# projects

application_id: 7851181
project_number: 5R21DC009624-02
project_title: Olfactory Support Cells
administering_ic: NIDCD
award_notice_date: 2010-05-05
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: DC
serial_number: 009624
program_official: DAVIS, BARRY
project_start_date: 2009-07-01
project_end_date: 2012-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Description (provided by applicant): The support cells of the olfactory epithelium have received little direct attention yet several lines of evidence indicate that they are critical for maintaining or regulating the olfactory sensory nerve cells the ongoing replacement of olfactory sensory nerve cells and the local environment that allows odor detection. A detailed molecular understanding of the two major types of support cells sustentacular cells and Bowman's gland cells is lacking. Fortuitously we have developed a mouse strain that will allow us to extract two dissociated cell samples: One highly enriched for sustentacular cells the other for Bowman's gland acinar cells. Aim 1 will therefore investigate whether two support cell transcriptomes show overrepresentation of biological processes hypothesized to be active in these support cells: Clearance of foreign chemicals cell adhesion clearance of dying cells secretion and certain cell signaling pathways. The outcome of this aim will also include a database of the probability of expression in sustentacular cells and Bowman's gland acinar cells for more than 10000 genes. Aim 2 delves more deeply into a mechanism we hypothesize controls phagocytosis by sustentacular cells one of the few documented functions of these cells. We hypothesize that signaling through the receptor tyrosine kinase Tyro3 regulates clearance of dying nerve cells by sustentacular cells. Overall this project is another step toward a complete understanding of gene expression patterns in the olfactory epithelium and will identify most functions present in the little-studied support cells of this tissue. In addition these experiments are relevant to age-dependent loss of olfactory function because deficits in Tyro3 receptor family signaling in the support cells of several other tissues are known to lead to age-related disorders such as retinal degeneration. PUBLIC HEALTH RELEVANCE: The olfactory system has evolved to detect and discriminate many thousands of distinct volatile chemicals in part by generating a favorable microenvironment and retaining the ability to replace damaged olfactory nerve cells even as aging occurs. Investigating how the support cells of the epithelium contribute to odor detection and nerve cell replacement is bound to improve our understanding of how cellular interactions contribute to the ability of the olfactory system to function throughout an animal's life span. This project investigates the molecular capabilities of the support cells of the epithelium and a hypothesized mechanism by which support cells clear dying nerve cells to make way for new nerve cells.

project_terms:
Abbreviations;Acinar Cell;Afferent Neurons;Aging;Animals;Apoptotic;Binding (Molecular Function);Bioinformatics;Biological Process;Cell Adhesion;Cell physiology;Cell secretion;Cells;Chemicals;DNA;Data;Data Set;Databases;Detection;Disease;Environment;Epithelium;Family;Fluorescence-Activated Cell Sorting;Gene Expression;Genes;Gland;Green Fluorescent Proteins;Immune;In Situ Hybridization;Ion Transport;Knock-out;Knowledge;LacZ Genes;Lead;Longevity;Messenger RNA;Molecular;Molecular Profiling;Mouse Strains;Mucous body substance;Mus;Neurons;Odors;Olfactory Epithelium;Olfactory Nerve;Outcome;Pathway interactions;Pattern;Phagocytosis;Probability;Receptor Protein-Tyrosine Kinases;Reporter;Retinal Degeneration;Sampling;Signal Pathway;Signal Transduction;Site;Structure of respiratory epithelium;Supporting Cell;System;Testing;Tissues;Xenobiotics;afferent nerve;age related;axl receptor tyrosine kinase;cell type;directed attention;improved;postnatal;public health relevance;receptor;recombinase;relating to nervous system;reproductive;research study;sustentacular cell

public_health_relevance:
Project Narrative. The olfactory system has evolved to detect and discriminatemany thousands of distinct volatile chemicals in part by generating a favorablemicroenvironment and retaining the ability to replace damaged olfactory nervecells even as aging occurs. Investigating how the support cells of the epitheliumcontribute to odor detection and nerve cell replacement is bound to improve ourunderstanding of how cellular interactions contribute to the ability of the olfactorysystem to function throughout an animal's life span. This project investigates themolecular capabilities of the support cells of the epithelium and a hypothesizedmechanism by which support cells clear dying nerve cells to make way for newnerve cells.


application_id: 7850303
project_number: 3R01DC008861-01A2S1
project_title: Role of Staircase Hair Bundle Morphology in Auditory Mechanotransduction
administering_ic: NIDCD
award_notice_date: 2009-07-17
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DC
serial_number: 008861
suffix: A2S1
program_official: FREEMAN, NANCY
project_start_date: 2009-07-17
project_end_date: 2011-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
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): While number of proteins responsible for structural integrity of the mechanosensory bundle of the inner ear hair cells has been identified how most of these proteins contribute to mechano-electrical transduction is still unknown. Also unknown is whether the lack or modification of MET contributes to the development of deafness and/or vestibular disorders that result from mutations of hair bundle proteins. The goal of the current project is to determine the role of the myosin XVa-based stereocilia elongation complex in mechanotransduction. In homozygous shaker 2 mice (Myo15sh2/sh2) a recessive point mutation in the motor domain of myosin XVa prevents normal localization of this protein to the tips of stereocilia resulting in abnormally short stereocilia. According to our preliminary data cochlear outer hair cells of young postnatal Myo15sh2/sh2 mice possess numerous obliquely oriented "tip links" and apparently normal mechanotransduction. In contrast Myo15sh2/sh2 inner hair cells have equally short stereocilia without any obliquely oriented tip links but with numerous "top-to-top" links perpendicular to the core of stereocilia. In spite of their abnormal morphology Myo15sh2/sh2 inner hair cells have a prominent transduction current with "wild type" nanoampere-scale amplitude but abnormal directional sensitivity and no rapid Ca2+dependent deactivation known as "fast adaptation". The central hypothesis of the proposal is that the myosin XVa- based stereocilia elongation complex is not required for mechanosensitivity of hair cells but may affect directional sensitivity and adaptation of mechanotransduction. This study will determine: 1) the role of myosin XVa in directional sensitivity of the hair bundle; 2) localization of known molecular components of stereocilia links in the myosin XVa-deficient hair bundles; 3) the role of myosin XVa and its molecular partner whirlin in the fast adaptation of the transduction current. This study represents a step toward my long-term goal to understand how the hair cells acquire and maintain mechanosensitivity in normal and pathological conditions. Apart from being important for understanding the basic mechanisms of hair cell mechanotransduction this study will establish how developmental abnormalities of stereocilia growth may affect the transduction machinery. This project will also be the first to study mechanotransduction during restoration of the hair bundle morphology and/or tip links in mammalian cochlear hair cells. Finally our study will provide a wealth of data on hair cell function in shaker 2 and whirler mice the animal models for DFNB3 and DFNB31 hereditary deafness in humans. This research is relevant to public health because it investigates exactly how sensory cells of the inner ear acquire and maintain mechanosensitivity in normal and pathological conditions. Our experimental results will help scientists to better understand prevent and develop treatments for developmental abnormalities in the sensory cells of the inner ear which lead to congenital deafness.

project_terms:
Affect;Animal Model;Auditory;Cell physiology;Cells;Complex;Data;Deafness;Development;Disease;Goals;Growth;Hair;Hair Cells;Human;Inherited;Inner Hair Cells;Kinetics;Labyrinth;Lateral;Lead;Link;Mediating;Microscopy Electron Scanning;Modification;Molecular;Morphology;Motor;Mus;Mutation;Myosin ATPase;Outer Hair Cells;Point Mutation;Protein Isoforms;Proteins;Recovery;Research;Role;Scaffolding Protein;Scientist;Sensory;Stereocilium;Structure;Technology;Testing;Utricle structure;base;congenital deafness;human CDH23 protein;human PTPRT protein;insight;numb protein;postnatal;prevent;public health medicine (field);repaired;research study;response;restoration

public_health_relevance:
NARRATIVEThis research is relevant to public health because it investigates exactly how sensory cells of the inner earacquire and maintain mechanosensitivity in normal and pathological conditions. Our experimental resultswill help scientists to better understand prevent and develop treatments for developmental abnormalities inthe sensory cells of the inner ear which lead to congenital deafness.


application_id: 7849591
project_number: 5R01HL068440-09
project_title: Factor XIII Activation and Substrate Specificity
administering_ic: NHLBI
award_notice_date: 2010-05-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 068440
program_official: LINK, REBECCA P
project_start_date: 2002-07-08
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1-HEME-C(03)M]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): In blood clotting the enzyme thrombin cleaves fibrinogen sites for fibrin polymerization are revealed and fibrin clot formation begins. Activated Factor XIII is responsible for catalyzing the formation of covalent crosslinks between fibrin molecules and in fibrin-enzyme complexes. Factor XIII can be activated through cleavage of an activation peptide segment by thrombin or nonproteolytically in the presence of high calcium or high sodium/low calcium. The long-term objective of our research project is to examine in solution the structural features that govern the activation and substrate specificity of Factor XIII. Understanding these molecular details is critical considering the role of FXIII in increasing the risk of heart disease stroke and arteriosclerosis. The specific aims are an extension of ongoing studies and will address three hypotheses: 1) The reactive glutamines of certain FXIII substrates primarily target a distinctive surface within the transglutaminase active site region. Such studies are important since the substrate specificity of FXIII is not clearly defined 2) FXIII undergoes subtle conformational changes upon activation. The degree and surface coverage of these changes will increase following introduction of a substrate or inhibitor and 3) The FXIII activation peptide segment utilizes key positions to promote effective interactions with a thrombin surface whose properties are regulated by individual thrombin residues. A model system for such studies is FXIII V34L a common polymorphism that has been correlated with protection against myocardial infarction and is more susceptible to thrombin cleavage than the native sequence. To test these hypotheses a combination of kinetic studies hydrogen/deuterium exchange chemical modification methods MALDI-TOF mass spectrometry solution NMR and surface plasmon resonance methods will be used. Information will be obtained on the selectivity of FXIII for glutamine-containing substrates on the solvent accessibility changes that FXIII undergoes upon activation and ligand binding and on the kinetic/structural features of the thrombin - FXIII Activation Peptide complex. Lay Summary: Factor XIII is a key enzyme in the formation of blood clots. While very important for wound healing the clots can also increase risk for heart disease and stroke. Research will focus on understanding how Factor XIII is turned on and how it selects its targets. Studies may lead to novel medical strategies to control the actions of Factor XIII and the resultant clot architecture.

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


application_id: 7849258
project_number: 3R01AA016166-02S2
project_title: Developmental Transitions and Risk for Alcohol Use
administering_ic: NIAAA
award_notice_date: 2009-06-08
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AA
serial_number: 016166
suffix: S2
program_official: SHIRLEY, MARIELA
project_start_date: 2009-06-10
project_end_date: 2010-10-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 2092801
contact_pi: SMITH, GREGORY T.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We propose to test an integrative model for adolescent risky behavior that incorporates key psychological features of the transition into adolescence the centrality of affect in adolescent risky behavior and the role of classic dispositional traits in shaping psychosocial learning. As individuals make the transition into adolescence they tend to experience increases in negative affectivity decreases in positive affectivity increases in sensation seeking and increases in urgency (the tendency to act impulsively when distressed). Many of these trait changes involve affectivity which we believe is important because affect appears to play a central if previously underappreciated role in adolescent risky behavior (Steinberg 2004). These trait changes are particularly important in light of advances in person-environment transaction theory. It appears that individual differences in personality cause individuals to learn different things from the same learning event: dispositional traits shape psychosocial learning (Smith et al. 2006). We propose to study the influence of trait changes on learning that disposes one to risky behaviors. We believe the trait of urgency is particularly important because urgency reflects mood-based impulsivity and is strongly related to several risky behaviors (Fischer et al. 2003; Smith et al. 2007a; Whiteside & Lynam 2003; Whiteside et al. 2005). In a longitudinal study of children from 5th grade (before the start of middle school) through 8th grade we will show the following. Following the onset of adolescence individual differences in the growth of urgency will predict subsequent individual differences in the growth of expectancies for problem drinking and other risky behaviors. Growth in those expectancies will predict subsequent individual differences in the onset of problem drinking and the other behaviors. Urgency's role will be different from that of sensation seeking: for example sensation seeking will predict quantity/frequency of drinking and urgency will predict problem drinking. Urgency's role will be different from that of negative and positive affectivity: the latter two traits will predict subsequent growth in depression but urgency will not. Urgency will predict growth in risky behaviors but affectivity will not. PUBLIC HEALTH RELEVANCE: This research will help us understand how the transition into adolescence can leave some children at risk for beginning to engage in risky behaviors. It will highlight the importance of emotion for some adolescents' risky behaviors and it will suggest mood-based interventions that might reduce risk.

project_terms:
Address;Adolescence;Adolescent;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Behavior;Binge Eating;Child;Development;Developmental Process;Distress;Emotions;Environment;Esthesia;Event;Expectancy;Frequencies (time pattern);Growth;Impulsivity;Individual;Individual Differences;Intercept;Intervention;Investigation;Learning;Left;Light;Longitudinal Studies;Measures;Modeling;Moods;National Institute on Alcohol Abuse and Alcoholism;Personality;Persons;Play;Process;Psychological reinforcement;Recording of previous events;Research;Risk;Risk Behaviors;Role;Shapes;Smoking;Testing;Time;Variant;base;behavior change;depression;drinking;early onset;experience;girls;middle school;prospective;psychologic;psychosocial;public health relevance;purge;theories;trait;underage drinking


application_id: 7849051
project_number: 5R21NS062886-02
project_title: Testing the efficacy of PGC-1alpha as a therapeutic target for Parkinson's diseas
administering_ic: NINDS
award_notice_date: 2010-06-07
opportunity_number: PAR-06-189
application_type: 5
activity_code: R21
ic: NS
serial_number: 062886
program_official: SUTHERLAND, MARGARET L
project_start_date: 2009-06-01
project_end_date: 2012-05-31
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 9047138
contact_pi: BUELER, HANS
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: Y
project_abstract:
Parkinson's disease (PD) the most frequent movement disorder is caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Post-mortem studies with PD brain tissue as well as the phenotypes of mice and flies lacking genes linked to recessive familial PD demonstrate that mitochondrial dysfunction and oxidative stress are important mechanisms underlying dopaminergic neuron death in both sporadic and familial PD. Peroxisome proliferator-activated receptor coactivator-11 (PGC-1a) is a transcriptional coactivator of nuclear receptors that stimulates mitochondrial biogenesis and function. PGC-1a induces the transcription of mitochondrial respiratory genes and increases expression of enzymes detoxifying reactive oxygen species protecting cells against death caused by chronic reductions in adenosine triphosphate (ATP) synthesis and oxidative stress. PGC-1a knockout mice develop axonal and neuronal degeneration and display increased sensitivity to oxidative stressors affecting the SNc and the hippocampus showing that endogenous PGC-1a protects against oxidative stress in the brain and is physiologically neuroprotective. In addition we found that PGC-1a reduces rotenone- induced oxidative stress in neuronal cell. Collectively these results suggest that PGC-1a is a prime candidate therapeutic protein for the treatment of neurodegenerative diseases that are caused by mitochondrial dysfunction and oxidative stress such as PD and amyotrophic lateral sclerosis. Here we propose to test the hypothesis that boosting mitochondrial biogenesis and function through recombinant adeno-associated virus (rAAV)-mediated expression of PGC-1a in dopamine neurons of the SNc protects against 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP)-induced nigrostriatal degeneration in mice a well-established model of sporadic PD. Specifically we will investigate: (1) whether rAAV-mediated expression of PGC-1a in the SNc inhibits dopamine neuron death and the decline of dopamine and its metabolites in the striatum of MPTP- treated mice; (2) whether ipsilateral nigral expression of PGC-1a results in contralateral amphetamine-induced turning behavior in MPTP-treated mice indicative of increased dopaminergic function of the rAAV- PGC-1a -injected hemisphere; and (3) whether viral-mediated expression of PGC-1a in dopamine neurons reduces overall protein nitration in the SNc and nitration of tyrosine hydroxylase and 1-synuclein in the striatum of MPTP-treated mice.

