetics);Protease Inhibitor;RNA replication;RNA Viral;Range;Rate;Resources;Risk Factors;Role;Solid;System;Tetracycline;Tetracycline Control;Tetracyclines;Therapeutic;Trans-Activators;Transcription Coactivator;Transcription Genetic;Transgenic Organisms;United States;Vaccines;Viral;Viral Proteins;Virus;Virus Replication;carcinogenesis;cost;men;mouse model;prevent;prophylactic


application_id: 7497784
project_number: 1R01MH083621-01
project_title: A Brief Clinic-Based HIV Prevention Program for African American Teen Males
administering_ic: NIMH
award_notice_date: 2008-09-30
opportunity_number: PAR-07-379
application_type: 1
activity_code: R01
ic: MH
serial_number: 083621
program_official: KAMATH, SUSANNAH M A
project_start_date: 2008-09-30
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1 RPHB-K (50)]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
20 year old;Acquired Immunodeficiency Syndrome;African American;Age-Years;Attention;Biological Assay;Brothers;Caring;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Condition;Condoms Unspecified;Depth;Effectiveness of Interventions;Emergency Situation;Enrollment;Female;Frequencies (time pattern);Funding;Future;Glare;Goals;Gonorrhea;HIV;Health;Health Educators;Hispanics;Incidence;Infection;Instruction;Intervention;Intervention Trial;Kentucky;Laboratories;Life;Low income;Medical Records;Medical Specialities;Methods;Modeling;Neisseria gonorrhoeae;Newly Diagnosed;Nucleic Acids;Numbers;Perception;Pliability;Population;Prevention program;Process;Randomized;Randomized Controlled Trials;Rate;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Resources;Risk;Risk Behaviors;Science;Services;Sex Behavior;Sexual Partners;Specimen;Techniques;Teenagers;Testing;Time;Translating;Translations;Treatment Efficacy;Trichomonas Infections;Trichomonas vaginalis;Uncertainty;United States;Upper arm;Urine;Vagina;Woman;Work;avoid sex;base;day;design;disorder prevention;efficacy trial;experience;follow-up;high risk men;improved;innovation;intervention program;male;man;men;neglect;prevent;programs;public health medicine (field);research to practice;response;safer sex;sex;size;theories;therapy design;urban area


application_id: 7497566
project_number: 5R21AI069027-02
project_title: Novel in vivo models for cell-type specific MyD88 signaling in the intestine
administering_ic: NIAID
award_notice_date: 2008-08-12
opportunity_number: PA-04-119
application_type: 5
activity_code: R21
ic: AI
serial_number: 069027
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2007-09-30
project_end_date: 2010-08-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1898921
contact_pi: KAETZEL, CHARLOTTE S
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Innate and acquired immune responses in the intestine must promote homeostasis in the presence of large numbers of commensal microorganisms while maintaining the capacity to defend the body against invasive pathogens. The adult human intestinal tract is inhabited by 100 trillion microorganisms 10 times more than the number of human cells in the entire body. Commensal bacteria provide multiple benefits to the host including processing of essential nutrients regulation of energy balance protection against pathogens and maintenance of epithelial integrity. However inappropriate immune responses to colonic bacteria can lead to chronic inflammatory bowel disease and life-threatening colitis. Host cells recognize microorganisms through pattern recognition molecules including Toll-like receptors (TLRs) which bind microbial cell wall constituents nucleic acids and other byproducts. MyD88 is a cytoplasmic adaptor protein that transduces signals emanating from most TLRs as well as members of the IL-1R family. Recent studies have demonstrated that mice genetically deficient in MyD88 expression are more sensitive to experimental colitis than are wild-type mice suggesting a key role for TLR and/or IL-1 R signaling in regulation of intestinal inflammation. Our preliminary data demonstrate that MyD88-deficient mice have severely depressed expression of the polymeric immunoglobulin receptor (plgR) a key anti-inflammatory molecule that mediates epithelial transport of protective IgA antibodies. Recent work by others has demonstrated that plgR-deficient mice are like MyD88-deficient mice particularly sensitive to chemically-induced colitis. The goal of the proposed research is to test the hypothesis that expression of MyD88 by epithelial cells is crucial for regulation of plgR gene expression and protection against experimental colitis. As a consequence of these studies we will generate novel chimeric and transgenic mouse models for studying epithelial-specific MyD88 signaling within the intact intestine. First we will analyze the susceptibility of these mice to experimental colitis. Second we will analyze patterns of pro- and anti-inflammatory gene expression in the colon. These experiments should increase our knowledge of epithelial-specific MyD88 signaling as well as cross-talk between epithelial and immune cells which is key to the identification of normal and dysregulated responses to colonic bacteria.