project_terms:
1-Methyl-4-phenyl-1236-tetrahydropyridine;Adenosine Triphosphate;Affect;Amphetamines;Amyotrophic Lateral Sclerosis;Antioxidants;Behavior;Biogenesis;Brain;Cause of Death;Cells;Cessation of life;Chronic;Complex;Contralateral;Corpus striatum structure;Disease;Dopamine;Enzymes;Functional disorder;Future;Gene Deletion;Gene Expression;Gene Transfer;Genes;Genetic Transcription;Goals;Hippocampus (Brain);Homeostasis;Homovanillic Acid;Ipsilateral;Knockout Mice;Lead;Link;Maintenance;Mediating;Mitochondria;Modeling;Movement Disorders;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Nuclear Receptors;Oxidative Stress;Oxidative Stress Induction;Parkinson Disease;Parkinsonian Disorders;Pathway interactions;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phenotype;Physiological;Proteins;Reactive Oxygen Species;Recombinant adeno-associated virus (rAAV);Recombinants;Respiratory Chain;Rodent;Role;Rotenone;Substantia nigra structure;System;Testing;Therapeutic;Therapeutic Effect;Toxin;Transcription Coactivator;Treatment Factor;Tyrosine 3-Monooxygenase;Viral;Viral Genes;adeno-associated viral vector;age related;brain tissue;dopaminergic neuron;efficacy testing;fly;mitochondrial dysfunction;mouse model;mtTF1 transcription factor;neuron development;nigrostriatal system;nitration;pars compacta;phenylacetic acid;protein aggregation;public health medicine (field);research study;respiratory;response;stressor;synuclein;therapeutic protein;therapeutic target

public_health_relevance:
Project NarrativeMitochondrial dysfunction and oxidative stress are key mechanisms underlying theprogressive death of nigral dopaminergic neurons and the development of Parkinson'sdisease (PD). This application proposes to investigate the efficacy of a protein that bothstimulates mitochondrial function and reduces oxidative stress as a therapeutic targetfor the treatment of Parkinson's disease by using viral gene transfer in a mouse model ofsporadic PD. If the experiments are successful our project could impact public health byproviding a target and its physiological pathway for which stimulatory drugs could bescreened in order to develop future therapies for PD and possibly otherneurodegenerative and age-related disorders.


application_id: 7848332
project_number: 5R01HL056652-13
project_title: Molecular Mechanisms of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2010-06-25
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-08-20
project_end_date: 2012-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): Platelet exocytosis is integral to hemostasis and vascular integrity. Conversely inhibiting exocytosis is an important target for clinically managing improper thrombosis. Thus understanding the molecular events required for platelet exocytosis will broaden our ability to control platelet function. From previously funded work it is clear that specific Soluble NSF Attachment Protein Receptors (v- and t-SNAREs) are required for platelet secretion. With this established our goals have now expanded to address how this exocytosis machinery is regulated. We hypothesize that platelet exocytosis is governed by proteins that control SNARE- SNARE interactions. Three specific aims are proposed: Aim 1) To determine which v-SNARE proteins are required for platelet granule release. Our work demonstrates that VAMP-8/endobrevin is required for platelet exocytosis. The goals of Aim 1 are to complete the characterization of VAMP-8's role to identify which VAMP (2 or 3) serves as the secondary v-SNARE and to determine when this mechanism is used. Aim 2) To define the pathway of interactions required for t-SNARE function in platelet exocytosis. Previous work assigned roles for SNAP-23 syntaxin 2 and 4. This aim focuses on proteins that regulate these t-SNAREs to promote granule release. The syntaxin chaperones of the Munc18 family and their effectors Munc13S and Doc2s will be examined using a combination of immunological and biochemical techniques to determine how these proteins interact during exocytosis. These data will expand our understanding of how the syntaxin t-SNAREs are regulated to pair with appropriate SNAREs and to mediate membrane fusion. Aim 3) To determine how the small GTP-binding protein ADP-ribosylation factor 6 (Arf6) participates in platelet activation. Members of the Arf family are associated with membrane trafficking specifically exocytosis. Our work shows that Arf6 is critical to platelet activation secretion and actin dynamics. This aim will directly address how changes in Arf6-nucleotide state affect actin cytoskeleton and secretion and will identify the Arf6 effectors required for those functions. These data will yield insight into the central role of this small GTP- binding protein in activated platelets. Overall the information gained from this proposal will help to identify new therapeutic targets that will be useful for modulating hyperactive platelets and to provide diagnostic reagents for determining how hypoactive platelets are defective.

project_terms:
ADP-ribosylation factor 6;Actins;Address;Adhesions;Affect;Agonist;Alpha Granule;Basic Science;Binding (Molecular Function);Biochemical;Biological Assay;Blood Platelets;Blood Vessels;Cells;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;Cytoskeleton;Data;Defect;Diagnostic Reagent;Disease;Elements;Event;Exocytosis;Family;Funding;GTP-Binding Proteins;Goals;Guanosine Triphosphate;Guanosine Triphosphate Phosphohydrolases;Hemorrhage;Hemostatic Agents;Hemostatic function;In Vitro;Inflammation;Knowledge;Learning;Lysosomes;Mediating;Membrane;Membrane Fusion;Membrane Protein Traffic;Membrane Proteins;Molecular;Molecular Chaperones;Molecular Target;Myocardial Infarction;Nucleotides;Pathway interactions;Physicians;Platelet Activation;Play;Process;Protein Secretion;Proteins;Recombinant Proteins;Relative (related person);Research;Research Personnel;Rest;Role;SNAP receptor;Signal Transduction;Specificity;Stimulus;Techniques;Thrombosis;Time;VAMP-2;Vesicle;Work;Wound Healing;base;cellubrevin;extracellular;insight;member;new therapeutic target;novel;programs;protein protein interaction;receptor;receptor function;research study;response;rho;rho GTP-Binding Proteins;soluble NSF attachment protein;stroke;syntaxin;syntaxin-2;therapeutic target


application_id: 7848326
project_number: 5R01DE019243-03
project_title: Mathematical Model of Parotid Acinar Differentiation
administering_ic: NIDCR
award_notice_date: 2010-05-20
opportunity_number: RFA-DE-08-001
application_type: 5
activity_code: R01
ic: DE
serial_number: 019243
program_official: BURGOON, PENNY W
project_start_date: 2008-09-16
project_end_date: 2013-05-31
study_section: 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_abstract:
DESCRIPTION (provided by applicant): The long term goal of the proposed project is to define the development of signaling networks that induce differentiation of cells into mature salivary serous acinar cells to allow gene therapy approaches to regenerating or replacing salivary tissue in patients. Millions of patients suffer loss of salivary gland function due to Sj"gren's syndrome or radiation therapy. Understanding the differentiation of salivary cells is a necessary step to enable the restoration of diseased or destroyed parotid salivary tissue. Previous work has described terminal differentiation of acinar cells histologically and by characterizing the expression of markers of differentiation but has not used genomics-level approaches or mathematical models to define regulatory pathways. The primary goal of the current application is to develop formal mathematical and statistical models that will identify networks which cause terminal differentiation of parotid acinar cells. The dynamic mathematical models will serve to generate hypotheses which will be tested and the model will be repeatedly refined by the incorporation of new data. This application is in response to the RFA "A Systems Approach to Salivary Gland Biology." Our overall hypothesis for these studies is that a mathematical model can identify key regulatory pathways that control parotid acinar cell differentiation. Specific Aim 1 will use Laser Capture Microdissection (LCM) to obtain RNA from embryonic and newborn rat parotid acinar cells for microarray analysis of the patterns of gene expression across the period of differentiation. A coupled Ordinary Differential Equation (ODE) model will be created to describe the hypothetical interactions that direct the process of differentiation. The hypotheses will be tested and the ODE model refined by a combination of RT-PCR IHC and Western blots. Since microRNAs are important regulators of development Specific Aim 2 will define the expression of microRNAs in acinar cells and the pattern of changes during differentiation. There are currently no publications describing microRNAs in the parotid tissue. The results will be used to revise the mathematical model of differentiation. Specific Aim 3 will create a statistical algorithm to validate and revise the ODE model by defining the sources of bias and variation as well as by assessing the model's predictive power overall and in its various sub-modules. This will allow confidence intervals to be associated with different pathways within the ODE model. Specific Aim 4 will use the ODE model to make hypotheses about specific pathways regulating gene expression in the parotid acinar cells. These hypotheses will be tested by transfection and transduction experiments and the results shall be used to refine and validate the mathematical model. This systems biology approach should identify molecular pathways that drive cytodifferentiation of parotid acinar cells. Project Narrative: The overall goal of this research is to define the molecular mechanisms which control differentiation of cells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer from salivary gland dysfunction due to Sj"gren's Syndrome radiation therapy or xerostomia due to essential medications. This research is a necessary foundation for developing new technologies such as gene transfer therapy and biologics for treating or alleviating the oral symptoms of xerostomia.

project_terms:
Acinar Cell;Address;Algorithms;American;Biological Response Modifier Therapy;Biology;Cell Differentiation process;Computing Methodologies;Confidence Intervals;Coupled;Data;Development;Differentiation Antigens;Embryo;Equation;Foundations;Functional disorder;Gene Expression;Gene Proteins;Gene Targeting;Gene Transfer;Genes;Genomics;Goals;Histologic;MicroRNAs;Microarray Analysis;Modeling;Molecular;Muscle;Natural regeneration;Neurons;Newborn Infant;Oral;Output;Parotid Gland;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Procedures;Process;Publications;RNA;Radiation therapy;Rattus;Regulation;Regulatory Pathway;Research;Reverse Transcriptase Polymerase Chain Reaction;Salivary;Salivary Glands;Serous;Signal Pathway;Signal Transduction;Sjogren's Syndrome;Small Interfering RNA;Source;Statistical Models;Symptoms;Syndrome;System;Systems Biology;Testing;Time;Tissues;Transfection;Validation;Variant;Western Blotting;Work;Xerostomia;cell type;expectation;gene therapy;laser capture microdissection;mathematical model;new technology;parotid cell;predictive modeling;prototype;research study;response;restoration;salivary acinar cell;salivary cell;transcription factor


application_id: 7848150
project_number: 5T01OH008846-05
project_title: Agricultural Safety and Health Training for Public Health Graduate Students
administering_ic: NIOSH
award_notice_date: 2010-05-26
opportunity_number: PAR-05-126
application_type: 5
activity_code: T01
ic: OH
serial_number: 008846
program_official: TALTY, JOHN
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: ZOH1-BSI(50)R
contact_pi_person_id: 2080884
contact_pi: MCKNIGHT, ROBERT H.
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_abstract:
DESCRIPTION (Provided by Applicant): We propose to develop and offer a training project grant (TPG) focused on agricultural health and safety for students seeking a Master of Public Health (MPH) or Doctor of Public Health (DrPH) degree. The program will be administered by the NIOSH-funded Southeast Center for Agricultural Health & Injury Prevention at the University of Kentucky College of Public Health. The proposed Health of Agricultural Populations (HAP) TPG will apply agricultural safety and health training across traditional public health coursework research training and field experiences. The HAP-TPG will add cross-cutting competencies for occupational safety and health in agriculture into four public health disciplines specifically health services management health behavior epidemiology and environmental health. The HAP-TPG expands on a successful small-scale MPH and DrPH agricultural health curriculum funded in 2001 via the Southeast Center. The currently offered agricultural health curriculum sequence is not a TPG and it provides only fractional tuition and research support without stipends. As of August 2005 2 DrPH students and 2 MPH students have graduated with a HAP Emphasis Area designation and 9 students (8 MPH and 1 DrPH) are currently enrolled in the HAP curriculum. We anticipate 6 additional students will join the program when fall semester 2005 classes begin. MPH students in the proposed HAP-TPG will require 41-44 semester hours to graduate of which 20 semester hours will be directly related to agricultural health and safety and injury research. DrPH students in the proposed HAP-TPG will need to complete 74-78 semester hours to graduate of which 23-29 semester hours will be HAP-TPG related. Between 2006 and 2011 at least 16 MPH and 4 DrPH graduates of the TPG are expected. Strong evaluation and diversity recruitment strategies are planned. The University of Kentucky is committing $58128 per year for tuition for students enrolled in this TPG. The new TPG program is highly relevant to public health because it will increase the number of public health practitioners and researchers who address agricultural occupational problems through prevention intervention practice and research.


application_id: 7847640
project_number: 5R21AI079457-02
project_title: The role of the host Ca/Mn pump in emergence of novel viral RNA recombinants
administering_ic: NIAID
award_notice_date: 2010-07-05
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 079457
program_official: PARK, EUN-CHUNG
project_start_date: 2009-05-22
project_end_date: 2012-04-30
study_section: Special Emphasis Panel[ZRG1-IDM-P(91)S]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Emergence of new viruses is a continuing threat to our society. Evolution of plus- stranded RNA viruses is frequently driven by RNA recombination a process that joins noncontiguous RNA segments together creating novel combinations of genes or regulatory RNA sequences. Recombination is important for RNA viruses to overcome immunity jump species and change viral pathogenicity in all types of living organisms. Studies on viral RNA recombination are critical to understand the recombination process and the role of specific host genes whose roles in the recombination process are currently unknown. The investigator will use Tomato bushy stunt virus (TBSV) which is currently the most advanced among viral systems to progress rapidly in understanding the mechanism of RNA recombination and the role of the host genes. The investigator's research opens up a completely new area with the powerful TBSV-yeast model system which has led to genome-wide screens identifying host genes suppressing RNA recombination for the first time. Additional advantage of the similarity of TBSV replicase proteins to proteins of important pathogens such as Hepatitis C virus (HCV) dengue virus West Nile virus and other Flaviviruses and Pestiviruses. Collectively the major advances with TBSV allow the investigator to conduct experiments on the roles of host factors that are currently only feasible with TBSV but will open new approaches for studying RNA recombination/evolution for important human pathogens. This proposal focuses on one of the key host factors suppressing RNA recombination. The experiments will dissect the role of Pmr1p Ca2+/Mn2+ pump in viral RNA recombination. Pmr1p is a ubiquitous and conserved protein in eukaryotes. The human homologs of Pmr1p have been shown to play critical roles in genetic diseases such as Hailey- Hailey Disease and Darier disease. In the absence of Pmr1p the rate of TBSV RNA recombination is extremely high demonstrating the critical role of the host in viral RNA recombination. In order to characterize the role of Pmr1p in RNA recombination the investigator will use the advanced genetics tools available for yeast in combination with biochemical approaches. The results obtained in cell-free systems and in yeast model host will also be confirmed in a native plant host. In addition in vitro experiments will be conducted with the RdRp of HCV an important human pathogen to expand our knowledge on the possible role of Ca2+/Mn2+ pumps in HCV RNA recombination. The following are major strengths of the proposal: (i) Viral RNA recombination is clearly of immense importance for viruses to overcome immunity jump species and change pathogenicity in all types of living organisms. (ii) The combination of yeast and in vitro systems developed by the investigator is currently the only one in the world suitable for studying the mechanism of host factors involvement in viral RNA recombination. (iii) This research is expected to lead to groundbreaking new discoveries in viral RNA recombination. The highly tractable in vitro and in vivo TBSV system developed by the investigator could prove highly beneficial to studies of other less amenable RNA viruses. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus recombination/evolution host-virus interaction and the emergence of new viruses. PUBLIC HEALTH RELEVANCE: Emergence of new viruses is a continuing threat to our society. New plus-stranded RNA viruses emerge frequently due to RNA recombination. Recombination is important for RNA viruses to overcome immunity jump to new host species or change the severity of symptoms in all types of living organisms. The roles of the host in virus recombination are currently poorly understood due to the lack of tractable virus-host systems. The investigator will use Tomato bushy stunt virus (TBSV) which is currently the most advanced among viral systems to study RNA recombination and the role of the host genes. This proposal focuses on one of the key host factors suppressing RNA recombination by dissecting the role of a Ca2+/Mn2+ pump in viral RNA recombination. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus recombination/evolution host-virus interaction and the emergence of new viruses.

project_terms:
Animals;Area;Biochemical;Biological Assay;Bioterrorism;Cell-Free System;Cells;Dengue Virus;Eukaryota;Evolution;Familial benign pemphigus;Flavivirus;Gene Combinations;Genes;Genetic;Genetic Recombination;Genome;Hepatitis C virus;Hereditary Disease;Homologous Gene;Human;Immunity;In Vitro;Integration Host Factors;Keratosis Follicularis;Knowledge;Lead;Life;Messenger RNA;Modeling;Organism;Pathogenicity;Pestivirus;Plant Viruses;Plants;Play;Positioning Attribute;Process;Proteins;Pump;RNA;RNA Viruses;RNA-Directed RNA Polymerase;Recombinants;Regulation;Research;Research Personnel;Ribonucleic Acid Regulatory Sequences;Role;Severities;Social Welfare;Societies;Symptoms;System;Testing;Time;Tomatoes;Tombusvirus;Viral;Viral Physiology;Virus;Virus Diseases;West Nile virus;Work;Yeast Model System;Yeasts;advanced system;base;genome wide association study;health economics;in vivo;in vivo Model;novel;novel strategies;pathogen;public health relevance;replicase;research study;tomato bushy stunt virus;tool;viral RNA;virology;virus host interaction


application_id: 7847306
project_number: 3R01EY012998-08A1S2
project_title: Determinants of extraocular muscle function
administering_ic: NEI
award_notice_date: 2009-06-05
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: EY
serial_number: 012998
suffix: A1S2
program_official: ARAJ, HOUMAM H
project_start_date: 2009-06-01
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(07)M]
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_abstract:
DESCRIPTION (provided by applicant): The ocular motor system is arguably the best understood mammalian motor system. However the extraocular muscles its effector arms remain somewhat of a black box. From a peculiar phenotype and extreme functional profile to a disparate response to some neuromuscular disorders these small muscles deviate from the skeletal muscle stereotype. Our results have demonstrated that the extraocular muscles have alternative arrangements for metabolic pathways considered vital for other skeletal muscles. Moreover our pilot studies suggest that their mitochondria have unique properties as well a fact that may explain their susceptibility to some mitochondrial myopathies. In this project we will test the hypothesis that mitochondria are functionally different in the extraocular muscles and their content and properties are determined by visual experience and altered by aging. We will combine well-established functional and biochemical assays with models of visual deprivation and aging to achieve the following aims: (1) determine the factors that limit mitochondrial function in the extraocular muscles; (2) test whether extraocular muscle mitochondrial content and function are influenced by postnatal visual experience; and (3) determine how aging alters mitochondrial content and function in the extraocular muscles. The results will address three important gaps in our understanding of the basic biology of the extraocular muscles: the functional properties of their mitochondria the development of their metabolic properties in the postnatal period and aging. Therefore we expect that the new knowledge will be applicable to disorders of ocular motility in the young (strabismus) and the aged (mitochondrial myopathies).  PUBLIC HEALTH RELEVANCE: This project will study how the mitochondria the cellular energy factories of the cells are different in the small muscles that move the eyes. It will also demonstrate how normal vision early in life is very important to allow the eye muscles to achieve their capacity to generate energy and sustain high activity levels. Finally these studies will explore the deleterious consequences of aging on eye muscle function.

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;Creatine Kinase;Data;Dependence;Development;Electron Transport;Eye;Eye Movements;Fatigue;Incidence;Knowledge;Life;Limb structure;Metabolic;Metabolic Pathway;Mitochondria;Mitochondrial Myopathies;Modeling;Motor;Muscle;Muscle Mitochondria;Muscle Proteins;Muscle function;Myosin ATPase;Neuromuscular Diseases;Ocular Motility Disorders;Pediatrics;Phenotype;Pilot Projects;Predisposition;Property;Protein Isoforms;Research Personnel;Resistance;Resolution;Sensory;Skeletal muscle structure;Stereotyping;Strabismus;System;Testing;Time;Training;Upper arm;Vision;Visual;age related;aged;cell motility;critical period;dark rearing;early experience;end of life;experience;oculomotor;orbit muscle;postnatal;programs;protein complex;public health relevance;research study;respiratory;response;visual deprivation


application_id: 7846933
project_number: 3R21CA124811-02S1
project_title: Regulation of miRNA expression in breast cancer cells
administering_ic: NCI
award_notice_date: 2009-06-04
opportunity_number: PA-06-299
application_type: 3
activity_code: R21
ic: CA
serial_number: 124811
suffix: S1
program_official: ARYA, SURESH
project_start_date: 2007-06-01
project_end_date: 2009-10-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ERalpha) positive breast cancer. With adjuvant therapy however initially TAM-sensitive tumors become TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring small non-coding RNA molecules that are related to but distinct from small interfering RNAs (siRNAs). miRNAs are involved in regulating the translation and processing of mRNAs usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded. The human genome is thought to contain > 400 miRNAs. Abberant patterns of miRNA expression have been recently implicated in human breast cancer and one study showed that miRNAs were differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ERalpha and progesterone receptor expression tumor stage number of positive lymph nodes and vascular invasion. However to date no one has examined whether estradiol (E2) or selective ER modulators/antiestrogens affect the pattern of miRNA expression in human breast cancer or whether miRNA expression patterns correlate with acquired antiestrogen-resistance. Specific Aim 1 is to identify miRNAs that are regulated by estradiol (E2) and 4-hydroxytamoxifen (4-OHT) in antiestrogen-sensitive MCF-7 breast cancer cells. Aim 1 tests the hypothesis that E2 and 4-OHT differentially regulate the expression of miRNAs in human breast cancer cells. Further we suggest these miRNAs in turn regulate the mRNA stability of genes encoding proteins involved in differentiation and cell proliferation. Specific Aim 2 tests the hypothesis that miRNA expression is dysregulated in antiestrogen/TAM-resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2-regulated and 4-OHT-regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with patient response to tamoxifen therapy. It is our long term hope that miRNAs may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain TAM/antiestrogen-resistance and become invasive and metastatic.

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


application_id: 7846594
project_number: 3R03CA135123-01S1
project_title: SNARE-Mediated Exocytosis in Migration of Pancreatic Cancer Cells
administering_ic: NCI
award_notice_date: 2009-05-29
opportunity_number: PA-06-314
application_type: 3
activity_code: R03
ic: CA
serial_number: 135123
suffix: S1
program_official: AULT, GRACE S
project_start_date: 2009-06-01
project_end_date: 2009-10-31
study_section: Special Emphasis Panel[ZRG1-ONC-U(92)S]
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
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;Recycling;Research;Role;SNAP receptor;Signal Transduction;Site;Small Interfering RNA;Transport Vesicles;Travel;United States;Vesicle;Work;adhesion receptor;base;cancer cell;cell motility;cellubrevin;cellular imaging;effective therapy;migration;mutant;novel;prevent;public health relevance;receptor;target SNARE proteins;therapeutic target;trafficking;vesicular SNARE proteins


application_id: 7846524
project_number: 3R03CA139537-01S1
project_title: DNA polymerase iota as a putative tumor suppressor
administering_ic: NCI
award_notice_date: 2009-05-29
opportunity_number: PAR-08-055
application_type: 3
activity_code: R03
ic: CA
serial_number: 139537
suffix: S1
program_official: PERLOFF, MARJORIE
project_start_date: 2009-06-01
project_end_date: 2010-09-30
study_section: ZCA1-SRLB-R(J1)
contact_pi_person_id: 1969289
contact_pi: MCGREGOR, WILLIAM G
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Recent advances implicate error-prone DNA polymerases in the generation of virtually all mutations induced by environmental carcinogens in higher eukaryotic cells. These data have supported the promise of cancer chemoprevention based on the selective modulation of the activity of these proteins based on the assumption that reducing the mutant frequency will reduce the incidence of cancer. However carcinogenesis studies using newly-developed mouse models in which one or another of these polymerases is deficient have yielded unexpected results. Specifically the deficiency of one such polymerase termed DNA polymerase iota (pol iota) resulted in greatly decreased mutation frequencies induced by ultraviolet (UV) radiation in an endogenous reporter gene. These results would predict a protective effect against the carcinogenic effects of UV. However pol iota-deficient animals exhibited a highly accelerated development of aggressive skin cancer. This unexpected result is not consistent with the somatic mutation hypothesis of carcinogenesis and highlights the fact that there are critical gaps in our knowledge of the cellular function of this universe of polymerases. This application proposes to examine the putative tumor suppressor function of pol iota and is directly responsive to the current Program Announcement since modulation of the activity of enzymes in this pathway has been proposed as a potential antimutator strategy. This application addresses the overall hypothesis that DNA polymerase iota acts as a tumor suppressor by a mechanism that is distinct from its activity as an error-prone polymerase. To examine this we propose a pilot project that will consist of two Specific Aims. In Aim 1 we propose to examine the effect of polymerase iota deficiency on UV-induced changes in gene expression and on damage-induced cell cycle checkpoints in murine and human cells. In Aim 2 we will examine the effect of polymerase iota deficiency in UV carcinogenesis studies that employ novel murine models. This application will fill critical gaps in our knowledge of how cancer is initiated by the most ubiquitous environmental carcinogen. The ultimate goal of this research is to understand how carcinogens cause cancer in order to design strategies to prevent the disease.

project_terms:
Address;Animals;Backcrossings;Base Pairing;Bypass;Cancer Etiology;Candidate Disease Gene;Carcinogens;Cell Cycle Checkpoint;Cell Cycle Progression;Cell physiology;Cells;Cellular biology;Chemopreventive Agent;Complex;DNA biosynthesis;DNA polymerase iota;DNA-Directed DNA Polymerase;Data;Development;Disease;Dose;Environmental Carcinogens;Enzymes;Eukaryotic Cell;Exhibits;Frequencies (time pattern);Future;Gene Expression;Generations;Genome;Goals;Grant;Histology;Homologous Protein;Human;In Vitro;Incidence;Induced Mutation;Investigation;Knock-out;Knowledge;Lesion;Malignant Neoplasms;Mammalian Cell;MicroRNAs;Modeling;Molecular;Mus;Mutagenesis;Mutation;Mutation Spectra;NIH Program Announcements;Nucleotide Excision Repair;Pathway interactions;Penetrance;Pilot Projects;Polymerase;Proteins;RNA Interference;Reporter Genes;Research;Role;Skin;Skin Cancer;Somatic Mutation;Sunlight;System;Testing;Tumor Suppressor Proteins;UV induced;Ultraviolet Rays;adduct;base;cancer chemoprevention;cancer prevention;carcinogenesis;combinatorial;design;enzyme activity;in vivo;insight;mouse model;mutant;novel;prevent;programs;protective effect;tumor;tumorigenesis;ultraviolet;ultraviolet damage;ultraviolet irradiation

public_health_relevance:
Project NarrativeThis application proposes to examine the cell biology of accessory DNA polymerasesthat are known to be required for mutagenesis induced by ultraviolet light. The reasonfor doing this is that mice that have a deficiency of one these error-prone polymeraseshave a low mutation frequency but unexpectedly develop cancer faster than polymerase-proficient mice. This application is responsive to the Cancer Prevention Small Grantprogram because modulation of the basic mutagenesis pathway is under activeinvestigation as a chemopreventive strategy.


application_id: 7846237
project_number: 5F31ES016719-03
project_title: Curcumin inhbits BPDE-induced damage by lowering the threshold of p53 activation
administering_ic: NIEHS
award_notice_date: 2010-05-04
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: ES
serial_number: 016719
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-05-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-L(29)L]
contact_pi_person_id: 8797117
contact_pi: ROGERS, ERICA NICOLE
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): Lung cancer the leading cause of cancer-related deaths in America is most commonly caused by long-term exposure to tobacco smoke carcinogens such as benzo[a]pyrene (BaP) which is metabolized into the ultimate metabolite benoz[a]pyrene-78-dihyrodiol-910-epoxide (BPDE). Despite improvements in the treatment and management of lung cancer these methods fail to reduce the overall mortality rate of this disease. While dietary components such as curcumin (turmic spice) show promising effects against BPDEinduced carinogenesis its exact mode of action is not fully understood. The objective of this project is to elucidate whether pretreatment with curcumin inhibits BPDE-induced DMA damage by activating p53. We hypothesize that curcumin may reduce the mutagenic activity of low dose BPDE by lowering the threshold of p53 activation thereby inducing DNA repair and cell cycle arrest at lower BPDE exposures. In Specific aim 1 the expression of p53 and p53-regulated proteins as well as cell cycle progression will be monitored by Western blot and flow cytometric analysis respectively to determine whether curcumin influences cell cycle arrest in response to BPDE exposure. Because global genomic repair (GGR) removes most BPDE-DNA  
adducts in a p53-dependent manner Specific aim 2 will use immunoslot blot [32P]-postlabeling and  
UvrABC mediated gene and strand-specific southern blot assays to analyze whether curcumin affects p53 activation and thus the relative extent of BPDE-DNA adducts formed and removed in genomic DNA. In Specific aim 3 Northern and Western blot assays will be used to investigate the role of curcumin in the induction of damage recognition proteins of the GGR pathway (XPC DDB2) which are p53-dependent. Furthermore it is believed that conjugation of glutathione (GSH) to BPDE by glutathione-S-transferase (GST) interacts with the expression of p53 to inactivate BPDE. In Specific aim 4 Western blot and GST colorimetric assays will be used to monitor the expression of proteins involved in the GSH detoxification system as well as the overall activity of GST respectively. This aim will provide a better understanding of potential alternative routes that may inactivate BPDE and how curcumin may influence this activity. By investigating the effects of curcumin on p53-mediated responses to DNA damage a better understanding of the potential role of curcumin in preventing tobacco carcinogen-induced mutagenesis and carcinogenesis will be gained. In addition the results from this project will benefit the public by providing easy and inexpensive alternative methods in preventing initial and continuing signs of lung cancer.