project_terms:
Adaptor Proteins Signal Transducing;Administration Oral;Adult;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Bacteria;Binding (Molecular Function);Bone Marrow;Cell Wall;Cells;Chimera organism;Chronic;Colitis;Colon;Data;Depressed mood;Development;Epithelial;Epithelial Cells;Equilibrium;Family;Gene Expression;Genus Cola;Goals;Homeostasis;Human;Immune;Immune response;Immunoglobulin A;Inflammation;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Interleukin-1;Intestines;Invasive;Knowledge;Lamina Propria;Lead;Life;Maintenance;Mediating;Mice Congenic;Mice Transgenic;Microarray Analysis;Models Experimental;Mononuclear;Mus;Nucleic Acids;Numbers;Nutrient;Pattern;Pattern Recognition;Polymeric Immunoglobulin Receptors;Predisposition;Process;Promotor (Genetics);Proteins;Range;Regulation;Research;Role;Signal Transduction;Sodium Dextran Sulfate;Testing;Time;Tissues;Toll-like receptors;Transgenes;Transgenic Organisms;Wild Type Mouse;Work;cell type;commensal microbes;energy balance;in vivo Model;member;microbial;microorganism;mouse model;novel;pathogen;research study;response;selective expression


application_id: 7497114
project_number: 5R44AR052984-03
project_title: Partial-thickness wound healing via topical ATP delivery
administering_ic: NIAMS
award_notice_date: 2008-08-23
opportunity_number: PA-06-120
application_type: 5
activity_code: R44
ic: AR
serial_number: 052984
program_official: BAKER, CARL
project_start_date: 2005-09-09
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(12)B]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 177868366
duns_number: 177868366
fips: US
organization_id: 10002342
organization_name: NOVERA, LLC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021250
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
budget_end_date: 2010-08-31
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of our program is to develop safe and effective techniques to combat tissue damage caused by ischemia. The specific aims of this proposal are to investigate high-energy phosphate contents in human non-healing chronic wounds to further improve our direct intracellular energy delivery technique to use this technique in wound treatment and to study some of the mechanisms by which intracellular energy supply enhances wound healing. Our central hypotheses are that depletion of high energy phosphate contents is the fundamental cause of non-healing chronic wounds; and that direct intracellular delivery of ATP to the wound will improve the microenvironment and substantially enhance the healing process. Results from our Phase I study also found that: 1) tissue biopsies taken from human chronic wounds showed significantly reduced high-energy phosphate contents; 2) intracellular ATP delivery using VitaSolTM substantially increased wound tissue high-energy phosphate contents in a rabbit ear model; and 3) intracellular ATP delivery caused extremely fast granular tissue growth. Using minimally invasive surgical procedures we have also developed a new rabbit ischemic wound model that has been used successfully for the first time in diabetic animals. Results from the Phase I study have proven our basic concept. Three aims will be pursued in this Phase II study: 1. The first testable hypothesis is that wound tissue hypoxia results in decreased high-energy phosphate availability and this reduction is the major cause of non-healing in chronic wounds. End point: high-energy phosphate contents in various chronic human wounds. 2. The second hypotheses to be tested is that unilamellar lipid vesicles containing encapsulated ATP can be manufactured on a large scale and further that these vesicles can be used for wound care with little systemic reactions. End point: a specific formulation of stable lyophilized unilamellar lipid vesicles containing ATP with good tissue penetration suitable for wound care and a cGMP process capable of producing these vesicles. 3. The third testable hypothesis is that intracellular ATP delivery will increase wound tissue energy levels induce coordinated upregulation of growth factors and other healing mechanisms to facilitate healing process. End point: tissue high-energy phosphate contents and their relationship with growth factors and healing speed. None of the 3 topics outlined above has been explored in the past. The success of this project and the expanded use of this new intracellular energy delivery technique will likely have a major impact on medicine. It will not only improve care for chronic wounds but also improve our ability to treat various ischemic conditions such as shock stroke severe trauma heart attack spinal cord injury cardiopulmonary bypass organ transplant acute or chronic lung diseases and many other conditions involving ischemia. The specific aims of this Phase II proposal are to investigate high-energy phosphate contents in human non-healing chronic wounds to further improve our direct intracellular energy delivery technique to use this technique in wound treatment and to study some of the mechanisms by which intracellular energy supply enhances wound healing. Our Phase I project has improved formulation encapsulation rate and particle size of our intracellular ATP delivery preparation measured high-energy phosphate contents in human chronic wounds and used the intracellular ATP delivery in animal models. Our intracellular ATP delivery technique caused extremely fast granular tissue growth in rabbit ear wounds. None of the tasks outlined in the current project has been explored in the past. The success of this project and the expanded use of this new intracellular energy delivery technique will likely have a major impact on medicine. It will not only improve care for chronic wounds but also improve our ability to treat various ischemic conditions such as shock stroke severe trauma heart attack spinal cord injury cardiopulmonary bypass organ transplant acute or chronic lung diseases and many other conditions involving ischemia.