project_terms:
78-Dihydro-78-dihydroxybenzo(a)pyrene 910-oxide;Affect;Americas;Benzo(a)pyrene;Biological Assay;Cancer Etiology;Carcinogens;Cell Cycle Arrest;Cell Cycle Progression;Cells;Cessation of life;Curcumin;DNA;DNA Adducts;DNA Damage;DNA Repair;DNA repair protein;Dietary Component;Disease;Dose;Drug Metabolic Detoxication;Epoxy Compounds;Exposure to;Genes;Genomics;Glutathione;Glutathione S-Transferase;Lesion;Lung;Malignant neoplasm of lung;Mediating;Mediation;Methods;Monitor;Mortality Vital Statistics;Mutagenesis;Pathway interactions;Proteins;Pyrenes;Regulation;Relative (related person);Role;Route;Southern Blotting;Spices;System;TP53 gene;Tobacco smoke;Tobacco-Associated Carcinogen;Western Blotting;benzo(a)pyrene-78-dihydrodiol-910-epoxide-DNA;carcinogenesis;prevent;protein expression;repaired;response


application_id: 7846224
project_number: 5F32NS063744-02
project_title: Therapeutic Strategies for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2009-08-24
opportunity_number: PA-07-107
application_type: 5
activity_code: F32
ic: NS
serial_number: 063744
program_official: KLEITMAN, NAOMI
project_start_date: 2008-09-15
project_end_date: 2010-01-05
study_section: Special Emphasis Panel[ZRG1-F01-V(20)L]
contact_pi_person_id: 8477680
contact_pi: VAISHNAV, RADHIKA ANAND
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): Spinal cord injury (SCI) is a devastating condition that affects active individuals of all ages for whom treatment options remain inadequate. Two well-established injury mechanisms are reactive oxygen species (ROS)-mediated oxidative damage to lipids and proteins; and the activation of calcium-dependent proteases (calpains) and consequent breakdown of a number of proteins including cytoskeletal proteins. Despite the progress made in understanding the cellular and molecular mechanisms of neurodegeneration following acute SCI treatment of this condition has remained a challenge. Therapeutic intervention against ROS mediated oxidative damage using the antioxidant compound Tempol at short time points following acute SCI has been shown to be at least partially neuroprotective. To achieve a greater protective effect following SCI it would be advantageous to combine more than one therapeutic approach. The overall aim is to systematically block post-traumatic neurodegeneration following SCI by scavenging ROS and inhibiting calpain-mediated proteolytic degradation of the neuronal cytoskeleton. Aim 1 will test the hypothesis that inhibition of calpain using a novel drug with high cell permeability and blood-brain barrier penetrability will decrease cytoskeletal damage to the neurons and promote neuroprotection in acute SCI. The rat PSI T10 spinal cord contusion injury model will be used in Aims 1 and 2. Shams injured rats with vehicle and injured rats treated with critically selected doses of the calpain inhibitor will be compared at specific time points following injury. Calpain-mediated cytoskeletal breakdown will be assessed using an immunochemical spectrin breakdown assay as an indirect measure of calpain activity. Tissue sparing functional and locomotor recovery will also be compared among the treatment and control groups. Aim 2 will test the hypothesis that a combination of antioxidant therapy with calpain inhibition will produce an additive and/or synergistic protective effect after SCI. The optimal dosing paradigm for the antioxidant Tempol as previously determined and for the novel calpain inhibitor as determined in Aim 1 will be used in this combinatorial approach. In addition to the methodology used in Aim 1 oxidative damage will be assessed using immunochemical approaches including slot blots Western blots and immunohistochemistry. The objective of this project is to develop a combinatorial therapeutic strategy for the treatment of SCI in a rat model. The findings of this study will provide a foundation for the design of future translational studies in human SCI.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;3-nitrotyrosine;Acute;Affect;Age;Animal Model;Animals;Antioxidants;Biological Assay;Blood - brain barrier anatomy;Calcium;Calpain;Cells;Clinical Trials;Control Groups;Contusions;Cysteine Protease;Cytoskeletal Proteins;Cytoskeleton;Data;Dose;Drug Kinetics;Event;Female;Figs - dietary;Foundations;Functional disorder;Future;Gender;Human;Immunohistochemistry;Individual;Injury;Intervention;Laboratories;Life;Lipids;Locomotor Recovery;Measures;Mechanics;Mediating;Methodology;Methods;Mitochondria;Modeling;Molecular;Nerve Degeneration;Nervous System Trauma;Neurons;Oxidative Stress;Peptide Hydrolases;Permeability;Peroxonitrite;Pharmaceutical Preparations;Pharmacologic Substance;Play;Property;Protein Structure Initiative;Proteins;Proteolysis;Rattus;Reactive Oxygen Species;Role;Spectrin;Spinal Cord;Spinal Cord Contusions;Spinal Cord transection injury;Spinal cord injury;Stretching;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Translating;Translations;United States;Western Blotting;antioxidant therapy;base;behavior test;calpain inhibitor;combinatorial;design;improved;injured;neurological recovery;neuroprotection;novel;numb protein;oxidative damage;pre-clinical;prevent;protective effect;protein activation;research clinical testing;sham surgery;translational study;treatment duration;treatment strategy;young adult


application_id: 7845763
project_number: 3R01HL086450-03S2
project_title: An Intervention for Promoting Smoke-free Policy in Rural Kentucky
administering_ic: NHLBI
award_notice_date: 2009-08-10
opportunity_number: PAR-06-039
application_type: 3
activity_code: R01
ic: HL
serial_number: 086450
suffix: S2
program_official: RILEY, WILLIAM T
project_start_date: 2009-07-01
project_end_date: 2011-09-30
study_section: Special Emphasis Panel[ZRG1-HOP-S(50)R]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this study is to test the effects of a community intervention on smoke-free policy outcomes in rural underserved communities. The intervention combines assessment of community readiness with tailored evidence-based dissemination and implementation strategies. Rural residents are more likely to be exposed to secondhand smoke than those living in urban areas reflecting a major rural-urban disparity in smoke-free laws. The overall goal of the study is to accelerate the 'diffusion-of-innovations curve' in rural communities through tailored evidence-based dissemination and implementation efforts. The long-term goal is to develop a best practices framework for disseminating scientific knowledge about the effects of secondhand smoke and smoke-free laws and implementing effective community policy change and maintenance strategies in rural underserved communities. A pretest posttest three-group quasi- experimental design will be used to test the primary hypotheses: Controlling for contextual factors (a) the overall change in stage of readiness for smoke-free policy will be greater for Treatment than Control communities; (b) media coverage will be more favorable toward smoke-free environments in Treatment than Control communities; and (c) Treatment communities will be more likely than Control communities to demonstrate smoke-free policy outcomes. Guided by a community readiness model the Intervention will have two components: (1) assessment of community stage of readiness; and (2) stage-specific tailored dissemination and implementation strategies. The main elements of Component II of the Intervention include translating and disseminating knowledge and building capacity and demand for smoke-free policy. The Treatment communities (n = 20) will participate in both components of the Intervention. Control I communities (n = 10) will participate in the community assessment of readiness at baseline and annually. The Control II communities (n = 10) will participate in community assessment of stage of readiness at the end of the study only. Community stakeholders will participate in key informant telephone interviews to assess community readiness for smoke-free policy. Print media clippings from all 51 daily and non-daily newspapers in study counties will be evaluated for pro/con slant related to smoke-free environments. Initial intermediate and final smoke-free policy outcomes will be measured. The potential influence of secular trends on the impact of this community intervention will be analyzed. The proposal is directly relevant to public health in that it has the potential to protect residents in rural underserved communities from premature death and disease from exposure to secondhand smoke.

project_terms:
Affect;Air;Cessation of life;Clip;Communities;Controlled Study;County;Diffusion of Innovation;Disease;Elements;Environment;Experimental Designs;Exposure to;Goals;Health;Intervention;Kentucky;Knowledge;Laws;Life;Maintenance;Measures;Modeling;NIH Program Announcements;Newspapers;Non-smoker;Outcome;Policies;Printed Media;Public Health Practice;Readiness;Research;Resources;Rural;Rural Community;Science;Smoke;Staging;Telephone Interviews;Testing;Time;Tobacco use;Translating;community intervention;contextual factors;evidence base;implementation research;informant;innovation;outreach;population based;premature;public education;public health medicine (field);public policy on tobacco;tobacco control;trend;urban area


application_id: 7845598
project_number: 5R01CA115942-05
project_title: Mechanism of PCNA-dependent 5'->3' Mismatch Excision
administering_ic: NCI
award_notice_date: 2010-05-18
application_type: 5
activity_code: R01
ic: CA
serial_number: 115942
program_official: OKANO, PAUL
project_start_date: 2006-07-01
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-GGG-E(90)S]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanism of human mismatch repair (MMR) and its impact on human health and disease. The importance of MMR is underscored by the fact that defects in MMR genes lead to severe genomic instability and eventually to cancer predisposition including hereditary non-polyposis colorectal cancer (HNPCC) and certain types of sporadic cancers. MMR in human cells is nick-directed and involves at least nine proteins which are MutS alpha MutS beta MutL alpha EXO1 polymerase delta PCNA RFC RPA and HMGB1. Despite extensive investigations on the initiation of mismatch-provoked excision which appears to require MutS alpha PCNA RPA and EXO1. However how mismatch recognition by MutS proteins leads to a strand-specific excision at a single-stranded break several hundred base pairs away from the mismatch is not understood. Three current models on mismatch- provoked excision are quite controversial in terms of how many MutS molecules are required and how the strand discrimination signal is recognized. Recently mismatch-provoked excision has been reconstituted. Interestingly EXO1 a 5'?>3' exonuclease was reported to be capable of bi-directional removal of mismatch; and EXO1-catalyzed 5' excision is independent of PCNA. Given the importance of PCNA in mismatch- provoked excision and the involvement of four exonucleases in the E. coli methyl-direct MMR we hypothesize that multiple nucleases are involved in the human reaction. Indeed we have recently identified a novel 5'?>3' mismatch excision pathway which depends on at least MutS alpha PCNA a novel 5' nuclease and a stimulating factor. This application proposes to purify and characterize both the novel 5' nuclease and the excision stimulating factor and eventually reconstitute the PCNA-dependent 5' excision reaction in vitro using purified proteins. The purified system will then be used to evaluate three controversial models to elucidate the molecular mechanism of mismatch-provoked excision. Since defects in mismatch excision genes e.g. the EXO1 gene are associated with cancer development identifying the components required for the novel 5' excision pathway will provide new diagnostic markers for HNPCC and other MMR deficient cancer syndromes.

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


application_id: 7845565
project_number: 5R01NS051568-04
project_title: Mechanisms of Cerebral Vascular Remodeling
administering_ic: NINDS
award_notice_date: 2010-05-21
opportunity_number: PAS-04-072
application_type: 5
activity_code: R01
ic: NS
serial_number: 051568
program_official: JACOBS, TOM P
project_start_date: 2007-06-01
project_end_date: 2012-05-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  High levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with cerebral- vascular disease dementia stroke and Alzheimer's disease. The ?-amino butyric acid (GABA) stimulates the inhibitory neurotransmitter GABA-A receptor and decreases vascular dementia and stroke. The novelty of this proposal is that Hcy specifically competes with the GABA-A receptors and acts as an excitotoxic neurotransmitter. Hcy activates cerebral vascular matrix metalloproteinases (MMPs) by inducing redox stress and reactive oxygen species (ROS): The long-term goal of this proposal is to understand the mechanisms of cerebral vascular remodeling in HHcy. The hypothesis of this proposal is that Hcy induces MMPs and suppresses tissue inhibitors of metalloproteinase (TIMPs) in part by inhibiting the GABA-A receptor. This leads to degradation of the matrix and disruption of the blood brain barrier We will test this hypothesis by three specific aims: Specific aim #1: To determine whether Hcy increases levels of NADH oxidase and ROS and decreases levels of thioredoxin and peroxiredoxin by attenuating the GABA-A receptor. Levels of NADH oxidase activity and thioredoxin in brain cortex of transgenic mouse model of HHcy (cystathionine  synthetase CBS -/+) and GABA-A receptor null mice treated with and without muscimol (GABA-A receptor agonist) will be measured. The mRNA levels will be measured by Q-RT-PCR. Specific aim #2: To determine whether Hcy increases metalloproteinase activity and decreases TIMP activity by antagonizing the GABA-A receptor. Levels of MMP-2 -9 -13 and TIMP-1 -2 -3 and -4 will be measured by innovative 2-D zymography functional proteome Western blots and Q-RT-PCR analyses. Specific aim #3: To determine whether Hcy alters brain microvascular reactivity and increases permeability of brain microvessels by augmenting GABA-A receptor. Brain microvascular permeability will be measured by in vivo video fluorography using fluorescence-labeled albumin. The vascular reactivity will be measured by a topical application of vasoactive agents. These studies will demonstrate a novel mechanism in which brain microvascular permeability changes during HHcy and vascular dementias and will have therapeutic ramifications for microvascular disease in Alzheimer's patients.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;A Mouse;Abbreviations;Adenosine Diphosphate;Agonist;Albumins;Alteplase;Alzheimer's Disease;Antioxidants;Arginine;Attenuated;Basement membrane;Blood - brain barrier anatomy;Blood Vessels;Brain;Butyric Acids;Caliber;Cerebrum;Collagen;Cystathionine;Dementia;Diabetic Angiopathies;Disintegrins;Endothelial Cells;Extracellular Matrix;Extravasation;Fluorescence;Functional disorder;GABA-A Receptor;Gelatinase A;Gelatinase B;Goals;Heterozygote;Homocysteine;Homocystine;Hydrolase;Hyperhomocysteinemia;Knock-out;Knockout Mice;Label;Ligase;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metalloproteases;Methionine;Methylenetetrahydrofolate reductase (NADPH);Microvascular Permeability;Muscimol;N-Methylaspartate;NADH oxidase;NADP;Neurotransmitters;Niacinamide;Nitric Oxide Synthase;Norepinephrine;Oxidation-Reduction;Patients;Permeability;Plasma;Polymerase Chain Reaction;Process;Proteome;Reactive Nitrogen Species;Reactive Oxygen Species;Research Personnel;Secondary to;Seizures;Stress;Structure of thyroid parafollicular cell;Testing;Therapeutic;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Topical application;Transgenic Mice;Vascular Dementia;Vascular Diseases;Vascular remodeling;Western Blotting;Wild Type Mouse;cerebrovascular;constriction;gamma-Aminobutyric Acid;human NOS3 protein;in vivo;innovation;micrography;mouse model;novel;peroxiredoxin;programs;receptor;relating to nervous system;stroke;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;vasoactive agent


application_id: 7845554
project_number: 5R03NS065451-03
project_title: Towards a Behavioral Index of Seizure Susceptibility
administering_ic: NINDS
award_notice_date: 2010-04-09
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: NS
serial_number: 065451
program_official: STEWART, RANDALL R
project_start_date: 2009-05-15
project_end_date: 2012-04-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
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: Y
project_abstract:
DESCRIPTION (provided by applicant): There is overwhelming clinical evidence of the interactions between sleep and epilepsy but the literature on seizure prediction has largely disregarded the effects of state of vigilance (SOV) on seizure generation. Existing seizure prediction algorithms (SPAs) are not accurate enough for use in epilepsy care due to high false prediction rates. Recent SPA assessments reveal that false seizure predictions are more likely during certain stages of sleep arousal or times of day. These observations suggest that (1) SPAs confuse certain normal states of vigilance with truly preictal states (should they exist) or (2) SPA measures merely track transitions to normal states of vigilance that are more susceptible to seizure. In order to investigate the mechanism of seizure generation from different brain states methods are needed to accurately track changes in SOV from continuous physiological measurements. We have developed SOV discrimination methods that utilize acceleration measurements from head-mounted accelerometers to significantly improve on methods that rely on EEG alone (Sunderam et al. J. Neurosci. Methods 2007). We propose to develop a methodology for tracking SOV in real time by (1) Applying a combination of supervised Fisher discrimination and unsupervised Bayesian discrimination to establish ground truth labels for SOV; and (2) Constructing state-space models (hidden Markov models and switching Kalman filters) to track the noisy nonstationary SOV dynamics. In the current project we will test the ability of these methods to perform accurate real-time brain state tracking using chronic EEG and kinematic measurements from a rodent model of temporal lobe epilepsy as well as normal controls. The output will be used to quantify the relative probability of seizure onset from different states of vigilance. The long term goal of this project is to track state of vigilance in epilepsy patients and investigate behavioral states with a high probability of seizure generation. The formulation of a behavioral index of seizure susceptibility will help improve the performance of SPAs and serve as the basis for state-dependent seizure detection anticipation and preventive control using low frequency electric field modulation. It will also be useful for testing whether candidate SPA measures truly discriminate between the preseizure period and normal behavioral states. PUBLIC HEALTH RELEVANCE: Our long term goal is to develop for use in implantable seizure control devices methods for real-time tracking of state of vigilance in epilepsy patients. Certain states particularly related to sleep and arousal are more likely to lead to seizure. The availability of a behavioral index of seizure susceptibility will lead to improved performance of existing seizure prediction and control algorithms.

project_terms:
Acceleration;Agreement;Algorithms;Animals;Arousal;Basic Science;Behavioral;Brain;Caring;Cephalometry;Chronic;Classification;Clinical;Data;Dependence;Detection;Devices;Discrimination (Psychology);Drug Formulations;Electroencephalography;Epilepsy;Evolution;Frequencies (time pattern);Generations;Goals;Gold;Human;Label;Lead;Literature;Measurement;Measures;Methodology;Methods;Modeling;Monitor;Output;Patients;Performance;Physiological;Predisposition;Preventive;Probability;Rattus;Recording of previous events;Relative (related person);Rodent Model;Seizures;Sleep;Sleep Stages;Space Models;Temporal Lobe Epilepsy;Testing;Time;Training;Work;base;electric field;implantable device;improved;indexing;kinematics;markov model;public health relevance;sleep epilepsy;success;vigilance;ward

public_health_relevance:
Project NarrativeOur long term goal is to develop for use in implantable seizure control devices methods for real-time trackingof state of vigilance in epilepsy patients. Certain states particularly related to sleep and arousal are morelikely to lead to seizure. The availability of a behavioral index of seizure susceptibility will lead to improvedperformance of existing seizure prediction and control algorithms.


application_id: 7845314
project_number: 7R21CA127792-03
project_title: Integrin Contributions to Pancreatic Cancer
administering_ic: NCI
award_notice_date: 2009-06-23
opportunity_number: PA-06-303
application_type: 7
activity_code: R21
ic: CA
serial_number: 127792
program_official: FORRY, SUZANNE L
project_start_date: 2008-04-08
project_end_date: 2011-01-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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): Pancreatic cancer has the highest death to incidence ratio (approximately 0.99) of all cancers. Survival time for pancreatic cancer patients is measured in months rather than years where the mean survival time is 3-6 months from the time of diagnosis. The major reasons for this dismal prognosis come from the fact that pancreatic cancers disseminate at a high frequency and are resistant to traditional chemotherapeutics and radiation for reasons that are unclear. We find it striking that pancreatic carcinomas display cytoarchitecture that is reminiscent of morphologically differentiated cells which by their nature are resistant to chemotherapies. We postulate that this observation may hold the key to the resistance of pancreatic cancers to treatment. The long- term goal of this project is to better understand the mechanisms governing the aggressive and drug-resistant nature of pancreatic carcinomas so that more effective treatments can be developed for pancreatic cancer. The objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4 which is associated with apoptosis resistance and is highly expressed in pancreatic carcinomas can contribute to the aggressive and resilient nature of pancreatic adenocarcinomas. The central hypothesis of this grant proposal is that the integrin ?6?4 and its ligands are upregulated early in tumor progression at high frequency and promote the chemotherapeutic resistance of pancreatic cancer cells by facilitating a unique three-dimensional architecture. Our first aim is to determine if the ?6?4 integrin can mediate resistance of pancreatic carcinoma cells to traditional chemotherapies. To study this phenomenon properly we expect that the accurate modeling of the context of the cells will be critical and thus have developed a three-dimensional culture system for this purpose. In our second aim we will define the stage at which integrin ?6?4 and its ligands are overexpressed and mislocalized in human pancreatic tumor progression. We are well positioned to undertake the proposed research since the principal investigator has a solid background in the biology of integrins in invasive carcinoma cells. We have the expertise and support of clinical scientists who are involved in the diagnosis and treatment of patients with pancreatic disease at UTMB. In addition we have well-developed models for studying integrin ?6?4 in pancreatic cancer which includes multiple pancreatic cell lines immunohistochemical staining of archival tissues for integrin ?4 subunit and three-dimensional cultures for studying the effects of cytoarchitecture. Ultimately our studies are significant because they will contribute to the understanding of drug resistance in pancreatic cancer that in time will allow us to decrease the morbidity and mortality of pancreatic cancer patients.  PUBLIC HEALTH RELEVANCE: The poor prognosis for pancreatic cancer patients persists due to a high incidence of invasion and metastasis and a lack of effective treatment options due to the drug-resistant nature of pancreatic cancer cells. Based on our preliminary data and knowledge of the biology of integrins in advanced cancers objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4 which is highly expressed in pancreatic carcinomas can contribute to the aggressive and apoptosis/drug-resistant nature of pancreatic carcinomas. Ultimately our studies will be significant because they will contribute to the understanding of drug resistance in pancreatic cancer that in time will allow us to decrease the morbidity and mortality of pancreatic cancer patients through the development of more effective treatments.

project_terms:
Advanced Malignant Neoplasm;Affect;Antigens;Apical;Apoptosis;Apoptotic;Appearance;Applications Grants;Architecture;Basement membrane;Biological Models;Biology;Blocking Antibodies;Breast;Cancer Patient;Carcinoma;Cell Line;Cells;Cellular biology;Cessation of life;Clinical;Data;Development;Diagnosis;Dimensions;Drug resistance;Ductal;ECM receptor;Employee Strikes;Environment;Epithelium;Event;Excision;Frequencies (time pattern);Goals;Head;Hemidesmosomes;Human;In Vitro;Incidence;Integrins;Killings;Knowledge;Laminin;Left;Ligands;Ligation;Localized Disease;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of pancreas;Mean Survival Times;Measures;Mediating;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Nature;Neoplasm Metastasis;Operative Surgical Procedures;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Diseases;Pancreatic carcinoma;Pathologist;Patients;Pharmaceutical Preparations;Phenotype;Positioning Attribute;Principal Investigator;Property;Radiation;Research;Resistance;Sampling;Scientist;Signal Transduction;Small Interfering RNA;Solid;Staging;Staining method;Stains;Study models;Surface;Surgeon;System;Testing;Time;Tissues;Tumor Cell Invasion;Up-Regulation (Physiology);Work;base;cancer cell;chemotherapy;effective therapy;human NTN1 protein;indexing;innovation;laminin-5;netrin-1;outcome forecast;overexpression;pancreatic neoplasm;public health relevance;receptor;response;tumor;tumor progression;two-dimensional


application_id: 7845298
project_number: 3R01CA102102-05S1
project_title: BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
administering_ic: NCI
award_notice_date: 2009-05-29
application_type: 3
activity_code: R01
ic: CA
serial_number: 102102
suffix: S1
program_official: FU, YALI
project_start_date: 2009-06-01
project_end_date: 2009-10-31
study_section: Bio-Organic and Natural Products Chemistry Study Section[BNP]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Gilvocarcins and jadomycins are angucyclin-derived anticancer drugs/antibiotics possessing unique molecular frames whose common biosynthetic key step is an oxidative rearrangement catalyzed by a closely related set of enzymes.     The gilvocarcins produced by various Streptomyces strains including Streptomyces griseoflavus Go 3592 represent a distinct family of interesting aryl C-glycoside antitumor drugs with a coumarin-based aromatic core that promote specific DNA interactions when photoactivated by near UV light. This class of anticancer drugs shows excellent antitumor activity and remarkably low toxicity. Its unprecedented molecular architecture in conjunction with its unique biological activity makes the gilvocarcins an excellent target for biosynthetic studies and the development of novel photoactivatable anticancer drugs through combinatorial biosynthesis. The drugs may be useful for the treatment of special cancers such as brain tumors colon skin lung and prostate cancers or leukemia. The jadomycins are antibiotics/antifungals whose structure is characterized by an unusual insertion of an amino acid building block after an oxidative bond breakage.    Previous biosynthetic studies suggest for both gilvocarcins and jadomycins a pathway dominated by a type-2 polyketide synthase (PKS) leading initially to an angucycline type drug intermediate which then oxidatively rearranges into the final molecular frame. Selected intriguing post-PKS tailoring steps namely the oxidative rearrangement (gilvocarcin and jadomycin biosynthesis) the unusual C-glycosylation step (gilvocarcin biosynthesis) and the formation of the vinyl group side chain of gilvocarcin V are key biosynthetic features responsible for the generation of structural elements which are essential for the unique biological activity of the gilvocarcin drugs. The investigation of these cascades of post-PKS tailoring biosynthetic key reactions found in both the jadomycin and gilvocarcin biosyntheses is a main goal of the research since it as an interesting model for post-PKS enzyme complexes their mechanisms interactions substrate binding/passing modes etc. This topic has never been studied in detail despite the importance of such tailoring steps for the biological activity of polyketide drugs. The understanding of these biosynthetic steps and the enzymes responsible for their execution will ultimately pave the way for the generation of more potential and more selective drugs through combinatorial biosynthetic methods. The following specific aims will be addressed: (1) Characterization of the late steps of the gilvocarcin and jadomycin biosynthesis; (2) Generation of new gilvocarcin analogues by inactivation and recombination of selected post-PKS tailoring genes; (3) Characterization of key enzymes of the gilvocarcin and the related jadomycin biosynthetic pathway to understand their mechanism-of-action and substrate specificity range their interaction; and (4) assessment of the antitumor activity of gilvocarcin and newly generated analogues from specific aim 2. The long-term goal of this research is to develop improved anticancer drugs for the treatment of special cancers.

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


application_id: 7844881
project_number: 5R01DC008168-04
project_title: Perceptual processing of indirect sound
administering_ic: NIDCD
award_notice_date: 2010-05-23
application_type: 5
activity_code: R01
ic: DC
serial_number: 008168
program_official: KING, KELLY ANNE
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1908853
contact_pi: ZAHORIK, PAVEL A
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant):  The processes by which we hear auditory events in most everyday acoustic environments that produce ndirect sound (e.g. echoes reflections reverberation) are complex and not well understood. Under certain circumstances indirect sound can facilitate speech communication and certain aspects of sound localization n other circumstances however indirect sound can produce deficits in these and other abilities that can be particularly large for individuals with hearing impairment. Recent results have demonstrated that some aspects of indirect sound processing appear to be affected by previous exposure to the acoustic environment which suggests a form of perceptual adaptation. Although these adaptation effects can be substantial for situations with a single echo the effects have not been evaluated in more realistic acoustic environments with complex patterns of indirect sound resulting from multiple echoes and reverberation. The ong-term goal of this project is a complete understanding of the mechanisms and the potentially adaptive processes that subserve auditory localization and communication in everyday acoustic environments with complex patterns of indirect sound and the potential impact of hearing loss on these processes. This goal will be addressed by the following Specific Aims: Specific Aim 1: Demonstrate and quantify environment- adaptation effects on sound localization and speech intelligibility for a single realistic acoustical environment configuration. Specific Aim 2: Determine the sensitivity of environment-adaptation effects to particular environments and source/listener configurations. Specific Aim 3: Quantify the time course of environment- adaptation effects. Specific Aim 4: Quantify the effects of source or listener motion on environment- adaptation effects. The research proposed to address these aims uses state-of-the-art virtual acoustic environment simulation techniques for auditory stimulus control that enable testing of listening situations that would not be possible in real environments. Knowledge gained from these studies will lead to an improved understanding of a significant public health problem: the impairment of communication and localization in acoustically reflective or reverberant environments resulting from hearing loss. This knowledge may facilitate improvements in both assistive technologies (signal processing algorithms within hearing aids and cochlear implants) and the acoustical design of listening environments. KEYWORDS: Sound Localization Spatial Hearing Speech Intelligibility Room Acoustics Adaptation Virtual Auditory Space.

project_terms:
Acoustics;Address;Affect;Algorithms;Arts;Auditory;Auditory system;Brain;Brain Stem;Cochlear Implants;Communication;Communication impairment;Complex;Dependence;Ear structure;Environment;Event;Exposure to;Goals;Hearing;Hearing Aids;Human;Individual;Knowledge;Lead;Mediating;Motion;Pattern;Performance;Positioning Attribute;Process;Property;Recording of previous events;Research;Research Personnel;Research Support;Role;Self-Help Devices;Sound Localization;Source;Speech;Speech Intelligibility;Stimulus;Surface;Techniques;Testing;Time;Travel;Work;auditory stimulus;base;computerized data processing;design;environmental adaptation;experience;hearing impairment;improved;interest;loss of function;precedence effect;programs;public health medicine (field);research study;simulation;sound;virtual


application_id: 7844877
project_number: 5R01HL087039-03
project_title: Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
administering_ic: NHLBI
award_notice_date: 2010-03-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 087039
program_official: WANG, LAN-HSIANG
project_start_date: 2008-04-15
project_end_date: 2013-03-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Every year sudden cardiac death claims up to 25000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER) thereby decreasing the number of functional channels expressed at the cell surface. Thus far mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations and unfortunately most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones co-chaperones and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression. PUBLIC HEALTH RELEVANCE: Every year sudden cardiac death claims up to 25000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7000 people have LQT1 or LQT2 which is caused by mutations in either the KCNQ1 or KCNH2 genes respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.

project_terms:
Action Potentials;Affect;Arrhythmia;Biochemical;Biogenesis;Cardiac;Cell surface;Cells;Complex;Data;Death Sudden Cardiac;Degradation Pathway;Disease;Endoplasmic Reticulum;Environment;Ethers;Gene-Modified;Genes;Genetic;Genotype;Goals;Health;Heart;Heart Diseases;Human;Imaging Techniques;Inherited;Intracellular Transport;Link;Long QT Syndrome;Mammalian Cell;Membrane;Missense Mutation;Modeling;Molecular;Molecular Chaperones;Mutation;Palpitations;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phenotype;Potassium Channel;Property;Quality Control;Rare Diseases;Research;Seizures;Syncope;Syndrome;Testing;Therapeutic;Transport Vesicles;Voltage-Gated Potassium Channel;cytotoxic;intracellular protein transport;loss of function;new therapeutic target;novel;prevent;protein folding;protein misfolding;public health relevance;trafficking


application_id: 7844859
project_number: 5R01AG027219-05
project_title: SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT
administering_ic: NIA
award_notice_date: 2010-04-09
application_type: 5
activity_code: R01
ic: AG
serial_number: 027219
program_official: REFOLO, LORENZO
project_start_date: 2006-08-01
project_end_date: 2013-10-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Mounting evidence suggests that individuals with mild cognitive impairment (MCI) have an increased likelihood to develop Alzheimer's disease (AD). It is unclear what early pathophysiological changes may underlie this transition. The brains of individuals with definite AD manifest several pathological changes including a substantial loss of synapses in association areas of the neocortex. Recent work has now demonstrated that synaptic loss provides an excellent correlation with cognitive ability and provides a strong correlate of dementia. The relationship between synapse loss early cognitive decline such as that observed in MCI is poorly understood. There is increasing evidence that amyloid beta peptide (Abeta) and oxidative damage may be fundamentally involved in the pathogenesis of AD and contribute to MCI. The interaction between Abeta oxidative damage and synapse loss may provide important keys to the mechanisms that lead to MCI. This proposal will examine the hypothesis that synapse loss is associated with cognitive deficits observed in the early phase of the disease process and is responsible for amnestic memory problems associated with MCI. Studies will be carried out on short postmortem interval brains from individuals characterized as no cognitive impairment (NCI) MCI and early AD and evaluation of total synapses will be obtained by coupling unbiased stereology with transmission electron microscopy. Since Abeta is considered by many researchers to play an important role in progression of AD we will study the relationship of soluble Abeta1-42 with synaptic loss and pre/post synaptic proteins. The specific aims will also test the hypothesis that oxidative damage is an early indicator of MCI and is associated with changes in total synaptic numbers in neocortical association areas known to be affected early in AD. Finally we will study possible changes in mitochondrial bioenergetics that occur in MCI and early AD since mitochondria can be affected by both Ap and oxidative stress and are important for synapse function. Successful completion of the proposed studies will lead to new insights into the mechanisms underlying MCI and early AD and contribute to the development of effective pharmacologic therapies for AD.