project_terms:
Acute;Animal Model;Animals;Biopsy;Cardiopulmonary Bypass;Caring;Chronic;Chronic Care;Chronic lung disease;Clinical Trials Phase I;Clinical Trials Phase II;Condition;Cyclic GMP;Ear structure;Encapsulated;End Point;Formulations Drug;Goals;Growth;Growth Factor;Healed;Human;Hypoxia;Ischemia;Lipids;Measures;Medicine;Modeling;Myocardial Infarction;Organ Transplantation;Oryctolagus cuniculus;Particle Size;Penetration;Phase;Preparation;Process;Rate;Reaction;Shock;Speed (motion);Spinal cord injury;Supply Energy;Surgical Procedures Minimally Invasive;Techniques;Testing;Thick;Time;Tissues;Trauma;Up-Regulation (Physiology);Vesicle;Wound Healing;concept;diabetic;healing;improved;inorganic phosphate;programs;stroke;success;wound


application_id: 7496137
project_number: 5R21NS060924-02
project_title: Calcitriol-Induced Restoration of Dopamine in a Model of Parkinson's Disease
administering_ic: NINDS
award_notice_date: 2008-03-27
opportunity_number: PAR-06-189
application_type: 5
activity_code: R21
ic: NS
serial_number: 060924
program_official: SUTHERLAND, MARGARET L
project_start_date: 2007-09-15
project_end_date: 2011-03-31
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 7875148
contact_pi: CASS, WAYNE A
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Current therapies for PD offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or even restore function to damaged neurons would be of substantial benefit. Trophic factors such as glial cell line-derived neurotrophic factor (GDNF) are promising therapeutic candidates because of their neuroprotective and neurorestorative effects on nigrostriatal dopamine (DA) neurons in animal models of PD. However while the protective and restorative effects of GDNF have been well documented the use of exogenous GDNF is problematic as it does not cross the blood brain barrier and must be administered directly into the brain. Thus non-invasive treatments that can upregulate endogenous levels of trophic factors such as GDNF could be of significant benefit to individuals suffering from PD. Calcitriol the active metabolite of vitamin D has been shown to upregulate GDNF levels in the brain including in the striatum and substantia nigra and is partially protective against various CNS insults. The systemic administration of calcitriol may therefore be able to help restore normal function to DA neurons damaged by degenerative processes in patients with PD and may be able to slow down or halt progression of the disease. The proposed experiments will examine the effects of calcitriol in a 6-hydroxydopamine (6-OHDA) animal model of early PD. It is hypothesized that calcitriol will be effective in reversing 6-OHDA-induced behavioral changes and damage to nigrostriatal DA neurons in rats. The proposed experiments will determine the extent to which calcitriol treatment promotes recovery of behavior and striatal DA release and content in animals previously administered neurotoxic doses of 6-OHDA. Four weeks after administration of 6-OHDA rats will begin treatment with various doses and time courses of calcitriol. Behavior in vivo microdialysis and post- mortem analyses will be used to evaluate the restorative effects of calcitriol. As PD usually affects older individuals young middle-aged and aged rats will be examined to provide a more comprehensive evaluation of the effects of calcitriol in this model. These studies will begin to define the restorative effects of calcitriol on behavior and on functional measures of DA terminal integrity and determine if the effects of calcitriol are dependent on the age of the animal. to Public Health: The proposed studies will determine if calcitriol can help restore normal behavior and normal levels of dopamine release and content in an animal model of Parkinson's disease. If calcitriol proves effective the results of the experiments in this proposal may lead to novel and improved treatment strategies for persons suffering from this debilitating disease. In addition as calcitriol is already approved for clinical use in humans for other diseases evidence of efficacy in animal models of Parkinson's disease would facilitate initiation of clinical trials.