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


application_id: 7844264
project_number: 3R01CA119028-05S1
project_title: Mechanisms of As-Induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2009-09-25
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 119028
suffix: S1
program_official: BLAIR, DONALD G
project_start_date: 2006-02-01
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1 OBT-M (96)]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: HUANG, CHUANSHU
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Arsenic remains a top environmental concern in the United States as well as world-wide because of its global existence and serious health impacts. Epidemiological studies provide ample evidence that arsenite exposure is associated with the increased incidence of skin and lung cancers. The scope of the parent grant addresses the relation of reactive oxygen species (ROS) generation and skin carcinogenesis due to arsenite exposure in both the human keratinocytes and the mouse skin models. While the scope of current competitive revision seeks to evaluate the contribution and molecular mechanisms of linking the arsenite-induced chronic inflammation to lung carcinogenesis both in vitro and in vivo this competitive revision seeks to expand the original scope of study from ROS generation in the mediation of skin carcinogenesis to identification of the molecular mechanisms that link arsenite-induced chronic inflammation to lung tumorigenicity in vitro and in vivo in cellular as well as animal response to arsenite exposure. Although both the parent grant and the current competitive revision propose to study the mechanisms implicated in the carcinogenic effects of arsenite exposure this revision is specifically intended to identify the contribution of key inflammatory mediators TNF-1 and COX-2 to arsenite-induced development of tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo as well as the molecular mechanisms involved in this tumorigenic process. The main hypothesis of this revision is that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and subsequently results in the induction of lung epithelial cell tumorigenicity due to arsenic exposure. The overall goal of this proposal is to determine role of TNF-1 and COX-2 in arsenite-induced HBECs' tumorigenicity as well as the central role of TNF-1 in the maintenance of lung chronic inflammation during arsenic exposure both in vitro and in vivo. There are two Specific Aims proposed for this investigation: 1) To determine the contribution of TNF-1 and COX-2 to the development of tumorigenicity of HBECs due to arsenic exposure; 2) To assess the central role of TNF-1 in arsenic-induced lung chronic inflammation and its mechanisms in vivo. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the chronic lung inflammatory microenvironment and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information that is needed for the designing more effective agents for the prevention of and therapy for inflammation-associated lung cancers. Furthermore funding of this competitive revision will save two jobs one part-time for Dr. Jianxiu Yu and one for Dongyun Zhang both of whom provide valuable expertise and are crucial for the proposed studies. The finding will also create new training opportunity for two postdoctoral fellows in the proposed research field. Since we have most of research tools and research animals are either available in our laboratory or commercially we believe that the proposed studies will be achieved within two years.  
  
PUBLIC HEALTH RELEVANCE: Arsenic remains the top environmental concern in United States as well as world wide and the existence of a sustained lung chronic inflammatory microenvironment is thought to be a major driving force for the development of lung cancers due to arsenite exposure however the molecular mechanisms linking arsenite exposure to lung chronic inflammation are totally unknown. This application is to test the hypothesis that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and induction of lung epithelial cell tumorigenicity due to arsenic exposure. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the lung chronic inflammatory microenvironment and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information needed for designing more effective agents for prevention and therapy of the inflammation-associated lung cancers.

project_terms:
1-Phosphatidylinositol 3-Kinase;Abbreviations;Address;Alkaline Phosphatase;Animal Experimentation;Animals;Arsenic;Arsenites;Cell Line;Cells;Chronic;Cyclic AMP-Dependent Protein Kinases;Cytomegalovirus;Data;Development;EGF gene;Electron Spin Resonance Spectroscopy;Embryo;Epidemiologic Studies;Epidermal Growth Factor;Epithelial Cells;Exposure to;Feedback;Fibroblasts;Figs - dietary;Funding;Generations;Glycogen Synthase Kinase 3;Goals;Grant;Health;Human;Immunoglobulin G;In Vitro;Incidence;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;International Agency for Research on Cancer;Investigation;Laboratories;Link;Lipids;Lung;Lung Inflammation;MAP Kinase Gene;MAPK8 gene;MEKs;Maintenance;Malignant neoplasm of lung;Mediating;Mediation;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Nuclear;Occupations;PTGS2 gene;Pathway interactions;Phosphatidylinositols;Phosphotransferases;Play;Postdoctoral Fellow;Prevention therapy;Process;Protein Kinase;ROS1 gene;Reactive Oxygen Species;Research;Role;Signal Transduction;Skin;Skin Carcinogenesis;Small Interfering RNA;Superoxide Dismutase;T-Cell Activation;T-Lymphocyte;Testing;Time;Training;Transcription Factor AP-1;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Tumorigenicity;United States;base;carcinogenesis;cyclooxygenase 2;design;driving force;extracellular;fetal bovine serum;in vivo;inhibitor/antagonist;keratinocyte;lung carcinogenesis;nuclear factors of activated T-cells;parent grant;platelet protein P47;public health relevance;response;stress-activated protein kinase 1;success;tool;tumorigenic

public_health_relevance:
PROJECT NARRATIVEArsenic remains the top environmental concern in United States as well as world wide and the existence of asustained lung chronic inflammatory microenvironment is thought to be a major driving force for thedevelopment of lung cancers due to arsenite exposure however the molecular mechanisms linking arseniteexposure to lung chronic inflammation are totally unknown. This application is to test the hypothesis that TNF-plays a central role in the formation and maintenance of sustained chronic lung inflammation and induction oflung epithelial cell tumorigenicity due to arsenic exposure. Success of the revision will facilitate ourunderstanding of the molecular mechanism(s) of the formation and maintenance of the lung chronicinflammatory microenvironment and its role in lung cancer development induced by arsenic exposure. A betterunderstanding of those issues may provide valuable information needed for designing more effective agentsfor prevention and therapy of the inflammation-associated lung cancers.


application_id: 7844245
project_number: 3R03DC007983-03S1
project_title: Molecular mechanisms of aging in the intrinsic laryngeal muscles
administering_ic: NIDCD
award_notice_date: 2009-05-28
opportunity_number: PAR-04-062
application_type: 3
activity_code: R03
ic: DC
serial_number: 007983
suffix: S1
program_official: SHEKIM, LANA O
project_start_date: 2009-06-01
project_end_date: 2009-10-31
study_section: ZDC1-SRB-Y(52)
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): As individuals age muscle weakness and neuromuscular disorders have the potential to diminish the quality of life increase health care costs and lead to institutionalization. The larynx is part of a complex motor system that serves dually as the vibratory source of phonation and as a valve that separates and protects the airway from the digestive tract. In the elderly age-related changes in the intrinsic laryngeal muscles may compromise voice quality thus impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal dysfunction may also cause dysphagia and increase the risk of aspiration which may translate to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age; however the biology of these small muscles remains largely unexplored. This project in response to the NIDCD Small Grant (R03) Program will achieve two objectives: (1) it will determine how age alters neuromuscular junction organization and function in the intrinsic laryngeal muscles; (2) it will provide a mechanism to further the professional development of the PI leading to scientific independence. The studies will test the central hypothesis that aging disrupts the organization and stability of the neuromuscular junction in the intrinsic laryngeal muscles. Using the Fischer 344-Brown Norway F1 hybrid rat model of aging the studies will examine to what extent aging alters NMJ organization in the posterior cricoarytenoid (PCA vocal fold abductor) and thyroarytenoid (TA vocal fold adductor) muscles. Three Specific Aims will be accomplished. Specific Aim 1 will test whether age changes NMJ ultrastructure and the expression of acetylcholine receptor subunits in the intrinsic laryngeal muscles. Specific Aim 2 will evaluate if aging represses cellular signaling pathways that initiate and sustain NMJ organization in the intrinsic laryngeal muscles. Specific Aim 3 will assess to what extent age alters the acetylcholine vesicle release system in the presynaptic terminals of the intrinsic laryngeal NMJs. This project will generate novel data on how age disrupts NMJ organization in the intrinsic laryngeal muscles and will provide the bases for interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles. In addition the anticipated results will be of relevance to diseases not associated with aging but that affect NMJ structure and function such as myasthenia gravis and the Lambert- Eaton myasthenic syndrome.

project_terms:
Acetylcholine;Achievement;Affect;Age;Aging;Architecture;Biochemical;Biological;Biology;Calcium Channel;Cell physiology;Cells;Cholinergic Receptors;Complex;Data;Deglutition Disorders;Development;Disease;ERBB2 gene;Elderly;Ensure;Functional disorder;Gastrointestinal tract structure;Glycoproteins;Goals;Grant;Health Care Costs;Hybrids;Individual;Institutionalization;Intervention;L-Type Calcium Channels;Lambert-Eaton Myasthenic Syndrome;Laryngeal muscle structure;Larynx;Lead;Maintenance;Mentorship;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Motor;Muscle;Muscle Weakness;Myasthenia Gravis;National Institute on Deafness and Other Communication Disorders;Neuromuscular Diseases;Neuromuscular Junction;Norway;Phenotype;Phonation;Presynaptic Terminals;Principal Investigator;Quality of life;Rattus;Risk;Scientist;Signal Pathway;Signal Transduction;Source;Structure;System;Testing;Translating;Utrophin;Vesicle;Voice Quality;age effect;age related;base;neuromuscular;neuromuscular transmission;novel;prevent;programs;research study;response;stoichiometry;synaptotagmin;syntaxin;vesicle-associated membrane protein;vocal cord


application_id: 7843722
project_number: 5R01CA115801-04
project_title: Redox Modulation of Prostate Cancer
administering_ic: NCI
award_notice_date: 2010-05-28
application_type: 5
activity_code: R01
ic: CA
serial_number: 115801
program_official: BERNHARD, ERIC J
project_start_date: 2007-08-01
project_end_date: 2012-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1941793
contact_pi: ST CLAIR, WILLIAM H
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant):  The nuclear factor kappa beta (NF-kB) a redox-sensitive transcription factor is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme manganese superoxide dismutase and the antiapoptotic protein BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands. Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells. Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity. Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit.

project_terms:
Androgens;Antioxidants;Binding Sites;Cancer Etiology;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Clinical Treatment;Code;Data;Development;Dominant-Negative Mutation;Dose;Enhancer Elements (Genetics);Enzymes;Family;Family member;Free Radicals;Gene Targeting;Genes;Genetic Transcription;Goals;Growth;Hormones;Human;Implant;In Vitro;Interruption;Intervention;LNCaP;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Mediating;Modeling;Monitor;Mus;NF-kappa B;Nature;Nude Mice;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Pattern;Play;Process;Promotor (Genetics);Prostate;Proteins;RNA;Radiation;Radiation Tolerance;Reactive Oxygen Species;Regulator Genes;Resistance;Role;Signal Transduction;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Time;Translating;Tumor Necrosis Factor Ligand Superfamily Member 6;androgen independent prostate cancer;base;cancer cell;design;direct application;implantation;improved;in vitro Model;in vivo;in vivo Model;inhibitor/antagonist;insight;male;member;men;mutant;neoplastic cell;novel strategies;overexpression;prevent;radiation effect;radiation resistance;research study;response;survivin;transcription factor;tumor


application_id: 7843608
project_number: 5R03DK084166-02
project_title: Role of miR-30d in insulin gene expression in pancreatic beta cells
administering_ic: NIDDK
award_notice_date: 2010-07-01
opportunity_number: PAR-06-172
application_type: 5
activity_code: R03
ic: DK
serial_number: 084166
program_official: HYDE, JAMES F
project_start_date: 2009-07-01
project_end_date: 2010-12-31
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):  
My long-term goal is to study the role of microRNAs (miRNAs) in regulating beta-cell function and to elucidate the role of miRNAs in the development of type-II diabetes. MiRNAs are small noncoding ribonucleotides that bind mRNAs and function mainly as translational repressors in mammals. miRNAs have been implicated to play a role in many diseases including diabetes. Several reports indicate an important function for miRNAs in insulin secretion and pancreatic beta cell development. We have recently carried out a screen in the pancreatic beta cell line MIN6 to identify miRNAs with altered abundance in response to changes in glucose concentrations. This screen resulted in identification of more than 50 glucose-regulated miRNAs from a total of 108 miRNAs detectable in MIN6 cells. Many of the identified miRNAs including miR-124a miR-107 and miR-30d were upregulated in the presence of high glucose. Interestingly we found that overexpression of miR-30d increased insulin gene transcription. Moreover the induction of insulin by overexpression of miR-30d is associated with increased expression of the beta-cell specific transcription factor MafA. This suggests that the putative target genes of miR-30d may be negative regulators of MafA/insulin gene expression. To determine the function of miR-30d in insulin gene transcription I will: 1) Identify miR-30d target genes involved in regulation of insulin gene transcription. 2) Characterize the biological function of miR-30d in pancreatic beta cell lines and primary mouse islets. The verified targets will be analyzed for their role in insulin gene expression by siRNA knock-down techniques. Moreover the effect of miR-30d on the target downstream signaling will be characterized. Finally the function of miR-30d in primary mouse islets will be confirmed using a recombinant adenovirus expressing miR-30d. The finding from this proposal will contribute to our understanding of miRNA function in insulin gene transcription.  
PUBLIC HEALTH RELEVANCE: Developing new approaches to restore insulin production and secretion from pancreatic beta cells is a major goal in diabetes research. MiR-30d is particularly interesting since our preliminary results indicate that it induces glucose-stimulated insulin gene expression. My objective in this proposal is to identify miR30d target genes and to characterize their function in insulin production. Taking into account that miR-30d also induces MafA expression this miRNA emerges as an important target that may be beneficial in enhancing islet function and may thus aid in the design of alternative therapies for the prevention and treatment of diabetes.

project_terms:
Accounting;Adenoviruses;Alternative Therapies;American;Beta Cell;Binding (Molecular Function);Biological Assay;Biological Process;Cardiovascular system;Cell Line;Cell physiology;Cells;Data;Development;Diabetes Mellitus;Disease;Gene Expression;Gene Targeting;Gene Transfer;Genes;Genetic Transcription;Gills;Glucose;Goals;Heart;Immunoblotting;Insulin;International;Journals;Light;Luciferases;Mammals;Manuscripts;MicroRNAs;Minor;Mus;Non-Insulin-Dependent Diabetes Mellitus;Northern Blotting;Oligonucleotides;Play;Prevention;Principal Investigator;Production;Progress Reports;Publications;Publishing;RNA;Recombinants;Regulation;Reporter;Reporting;Research;Ribonucleotides;Role;Screening Result;Signal Transduction;Small Interfering RNA;Structure of beta Cell of islet;Techniques;Time;Transcription Repressor/Corepressor;base;blood glucose regulation;design;endocrine pancreas development;insulin secretion;insulinoma;interest;islet;knock-down;meetings;novel;novel strategies;overexpression;posters;programs;public health relevance;research study;response;transcription factor

public_health_relevance:
Project Narrative Developing new approaches to restore insulin production and secretion frompancreatic beta cells is a major goal in diabetes research. MiR-30d is particularly interestingsince our preliminary results indicate that it induces glucose-stimulated insulin geneexpression. My objective in this proposal is to identify miR30d target genes and tocharacterize their function in insulin production. Taking into account that miR-30d alsoinduces MafA expression this miRNA emerges as an important target that may be beneficialin enhancing islet function and may thus aid in the design of alternative therapies for theprevention and treatment of diabetes.


application_id: 7843534
project_number: 5R03AG032009-02
project_title: Oxidative Stress and Myocardial Function
administering_ic: NIA
award_notice_date: 2010-04-30
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: AG
serial_number: 032009
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2009-05-15
project_end_date: 2011-04-30
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 6262679
contact_pi: SUMANDEA, MARIUS P
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): It is well established that cardiac contractile reserve declines while the incidence of heart failure increases dramatically with age. According to the "free radical theory of aging" cardiac dysfunction may be the result of oxidative stress-induced myocardial remodeling. Our long-term goal is to elucidate signal transduction and cellular and molecular mechanisms by which post-translational modifications of myofilament proteins lead to alterations in cardiac muscle function and ultimately to heart failure. The hypothesis underlying this work is that oxidative stress-induced modifications of cardiac contractile proteins are exacerbated with age and cardiac disease progression and lead to impaired myofilament function. To test this hypothesis we propose a comprehensive and versatile set of experiments using a mixture of mechano-energetic and biochemical/biophysical approaches. The proposed research will utilize the spontaneously hypertensive rat model regarded for years as a good model for human systemic hypertension recently demonstrated as an excellent model to study oxidative stress-associated contractile dysfunction. Our aims seek to: 1) Elucidate the oxidative stress-induced modifications of myofilament proteins in young adult and old spontaneously hypertensive rats compared with age matched normotensive Wistar-Kyoto rats. Experiments proposed here test the hypothesis that oxidative stress induces detectable modifications of myofilament proteins and that aging and hemodynamic stress (hypertension) lead to distinctive levels of modifications which may differentially modulate myofilament function. 2) Investigate the functional effects of oxidative stress with age and heart disease progression in WKY and SHR myocardium. Experiments proposed here test the hypothesis that oxidative stress-induced modifications of sarcomeric proteins alter myofilament activation and might be key determinants of cardiac dysfunction. Functional significance of oxidative stress-induced modifications will be evaluated in skinned papillary muscle fiber bundles and intact myocytes from SHR and WKY animals. Overall these experiments will result in a better understanding of the timing and the hierarchy of cellular events leading to cardiac dysfunction during the normal myocardial senescence and during the development of heart failure in the rat. This research could prove of paramount importance in unraveling mechanisms leading to heart failure and identifying new targets or target areas for rational drug design. PUBLIC HEALTH RELEVANCE: Heart failure the leading cause of death in the U.S. increases dramatically with age due of oxidative stress. We propose to study how age and oxidative stress modify the structure of heart muscle proteins and change function. We hope to prevent this by the use of antioxidants.