project_terms:
Address;Affect;Age;Amphetamines;Animal Model;Animals;Attenuated;Behavior;Behavioral;Blood - brain barrier anatomy;Brain;Calcitriol;Clinical;Clinical Trials;Corpus striatum structure;Daily;Disease;Disease Progression;Dopamine;Dopaminergic Cell;Dose;Evaluation;Grants Applications;Human;In Vitro;Individual;Injection of therapeutic agent;Invasive;Lead;Lesion;Measures;Microdialysis;Modeling;Neuraxis;Neurodegenerative Disorders;Neurons;Neurotoxins;Oxidopamine;Parkinson Disease;Patients;Personal Satisfaction;Persons;Process;Rattus;Recovery;Saline;Science of neurochemistry;Severities;Stimulus;Substantia nigra structure;Testing;Therapeutic;Time;Tissues;Toxin;Translational Research;United States;Vitamin D;Week;aged;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;improved;in vivo;mature animal;middle age;neurorestoration;neurotoxic;nigrostriatal pathway;novel;prevent;public health medicine (field);research study;restoration;young adult


application_id: 7495639
project_number: 5R01HL064894-07
project_title: Regulation and function of EC-SOD
administering_ic: NHLBI
award_notice_date: 2008-07-01
application_type: 5
activity_code: R01
ic: HL
serial_number: 064894
program_official: HARABIN, ANDREA L
project_start_date: 2000-09-01
project_end_date: 2010-06-30
study_section: Lung Cellular, Molecular, and Immunobiology Study Section[LCMI]
contact_pi_person_id: 1863574
contact_pi: FOLZ, RODNEY J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung and current studies indicates that EC-SOD plays a key role in the pathogenesis of oxidant-induced pulmonary and vascular injury and resulting inflammation. We and others have shown that EC-SOD overexpression in the lungs of mice protects the lungs against acute lung injury from hyperoxia exposure residual oil fly ash influenza pneumonia hemorrhage induced lung injury radiation pneumonitis bleomycin-induced lung fibrosis and preserves lung development in a neonatal model of hyperoxia. In cardiovascular disease models EC-SOD protects against ischemia-reperfusion injury attenuates hypertension and specific polymorphisms impart a significant increased risk for ischemic heart disease. Despite this work the precise mechanism of EC-SOD's protective role in these disease processes remains unclear. Recently we have begun to unravel factors important in regulating EC-SOD tissue and cell-specific expression. In this competing renewal application we will build on our most recent findings that have begun to explore molecular pathways that control EC-SOD gene expression. Based on our initial characterization of the human and mouse EC-SOD genes we now hypothesize that EC-SOD transcriptional expression is regulated by a family of transcription factors (Ets MZF-1 Kruppel and Sp1/Sp3) interacting at a proximal and distal promoter element located in the 5'-untranslated region of the murine EC-SOD gene. It is further proposed that the activity of these elements is modulated by epigenetic processes including histone acetylation and methylation. To test these hypotheses we propose 3 specific aims. Aim 1 will examine the contribution and identification of cis-elements and trans-activating factors regulating basal and cell specific EC-SOD expression in the lung. In Aim 2 we will identify and characterize transcription factor elements responsible for modulation of EC-SOD gene transcription. In Aim 3 will use a novel in vivo bioluminescence imaging system to examine the functional and spatial gene expression profile utilizing the newly discovered EC-SOD proximal and distal promoter elements in transgenic mice. It is anticipated that this work will provide new insights into our understanding of molecular mechanisms involved in the regulation of EC-SOD gene expression. This could lead to novel pharmacologic strategies for augmenting endogenous EC-SOD levels in the lungs and other tissues which would be predicted to reduce extracellular oxidative stress and attenuate lung disease processes.

project_terms:
5' Untranslated Regions;Affect;Animals;Antioxidants;Attenuated;Basal Cell;Be++ element;Beryllium;Bioluminescence;Bleomycin;Blood Vessels;Cardiac;Cardiovascular Diseases;Cells;Complex;Condition;Development;Disease;Disease model;Distal;Elements;Enzymes;Epigenetic Process;Event;Family;Fibrosis;Future;Gene Expression;Gene Expression Profile;Genes;Goals;Growth;Heart;Hemorrhage;Histone Acetylation;Human;Hyperoxia;Hypertension;Image;Indium;Inflammation;Inflammatory Response;Influenza;Injury;Ischemia;Knock-out;Kruppel-like transcription factors;Lead;Lung;Lung Injury Acute;Lung Neoplasms;Lung diseases;Manganese Superoxide Dismutase;Methylation;Mice Transgenic;Modeling;Molecular;Mus;Muscle Smooth Vascular;Myocardial Ischemia;Neonatal;Oxidants;Oxidative Stress;Pathogenesis;Pathway interactions;Physiological;Physiological reperfusion;Play;Pneumonia;Polymorphism Genetic;Process;Promotor (Genetics);Protein Overexpression;Radiation Pneumonitis;Regulation;Reperfusion Injury;Reperfusion Therapy;Reporter;Respiratory physiology;Risk;Role;Structure of parenchyma of lung;Superoxide Dismutase;System;Testing;Time;Tissues;Transcription Genetic;Transcriptional Regulation;Transgenic Organisms;Work;base;expectation;extracellular;gene therapy;in vivo;insight;interest;lung development;lung injury;novel;novel therapeutics;oil fly ash;prevent;transcription factor;tumor growth


application_id: 7495086
project_number: 5R25CA098220-05
project_title: Kentucky Cancer Prevention and Control Training Program (R25T)
administering_ic: NCI
award_notice_date: 2008-08-28
opportunity_number: PAR-00-064
application_type: 5
activity_code: R25
ic: CA
serial_number: 098220
program_official: MYRICK, DORKINA C
project_start_date: 2004-09-15
project_end_date: 2009-08-31
study_section: Education Study Section (G)[NCI-G]
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
project_abstract:
DESCRIPTION (provided by applicant):  This application requests five years of support to develop implement and evaluate a new education and career development program at the University of Kentucky (UK) -- the Kentucky Cancer Prevention and Control Training Program (KCPCTP).  The program will be designed to provide a specialized curriculum of cancer prevention and control training focusing on rural low-income populations.  One predoctoral and one postdoctoral trainee will be recruited in year one and two predoctoral and two postdoctoral trainees will be recruited in years 2-5.  Predoctoral trainees will be supported for 3-4 years and postdoctoral trainees up to 2 years.  Trainees may be from many disciplines including public health behavioral science hematology/oncology (postdoctoral only) and nursing.  The program will focus on cancer epidemiology behavioral science and tobacco control and will include coursework structured interactions with mentors and supervised research experiences.  Coursework will include core didactic courses elective didactic courses and special program initiatives.  The core didactic courses will provide instruction in cancer epidemiology biostatistics behavioral science in cancer prevention and control grant writing and research ethics and elective didactic courses will be selected from a wide range of opportunities across the University.  The special program initiatives will include participation in the cancer prevention and control seminar series a journal club and opportunities with an Agricultural Extension Program and an Integrative Medicine Clinic.  In addition to the coursework each trainee in the KCPCTP will have the support of at least two mentors who will provide guidance in selection of elective didactic courses and supervised research experiences focusing on cancer prevention and control among low income rural populations.  Resources to support trainees will be provided through faculty in the Cancer Control Program of the Markey Cancer Center University of Kentucky Prevention Research Center Kentucky Cancer Registry Kentucky School of Public Health School of Nursing Department of Kinesiology and Health Promotion and Departments of Behavioral Science and Internal Medicine in the School of Medicine.  Evaluation will focus on all aspects of the KCPCTP including recruitment and retention of trainees and faculty quantitative assessment of trainee accomplishments tracking of their success following completion of the program and qualitative evaluation to collect information on factors that facilitate or impede trainee progress.