project_terms:
Actomyosin Adenosinetriphosphatase;Affect;Age;Aging;Angiotensin II;Animals;Antioxidants;Area;Binding (Molecular Function);Biochemical Energetics;Biological Assay;Cardiac;Cause of Death;Cells;Contractile Proteins;Detergents;Development;Disease Progression;Drug Design;EUK-8;Event;Figs - dietary;Fluorescence;Free Radicals;Functional disorder;GTP-Binding Proteins;Goals;Heart Diseases;Heart failure;Human;Hydrogen Peroxide;Hydroxyl Radical;Hypertension;Hypertrophy;Immunoblot Analysis;Inbred SHR Rats;Inbred WKY Rats;Incidence;Iron;Lead;Length;Mass Spectrum Analysis;Measures;Mechanics;Membrane;Microfilaments;Modeling;Modification;Molecular;Muscle Cells;Muscle Fibers;Muscle Proteins;Muscle function;Myocardial;Myocardium;Nitric Oxide;Nitric Oxide Synthase;Oxidants;Oxidative Stress;Phosphorylation;Post-Translational Protein Processing;Production;Proteins;Rattus;Research;Saline;Sarcomeres;Signal Transduction;Skin;Stress;Structure;Superoxide Dismutase;Superoxides;System;Testing;Time;Ventricular Remodeling;Work;base;catalase;cost;gel electrophoresis;hemodynamics;inorganic phosphate;mimetics;morphometry;normotensive;oxidation;papillary muscle;prevent;public health relevance;research study;senescence;theories;young adult

public_health_relevance:
Project Narrative for "Oxidative Stress and Myocardial Function" Heart failure the leading cause of death in the U.S. increases dramatically with age due ofoxidative stress. We propose to study how age and oxidative stress modify the structure of heartmuscle proteins and change function. We hope to prevent this by the use of antioxidants.


application_id: 7842617
project_number: 5R21AI079483-02
project_title: CRASP-2 proteins of Lyme disease Borrelia
administering_ic: NIAID
award_notice_date: 2010-04-15
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 079483
program_official: BREEN, JOSEPH J
project_start_date: 2009-05-15
project_end_date: 2011-04-30
study_section: Special Emphasis Panel[ZRG1-IDM-A(90)S]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): The causative agent of Lyme disease Borrelia burgdorferi can persistently infect humans and other mammalian hosts for great lengths of time. Understanding the mechanisms by which Lyme disease spirochetes establish and maintain chronic infections will be crucial for developing improved treatments for long-term human infections. Lyme disease spirochetes are generally resistant to their hosts' alternative pathway of complement activation. Studies with cultured bacteria found that either of two borrelial outer surface proteins facilitates resistance to host complement. These proteins CRASP-1 and CRASP-2 (complement regulator-acquiring surface proteins 1 and 2) both bind the human complement regulatory proteins factor H and FHL-1 (factor H-like protein 1) plus other unidentified serum components. However we found production of CRASP-1 is repressed within the first few days of mammalian infection while CRASP-2 production is greatly induced during mammalian infection. Thus CRASP-2 is the only borrelial protein demonstrated to facilitate resistance to host complement that is produced during established mammalian infection. Our studies lead us to hypothesize that production of CRASP-2 during mammalian infection permits the bacterium to avoid killing by its host's alternative pathway of complement activation and thereby enables the spirochete to persistently infect humans. Experiments are outlined in this proposal to test our hypothesis by (1) evaluating the essential nature of CRASP-2 production during mammalian infection and the necessity for precise control of CRASP-2 synthesis and (2) characterizing mechanisms by which CRASP-2 expression is regulated. PUBLIC HEALTH RELEVANCE: The causative agent of Lyme disease can infect humans and other hosts for years possibly even for the lifetime of the individual. Our recent studies demonstrated that a borrelial protein named CRASP-2 helps protect Borrelia burgdorferi from killing by the human innate immune system and that CRASP-2 is produced at high levels during human infection. We propose to determine the mechanisms by which Lyme disease spirochetes control CRASP-2 synthesis with the long-term goal of developing therapies that will disrupt CRASP-2 expression during human infection and thereby render the bacteria sensitive to elimination from the body.

project_terms:
Bacteria;Binding (Molecular Function);Borrelia;Borrelia burgdorferi;Borrelia burgdorferi Group;Chronic;Complement;Complement 2;Complement Activation;Complement Factor H;Genes;Goals;Hand;Human;Immune system;Individual;Infection;Killings;Laboratories;Lead;Length;Lyme Disease;Mammals;Membrane Proteins;Names;Nature;Order Spirochaetales;Parents;Pathway interactions;Play;Production;Proteins;Resistance;Role;Serum;Staging;System;Temperature;Testing;Ticks;Time;genetic regulatory protein;improved;mutant;public health relevance;research study;therapy development;transmission process;vector

public_health_relevance:
Project NarrativeThe causative agent of Lyme disease can infect humans and other hosts for years possiblyeven for the lifetime of the individual. Our recent studies demonstrated that a borrelial proteinnamed CRASP-2 helps protect Borrelia burgdorferi from killing by the human innate immunesystem and that CRASP-2 is produced at high levels during human infection. We propose todetermine the mechanisms by which Lyme disease spirochetes control CRASP-2 synthesiswith the long-term goal of developing therapies that will disrupt CRASP-2 expression duringhuman infection and thereby render the bacteria sensitive to elimination from the body.


application_id: 7842478
project_number: 5R44HL088760-03
project_title: Portable pneumatic driver for counterpulsation therapy
administering_ic: NHLBI
award_notice_date: 2010-03-23
opportunity_number: PA-08-050
application_type: 5
activity_code: R44
ic: HL
serial_number: 088760
program_official: MILLER, MARISSA A
project_start_date: 2007-08-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-SBTS-E(10)B]
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: 2010-04-01
budget_end_date: 2012-03-31
project_abstract:
DESCRIPTION (provided by applicant): SCR Inc. (Louisville KY) is developing a chronic implantable CPD system to treat HF patients who may be responsive to long-term counterpulsation support. The CPD has been developed for superficial implantation via a pacemaker incision without the need to enter the chest and enables complete patient mobility. The CPD is a 32-ml stroke volume polyurethane-lined blood chamber designed to fit comfortably in a subcutaneous pocket on the right anterior chest contralateral to an implantable cardioverter defibrillator (ICD) or biventricular pacer device implantation site. The pumping chamber is connected to the systemic circulation by a short ePTFE graft anastomosed to the axillary artery. The CPD is controlled by a small wearable pneumatic driver connected by a percutaneous air line and triggered by the patient's 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 driver was equivalent to a standard commercially-available 40-ml IABP in a large animal model (n=12) over a range of physiologic conditions (hypotension hypertenstion and heart failure) demonstrating feasibility. In this phase II study the development and testing of the CPD driver will be completed to support a future FDA submission. This objective will be accomplished by (1) completing engineering development (2) demonstrating reliability and ergonomics and (3) demonstrating long-term safety of the CPD driver. 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 program detailed here leverages the development work of SCR and the engineering and development teams at Abiomed (Danvers MA). This partnership will be assisted and guided by an innovative group of physicians at Jewish Hospital (Louisville KY) 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 system into the clinic as a long-term counterpulsation therapy to treat late NYHA class III and early NYHA class IV HF patients and help restore their quality of life. PUBLIC HEALTH RELEVANCE: SCR Inc. (Louisville KY) 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 a portable pneumatic driver that the patient can carry restores mobility.

project_terms:
Acute;Air;Anastomosis - action;Animal Model;Anterior;Blood;Blood Circulation;Cannulas;Cardiac;Cardiovascular system;Carotid Arteries;Catheters;Chest;Chronic;Clinic;Clinical;Clinical Trials;Contralateral;Coronary;Counterpulsation;Data;Development;Devices;Diastole;Electrocardiogram;Engineering;Functional disorder;Future;Goals;Heart;Heart failure;Hospitals;Hypertension;Hypotension;Implant;Implantable Defibrillators;In Vitro;Institutes;Intra-Aortic Balloon Pumping;Location;Mechanics;Modification;Myocardial;Operative Surgical Procedures;Organ;Pacemakers;Patients;Performance;Perfusion;Phase;Physicians;Physiological;Polyurethanes;Pump;Quality of life;Research;Right-On;Safety;Site;Staging;Stroke Volume;Summary Reports;Support System;Surgical incisions;System;Systole;Testing;Thoracic aorta;United States Food and Drug Administration;Universities;Ventricular;Weight;Work;Workload;axillary artery;biomaterial compatibility;clinically relevant;design;ergonomics;follower of religion Jewish;good laboratory practice;hemodynamics;implantation;improved;in vivo;innovation;phase 1 study;phase 2 study;pre-clinical;programs;public health relevance;research study;subcutaneous;verification and validation

public_health_relevance:
SCR Inc. (Louisville KY) is developing a long-term counterpulsation device (CPD) to treat early stage heartfailure patients. The CPD has been developed for superficial implantation without the need to enter the chestand a portable pneumatic driver that the patient can carry restores mobility.


application_id: 7842121
project_number: 1S10RR029127-01
project_title: LTQ Orbitrap XL ETD mass spectrometer
administering_ic: NCRR
award_notice_date: 2010-06-10
opportunity_number: PAR-09-118
application_type: 1
activity_code: S10
ic: RR
serial_number: 029127
program_official: LEVY, ABRAHAM
project_start_date: 2010-06-10
project_end_date: 2012-06-09
study_section: Special Emphasis Panel[ZRG1 BCMB-K (30)]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  The Proteomics Core Facility at the University of Kentucky (UK) College of Medicine requests $947163 to acquire a LTQ Orbitrap XL/ETD hybrid mass spectrometer with an Eksigent nano-HPLC. The goal of this application is to provide advanced mass spectrometry capabilities to meet the proteomics needs of 19 highly productive NIH-funded investigators at UK. The LTQ Orbitrap/ETD hybrid mass spectrometer is a combination of a new linear ion trap (LTQ) a novel and high precision electrostatic ion trap (Orbitrap) mass analyzer and innovative electron transfer dissociation (ETD) technology. In comparison to the existing mass spectrometers for protein and peptide analysis this hybrid instrument simultaneously provides high sensitivity (attomoles) high spectrum repetition rates high mass resolution (60000 HWFM) high mass accuracy (< 5ppm) and complementary fragmentation techniques (both CID and ETD) during a single experiment. The instrumentation reaches a new level of sensitivity and confidence for identifying peptides and proteins. Moreover the ETD technology provides multiple unique advantages. Particularly it can preserve the post-translation modifications on peptides during fragmentation and allow the identification of exact modification sites. This equipment will provide state-of-the-art capabilities to the Proteomics Core Facility and enhance the ability of the facility to meet an ever-increasing volume and intensity of research support. This equipment is essential to these ongoing research programs and to stimulating and enabling new collaborative research initiatives on protein identification posttranslational modification characterization gene discovery and functional proteomics. Currently there is no LTQ Orbitrap/ETD mass spectrometer at UK or any universities in the Commonwealth of Kentucky. The purchase of the instrument is critical to the continuing expansion and enhancement of the proteomics research program in human disease and basic research at UK. As described in this application 19 NIH-funded investigators from 12 different departments have specific needs for this mass spectrometer. The requested instrument will have a major impact on research capabilities at our institution.  To ensure the maximal usage and proper maintenance the instrument will be housed in the Proteomics Core next to the laboratory of the PI. The PI has over 10 years experience in the area of biological mass spectrometry/proteomics. An Advisory Committee with both internal and external members is assembled for overall guidance for the usage of the shared instrument. Financial support for the long term maintenance and operation of the instrument is committed from the University. The research to be supported by this instrument spans a wide spectrum of biological and biomedical research including cutting-edge programs focused on neurological disorders cancer diabetes cardiovascular disease virology eye diseases and women's health. The addition of this instrument to the Proteomics Core Facility at UK Medical Center will significantly enhance the productivity and progress of these research programs thus advancing the NIH mission to improve public health.  The funding of this proposal will lead to the hiring and/or retention of more than six full-time positions including at least one in the University of Kentucky four at Thermo Fisher Scientific and one with Eksigent Technologies. Thus this proposal fits the criteria for Recovery Act funding.  The manufacturers of the instrumentation (Thermo Fisher Scientific and Eksigent Technologies) are committed to being environmentally responsible. In particular the splitless nano-HPLC manufactured by Eksigent Technologies uses significantly less organic solvents compared to other split-flow chromatography instruments thus generating hundreds- to thousands-fold less chemical waste. Moreover the biomedical research programs that will be enabled and supported by the requested instrumentation will make discoveries leading to better health of Americans. In summary the funding of this application will make the United States and the world healthier cleaner and safer.  
  
PUBLIC HEALTH RELEVANCE:  The Proteomics Core Facility at the University of Kentucky (UK) College of Medicine requests $947163 to acquire a LTQ Orbitrap XL ETD hybrid mass spectrometer with an Eksigent nano-HPLC. The goal of this application is to provide advanced mass spectrometry capabilities to meet the proteomics needs of 19 highly productive NIH-funded investigators at UK. The research to be supported by this instrument spans a wide spectrum of biological and biomedical research including cutting-edge programs focused on neurological disorders cancer diabetes cardiovascular disease virology eye diseases and women's health. The addition of this instrument to the Proteomics Core Facility will significantly enhance the productivity and progress of these research programs thus advancing the NIH mission to improve public health. The funding of this proposal will lead to the hiring and/or retention of more than six full-time positions meeting the intention of the Recovery Act. The requested instruments are environmentally friendly. In summary the funding of this application will make the United States and the world healthier cleaner and safer.

project_terms:
Advisory Committees;American;Area;Arts;Basic Science;Biological;Biomedical Research;Cardiovascular Diseases;Chemicals;Chromatography;Commit;Core Facility;Diabetes Mellitus;Dissociation;Electron Transport;Electrostatics;Ensure;Equipment;Eye diseases;Financial Support;Funding;Goals;Health;Housing;Hybrids;Institution;Intention;Ions;Kentucky;Laboratories;Lead;Maintenance;Malignant Neoplasms;Manufacturer Name;Mass Spectrum Analysis;Medical center;Medicine;Mission;Modification;Organic solvent product;Peptides;Positioning Attribute;Post-Translational Protein Processing;Productivity;Proteins;Proteomics;Recovery;Research;Research Personnel;Research Support;Resolution;Site;Techniques;Technology;Time;Translations;United States;United States National Institutes of Health;Universities;Women's Health;college;experience;gene discovery;human disease;improved;innovation;instrument;instrumentation;mass analyzer;mass spectrometer;meetings;member;nano;nervous system disorder;novel;operation;programs;public health medicine (field);public health relevance;research study;virology;wasting


application_id: 7841821
project_number: 5R01MH083621-03
project_title: A Brief Clinic-Based HIV Prevention Program for African American Teen Males
administering_ic: NIMH
award_notice_date: 2010-06-18
opportunity_number: PAR-07-379
application_type: 5
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)R]
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_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention has declared that AIDS is a "state of emergency" in the US relative to African Americans. Teen males attending STD clinics are one important yet often neglected population of African Americans at risk of HIV acquisition. Despite extremely high rates of STD acquisition (and subsequent infection) among this population effective clinic-based interventions specifically designed to reduce their sexual risk behavior for STD/HIV have not been developed/disseminated. A recent intervention trial (conducted by Dr. Crosby) demonstrated the efficacy of a brief clinic-based intervention designed to prevent subsequent STI acquisition among African American males 18 to 29 years of age. The proposed study will test the efficacy this intervention (in modified form) to reduce STI incidence among African American teen (15 to 20 years old). The primary hypothesis is that teens randomized to receive the intervention will have a lower incidence rate of laboratory-confirmed STIs at 2 and 6-month follow-up assessments (as well as 12-month follow-up conducted by a medical records review) compared to those receiving an attention-equivalent control condition. Teens (N = 840) will be recruited from a publicly-funded STD clinic located in an urban area of the South. After completing an A-CASI assessment teens will be rated on their ability to apply condoms to a penile model and then asked to donate a urine specimen for STI testing. Specimens will be tested for C. trachomatis N. gonorrhoeae and T. Vaginalis using nucleic acid amplification assays. Randomization will then be achieved by a concealment of allocation technique. Teens will be randomized to immediately receive: 1) a brief (60 minute) theory-based one-on-one interactive intervention delivered by a lay health advisor or 2) an attention equivalent control condition. The assessment battery will be repeated 2 months subsequent to enrollment and again 6 months after enrollment. A medical records review will be conducted 12 months after enrollment to compare clinic reported incidence rates between the randomized groups of teens. If incidence of STIs in this population of teens can be decreased as substantially as was found in the previous study of 18 to 29 year-old African American males (percent relative difference = 36.7) the public health significance for African American teen males will substantially contribute to rectify the racial disparity in HIV/STD experienced by African American teen males. By extension we suggest that their partners (typically African American teen females) will also benefit. Because our program is designed for ease of implementation the number of dissemination and translation issues will be greatly minimized thereby greatly facilitating the process of translating research into practice. PUBLIC HEALTH RELEVANCE: The proposed efficacy trial tests an innovative method of bridging the gap between research and practice. By providing a brief clinic-based HIV/STD prevention program to African American teen males attending an STD clinic the study will be the first to demonstrate that teen's sexual risk behavior can be reduced without excessive time and resources. The focus on African American teen males is also quite timely given the recent declaration by CDC that AIDS is a "state of emergency" for African Americans.