project_terms:
Active Learning;Address;Age;Agriculture;American;Appalachian Region;Area;Attention;Behavioral Sciences;Biometry;Cancer Burden;Cancer Center;Cancer Control;Cardiovascular Diseases;Chronic Disease;Clinic;Clinical;Colorectal;Communities;Community Services;Country;County;Depressed mood;Development;Discipline;Discipline of Nursing;Doctor of Philosophy;Educational Curriculum;Educational aspects;Educational process of instructing;Ethics Research;Evaluation;Faculty;Funding;Funding Agency;Generations;Goals;Grant;Health;Health Personnel;Health Promotion;Health Sciences;Health Services Accessibility;Health School;Hematology;Incidence;Instruction;Integrative Medicine;Internal Medicine;Journals;Kentucky;Kinesiology;Knowledge;Learning;Letters;Location;Low Income Population;Low income;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical center;Mentors;Mortality Vital Statistics;Personal Satisfaction;Population;Positioning Attribute;Poverty;Prevention Research;Program Development;Public Health Nurses;Public Health Nursing;Purpose;Qualitative Evaluations;Range;Rate;Recording of previous events;Recruitment Activity;Reporting;Request for Applications;Research;Research Personnel;Resources;Rest;Rural;Rural Community;Rural Health;Rural Population;Schools Medical;Schools Nursing;Schools Public Health;Series;Source;Structure;Students;Surgical Oncologist;Traineeship;Training;Training Programs;Training Support;Transportation;Uninsured;United States Dept. of Health and Human Services;Universities;Urination;Work;Writing;anticancer research;base;cancer epidemiology;cancer prevention;career;design;disability;experience;health disparity;improved;medically underserved;multidisciplinary;named group;neoplasm registry;next generation;oncology;pre-doctoral;prevent;programs;public health medicine (field);rural area;rural disparities;socioeconomics;success;tobacco control;trend


application_id: 7494840
project_number: 2R01MH063022-06A2
project_title: Implications of caveolae in Tat signaling and integrity of brain endothelium
administering_ic: NIMH
award_notice_date: 2008-03-29
opportunity_number: PA-07-089
application_type: 2
activity_code: R01
ic: MH
serial_number: 063022
suffix: A2
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2001-08-01
project_end_date: 2013-03-31
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
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
project_terms:
1-Phosphatidylinositol 3-Kinase;AIDS neuropathy;Abbreviations;Address;Affect;Animal Model;Anti-HIV Agents;Antiretroviral Therapy Highly Active;Astrocytes;Attenuated;Basic Science;Biology;Blood - brain barrier anatomy;Blood Vessels;Brain;Caveolae;Caveolins;Cell Line;Cell surface;Cells;Cellular Structures;Central Nervous System Infections;Characteristics;Clinical;Coculture Techniques;Cytoskeleton;DNA Sequence Rearrangement;Data;Development;Disease;Disruption;Down-Regulation;Elements;Endothelial Cells;Endothelium;Event;Functional disorder;GTP-Binding Proteins;Goals;Grants Applications;HIV;HIV Infections;HIV drug resistance;HIV-1;Heterotrimeric GTP-Binding Proteins;Homeostasis;Human;Infection;Infiltration;Inflammatory;Injury;Intercellular Junctions;Lead;Localized;Mediating;Membrane;Membrane Microdomains;Molecular;Mus;Nervous System Physiology;Neuraxis;Neuroglia;Neurologic;Neurons;Pathology;Pathway interactions;Play;Prevention;Process;Proteins;Receptor Signaling;Regulation;Research;Research Proposals;Risk;Role;Signal Pathway;Signal Transduction;Structure;Therapeutic;Tight Junctions;Tissues;Toxic effect;Vascular Endothelial Growth Factor Receptor-2;Virus;base;caveolin 1;cell injury;design;genetic regulatory protein;innovation;interest;neglect;neuropathology;neurotoxicity;neurovascular unit;novel;prevent;protective effect;protein expression;receptor;rho;sarcoma;tat Protein;trafficking;uptake


application_id: 7494462
project_number: 5K01DK078648-02
project_title: Role of microRNAs in insulin production and secretion in pancreatic beta-cells
administering_ic: NIDDK
award_notice_date: 2008-08-08
opportunity_number: PAR-05-066
application_type: 5
activity_code: K01
ic: DK
serial_number: 078648
program_official: HYDE, JAMES F
project_start_date: 2007-09-10
project_end_date: 2010-08-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 8781988
contact_pi: TANG, XIAOQING
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 candidate has been previously studying the mechanisms of insulin-regulated glucose transport in 3T3-L1 adipocytes using RNAi technology and later focused on the mechanisms of RNAi and profiling of microRNAs in cancer cells and mouse tissues. To continue her training in the field of diabetes she has recently joined Dr. Sabire Ozcan's laboratory. Dr. Ozcan's research focuses mainly on glucose-regulated insulin gene transcription in pancreatic beta-cells. The immediate career goal of the candidate is to better acquaint herself with experimental procedures and applications in the regulation of insulin gene expression and glucose regulation of pancreatic beta-cell function. This training will allow her to pursue her long-term goal which is to study the role of miRNAs in regulating beta-cell function and to elucidate the role of miRNAs in the development of type-ll diabetes as an independent investigator.  
Recent studies indicate that a novel population of cellular small RNAs termed microRNAs (miRNAs) may play an important role in the development of type 2 diabetes. The expression of these miRNAs may be highly regulated under various environmental and physiological conditions; dysregulation of these small RNAs may lead to the development of type 2 diabetes. For example miR-375 has been discovered to be specifically expressed in pancreatic beta cells and be important in insulin secretion. The functions of most miRNAs in beta cells await to be investigated. The hypothesis of the P.I. is that miRNAs are not functioning alone but rather multiple miRNAs act in cohort to regulate beta cell development and insulin production and secretion in response to glucose. The specific aims of this project are: (1) To profile miRNA expression in pancreatic beta cells in order to identify novel cell-specific and glucose-regulated miRNAs with a recently developed rational miRNA microarray technology; (2) To study the function of the identified glucose-regulated and beta cell-specific miRNAs in MIN6 cells by transfecting with synthetic miRNAs to study overexpression effects and with 2-O-methyl RNA antagomirs to investigate the effects associated with their down-regulation. The results obtained from the proposed activities may lead to the discovery of novel miRNAs or new roles of miRNA network in the development of type 2 diabetes and potential therapeutic approaches to treat or prevent this disease.

project_terms:
Adipocytes;Aftercare;Application procedure;Beta Cell;Cardiovascular Diseases;Cell Line;Cell physiology;Cells;Condition;Development;Diabetes Mellitus;Diabetes Mellitus Non-Insulin-Dependent;Disease;Down-Regulation;Gene Expression;Gene Silencing;Glucose;Goals;Insulin;Islets of Langerhans;Laboratories;Lead;Membrane;MicroRNAs;Microarray Analysis;Molecular Profiling;Mus;Oligonucleotides;Physiological;Play;Population;Production;Protein Overexpression;RNA;RNA Interference;Rattus;Regulation;Research;Research Personnel;Role;Small RNA;Structure of beta Cell of islet;Technology;Therapeutic;Tissues;Training;Transcription Genetic;blood glucose regulation;cancer cell;career;cohort;glucose transport;insight;insulin secretion;insulinoma;islet;novel;novel therapeutics;prevent;response


application_id: 7494360
project_number: 1R34MH077507-01A2
project_title: Enhancing Message Design in Tailored Computerized HIV/STI Interventions
administering_ic: NIMH
award_notice_date: 2008-03-14
opportunity_number: PAR-06-248
application_type: 1
activity_code: R34
ic: MH
serial_number: 077507
suffix: A2
program_official: CAMPBELL-ROSEN, HOLLY RENEE
project_start_date: 2008-03-14
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZMH1 ERB-H (03)]
contact_pi_person_id: 7899124
contact_pi: NOAR, SETH MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed study will involve the development and pilot testing of an interactive computerized tailored intervention program for HIV/STI prevention among at-risk heterosexually active African-American STI clinic patients aged 18-44. The Attitude-Social-Influence Efficacy model will serve as a conceptual foundation for the intervention and tailored feedback which will assess and give feedback to participants separately for main/steady and other/casual partners. Individual modules will be developed for key theoretical concepts and subsequently tied together into an integrated system. The tailored feedback will additionally be enhanced by crafting intervention messages to be high in message sensation value and by developing interactive intervention activities for skill-building which will be guided by both Social Cognitive Theory and skills training principles. The computerized intervention will be developed and guided using data collected from the target audience to ensure an empirically-based approach to tailoring. The intervention will also be developed with input from the target audience in order to maximize the appropriateness and persuasiveness of the feedback and the program including interactive components. The final year of the project will entail a pilot test of the intervention in order to gather preliminary data on the acceptability and efficacy of such an intervention for increasing safer sexual behaviors among at-risk heterosexually active African- Americans. The specific aims of the study are: 1) to develop tailored feedback on HIV/STI prevention based on the ASE model including condom attitudes social influences self-efficacy including communication / negotiation skills partner and behavioral risk correct condom use and condom stages of change; 2) to enhance the delivery of the tailored messages using sensation- seeking targeting (SENTAR) and skill-building using interactive activities guided by Social Cognitive Theory (SCT) and skills training principles; 3) to tie the individual theoretical modules together and develop a computerized intervention program for HIV/STI prevention which provides tailored risk reduction messages to participants based upon an assessment of participant characteristics; 4) to develop empirically sound cutpoints specific to the target audience to guide the message tailoring; and 5) in a wait-list control group design to pilot test the intervention for acceptability and efficacy in increasing condom use with main and casual partners among at-risk heterosexually active African-Americans relative to a "usual care" comparison condition. The current application is relevant to public health because it focuses on preventing HIV/AIDS in a high-risk group namely African-Americans. The application aims to develop and evaluate a computer-based program to help African-Americans who come to a sexually transmitted disease clinic adopt safer sex practices.

project_terms:
AIDS prevention;AIDS/HIV problem;Adopted;African American;Area;Attitude;Behavioral;Caring;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinic;Cognitive;Communication;Computers;Condition;Condoms Unspecified;Control Groups;Counseling;Data;Development;Educational process of instructing;Effectiveness;Ensure;Esthesia;Feedback;Fostering;Foundations;HIV;Health;Health Promotion;Heterosexuals;Human immunodeficiency virus test;Individual;Infection prevention;Internet;Intervention;Mediation;Meta-Analysis;Modeling;Outcome;Participant;Patients;Persons;Population;Prevention intervention;Printing;Relative (related person);Research;Resources;Risk;Risk Reduction;Robin bird;Self Efficacy;Sex Behavior;Sexual Partners;Sexually Transmitted Diseases;Sound - physical agent;Staging;Standardization;Surveys;System;Technology;Testing;Thinking function;Waiting Lists;Woman;aged;base;behavior change;computerized;concept;cost;design;intervention program;prevent;programs;public health medicine (field);safer sex;skills;skills training;social;social cognitive theory;theories