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;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;Methods;Modeling;Neisseria gonorrhoeae;Newly Diagnosed;Nucleic Acids;Perception;Population;Prevention program;Process;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Resources;Risk;Science;Services;Sex Behavior;Sexual Partners;Specimen;Techniques;Teenagers;Testing;Time;Translating;Translational Research;Translations;Treatment Efficacy;Trichomonas Infections;Trichomonas vaginalis;Uncertainty;United States;Urine;Vagina;Woman;Work;arm;avoid sex;base;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;experience;flexibility;follow up assessment;follow-up;high risk men;improved;innovation;intervention effect;intervention program;male;man;medical specialties;men;neglect;post intervention;prevent;programs;public health medicine (field);public health relevance;research to practice;response;safer sex;sex;sex risk;theories;therapy design;urban area


application_id: 7840415
project_number: 5R01CA137052-02
project_title: Identifying candidate modifier elements of a breast cancer risk associated allele
administering_ic: NCI
award_notice_date: 2010-05-10
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 137052
program_official: SHARMAN, ANU
project_start_date: 2009-05-08
project_end_date: 2014-04-30
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 6825342
contact_pi: SAMUELSON, DAVID J
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): Identifying candidate modifier elements of a breast cancer risk associated allele Project Summary/Abstract: A woman's risk of developing breast cancer is influenced by genetic epigenetic and environmental factors. Up to 30-40% of the risk of developing breast cancer is likely to be inherited. Breast cancer genetics is complex. The factors controlling disease risk are high penetrant genes with risk alleles that are low in population frequency and low penetrant modifier genes with risk associated alleles that are common in the population. Most of the genetic variation in breast cancer risk is unaccounted and the majority of the genes influencing susceptibility to breast cancer are likely controlled by common genetic variation. The common single nucleotide polymorphism (SNP) rs889312 marks a low penetrant breast cancer risk associated allele on human chromosome 5 (Nature 447 2007). The breast cancer risk associate gene and causal polymorphisms at this locus have not been identified. The human region is orthologous to rat mammary carcinoma susceptibility QTL Mcs1b. The rat Mcs1b locus has been narrowed to 1.2 Mb using congenics. These experiments used the Wistar Furth (WF) strain which is highly susceptible to 712- dimethylbenz[a]anthracene (DMBA)-induced mammary carcinomas as the genetic background. The Mcs1b Copenhagen (COP) allele on a WF background conferred a 60% reduction in DMBA-induced mammary carcinoma development to WF.COP congenics that were COP-homozygous and a 30% reduction to congenics that were COP/WF-heterozygous at Mcs1b. The objective of the proposed work is to use systems genetics in a model organism to identify quality candidate breast cancer risk genetic elements. This will be accomplished through the following specific aims: aim 1: fine map rat Mcs1b to a genomic interval less than 0.5 Mb by testing additional congenic lines carrying shorter segments of the Mcs1b locus as currently defined; aim 2: determine if the Mcs1b COP allele acts in an autonomous manner within the mammary gland by conducting rat mammary gland transplant experiments; and aim 3: identify and evaluate breast cancer candidate genes/genetic elements within rat Mcs1b by determining potential candidates and testing each to identify quality candidates. The final aim will be completed in stages that will incorporate comparative genomics genetic and expression analyses resequencing and in vitro and in vivo validation of candidates. PUBLIC HEALTH RELEVANCE: Breast cancer is a complex disease and the leading cause of death by cancer in US women aged 20- 59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breast cancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breast cancer basic research toward better understanding of the genetic etiology of this complex disease is warranted. The proposed research uses a comparative genetic approach to accomplish this and may also identify novel potential targets for breast cancer prevention.

project_terms:
Alleles;Animal Model;Anthracenes;Area;Automobile Driving;BRCA1 gene;BRCA2 gene;Basic Research Breast Cancer;Biological Assay;Biological Models;Breast Cancer Genetics;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinoma;Candidate Disease Gene;Cause of Death;Chromosomes Human Pair 2;Chromosomes Human Pair 5;Complex;DNA Resequencing;Development;Disease;Elements;Environmental Risk Factor;Epigenetic Process;Frequencies (time pattern);Functional RNA;Genes;Genetic;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Goals;Human;Human Chromosomes;In Vitro;Inbred Strains Rats;Incidence;Individual;Inherited;Intercistronic Region;Knowledge;Lead;Location;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Maps;Modeling;Molecular Genetics;Molecular Target;Mortality Vital Statistics;Nature;PTPRJ gene;Phenotype;Population;Predisposition;Principal Investigator;Quantitative Trait Loci;Rat-1;Rattus;Recombinants;Research;Research Project Grants;Risk;STAT5a Transcription Factor;Single Nucleotide Polymorphism;Staging;Susceptibility Gene;System;Testing;Transgenic Model;Translating;Transplantation;Variant;Variation (Genetics);Woman;Work;abstracting;aged;anticancer research;cancer prevention;cancer risk;candidate validation;comparative;comparative genomics;congenic;disorder risk;genetic analysis;genetic element;genome wide association study;in vivo;knockout gene;malignant breast neoplasm;novel;novel strategies;public health relevance;rat genome;research study

public_health_relevance:
Project Narrative: Breast cancer is a complex disease and the leading cause of death by cancer in US women aged 20-59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breastcancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breastcancer basic research toward better understanding of the genetic etiology of this complex disease iswarranted. The proposed research uses a comparative genetic approach to accomplish this and may alsoidentify novel potential targets for breast cancer prevention.


application_id: 7839523
project_number: 1S10RR029541-01
project_title: A High-Field Small Animal MR Imager for Biomedical Research
administering_ic: NCRR
award_notice_date: 2010-05-27
opportunity_number: PAR-09-118
application_type: 1
activity_code: S10
ic: RR
serial_number: 029541
program_official: LEVY, ABRAHAM
project_start_date: 2010-05-27
project_end_date: 2012-05-26
study_section: Special Emphasis Panel[ZRG1 SBIB-L (30)]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
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: Y
project_abstract:
DESCRIPTION (provided by applicant): This grant is to support the acquisition of a high-field small animal imager to support multiple NIH- funded investigators using small animals for biomedical research. The imager selected is a 7T Bruker ClinScan system which incorporates the advantages of Bruker magnet gradient coil and radiofrequency coil with the expertise and accomplishments of Siemens Medical Solutions to produce the RF electronics and controlling software. That the new imager will operate using syngo software which is the same as used on the Siemens TIM Trio also housed in the Magnetic Resonance Imaging and Spectroscopy Center (MRISC) will facilitate translation of imaging protocols between experimental animals and human research subjects and will aid in the acquisition of optimal imaging protocols on complex studies. The instrument will be installed in and administered by MRISC - a university core facility dedicated to the development of innovative preclinical and experimental MR imaging of experimental animals and humans. The imager will be operated and maintained by a group of experienced MR researchers. The imager will be sited next to the animal colony facility which houses non-human primates as well as rats and mice used for a variety of research studies.  
  
PUBLIC HEALH RELEVANCE: This High End Instrumentation Grant will provide a high field MR imager suitable for small animal in vivo imager to a multi-user group of productive NIH-funded biomedical researchers. This instrument will replace the current use of a clinical imager ill suited for imaging rodents with a state-of-the-art high field imager suitable for research into traumatic injury cancer cardiovascular and several other areas of research currently underway at the University of Kentucky.

project_terms:
Animals;Area;Arts;Biomedical Research;Cardiovascular system;Clinical;Complex;Computer software;Core Facility;Development;Electronics;Funding;Grant;Housing;Human;Human Subject Research;Image;Injury;Kentucky;Magnetic Resonance Imaging;Malignant Neoplasms;Medical;Mus;Protocols documentation;Rattus;Research;Research Personnel;Rodent;Site;Solutions;Spectrum Analysis;System;Translations;United States National Institutes of Health;Universities;animal colony;experience;in vivo;innovation;instrument;instrumentation;nonhuman primate;pre-clinical;radiofrequency;research study


application_id: 7838943
project_number: 3R01HL089380-02S1
project_title: Cardioprotective Mechanisms of Glutathione S-transferase P
administering_ic: NHLBI
award_notice_date: 2009-07-16
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: HL
serial_number: 089380
suffix: S1
program_official: SCHWARTZ, LISA
project_start_date: 2009-07-15
project_end_date: 2012-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The glutathione S-transferases (GSTs) are a superfamily of ubiquitously expressed enzymes that conjugate reduced glutathione (GSH) with toxic electrophiles. The GST isoforms have also been show to regulate ASK-1 and JNK activation via protein-protein interactions. In human populations the GST isoforms are distributed in a race- and gender-specific manner. The GSTs are expressed in cardiovascular tissues but the role of GST in cardiovascular physiology and pathology has not been studied. We propose that GSTP the most abundant cardiac isoform is an essential component of myocardial defense against oxidative stress and it protects the heart from acute oxidative damage during ischemia-reperfusion (I/R). To test this hypothesis we will assess the contribution of GSTP to cardiac protection during I/R in situ (Aim 1) metabolism of lipid peroxidation- derived aldehydes (acrolein and 4-hydroxy-trans-2-nonenal; HNE) which are the preferred endogenous substrates of this enzyme (Aim 2) and aldehyde detoxication (Aim 3). As a loss of function test GSTP-null mice will be exposed to I/R while in gain of function tests transgenic (TG) and TG mice crossed with null mice with cardiac-restricted expression of human polymorphic GSTP1-1 genes will be exposed to I/R and infarction determined. Using tracer kinetics and mass spectrometric analysis we will measure the extent to which glutathiolation accounts for the metabolism of these aldehydes before during and after ischemia in the heart (Aim 2). To delineate the contribution of GSTP we will compare metabolic pathways including aldehyde conjugation and peroxidase activity in hearts isolated of GSTP WT null and TG mice. In Aim 3 we will determine whether GSTP protects the heart from I/R-induced injury by increasing glutathione conjugation of aldehydes decreasing aldehyde formation decreasing aldehyde-protein adducts decreasing peroxide formation decreasing oxidative post-translation protein modifications (e.g. sulfenic acid) by glutathiolation and protecting myocardial GSH level. In addition we will determine if GSTP regulates JNK activation and JNK signaling thereby investigating a non-catalytic role of GSTP in protein-protein interactions. Successful completion of these studies may lead to the identification of a novel mechanism of cardioprotection by GSTP which may be useful in assessing the relative ischemic susceptibility of human populations polymorphic in GSTP and in developing more targeted anti-ischemic interventions.  PUBLIC HEALTH RELEVANCE The glutathione S-transferases (GSTs) are widely expressed enzymes that detoxify reactive compounds. In human populations the GSTs are distributed in a race- and gender-specific manner and GST polymorphisms are associated with increased cardiovascular disease risk. This study will assess if GSTP is an essential component of myocardial defense against injury of heart attacks. Successful completion of these studies may lead to the identification of a novel mechanism of cardioprotection by GSTP which may be useful in understanding the relative susceptibility of human populations polymorphic in GSTP to coronary heart disease and in developing more targeted cardioprotective interventions.

project_terms:
Ablation;Accounting;Acrolein;Acute;Affect;Affinity;Aldehydes;Antioxidants;Attenuated;Biochemical Pathway;Cardiac;Cardiac Myocytes;Cardiovascular Physiology;Cardiovascular system;Coronary Occlusions;Coronary heart disease;Doctor of Philosophy;Drug Metabolic Detoxication;Drug resistance;Enzymes;Epidemiology;Excision;Foundations;Future;Gender;Genes;Genetic;Genetic Polymorphism;Glutathione;Glutathione S-Transferase;Heart;Human;In Situ;Individual;Infarction;Injury;Intervention;Ischemia;Kinetics;Knockout Mice;Lead;Link;Lipid Peroxidation;MAPK8 gene;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Natural regeneration;Oxidative Stress;Pathology;Pathway interactions;Peroxidases;Peroxides;Phenotype;Population;Post-Translational Protein Processing;Predisposition;Principal Investigator;Production;Protein Isoforms;Proteins;Race;Reactive Oxygen Species;Reduced Glutathione;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Signal Pathway;Signal Transduction;Stress;Sulfenic Acids;Testing;Tissues;Tracer;Transgenic Mice;Transgenic Organisms;Translations;adduct;base;carcinogenesis;cardiovascular disorder risk;detoxication;enzyme substrate;gain of function;heart metabolism;insight;loss of function;novel;overexpression;oxidative damage;oxidized lipid;prevent;programs;protein protein interaction;public health relevance;translational study


application_id: 7838826
project_number: 3R01HL080394-03S1
project_title: Fibronogen-Induced Vasconstriction during Hypertension
administering_ic: NHLBI
award_notice_date: 2009-07-16
application_type: 3
activity_code: R01
ic: HL
serial_number: 080394
suffix: S1
program_official: RABADAN-DIEHL, CRISTINA
project_start_date: 2009-07-15
project_end_date: 2011-12-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Hypertension is accompanied by an increased content of plasma fibrinogen (Fg). We reported that binding of Fg to the arterial wall causes vasoconstriction which is mediated by intercellular adhesion molecule-1 (ICAM-1). In addition blockade of the endothelin type A receptors attenuated Fg-induced vasoconstriction. In our preliminary studies endothelial binding of Fg enhanced production of endothelin-1 (ET-1). Furthermore Fg binding to endothelial cells (ECs) resulted in phosphorylation of extracellular signal regulated kinase (ERK). Activation of ICAM-1 and another Fg endothelial receptor alpha5beta1 integrin leads to phosphorylation of ERK and c-Jun-NH2-terminal kinase (JNK). Fg-induced vasoconstriction is increased during hypertension and regulated production of ET-1 results from exocytosis of Weibel-Palade bodies (WPb). We hypothesize that during hypertension increased Fg binding to endothelial ICAM-1 (and possibly alpha5beta1) induces enhanced exocytosis of WPbs through ERK (and possibly JNK) signaling and results in increased production of ET-1 leading to enhanced vasoconstriction. Based on our finding that Fg binding to ECs changes EC proteome which may be associated with WPb exocytosis we will determine if these Fg-induced cellular changes are associated with ET-1 release and therefore with vasoconstriction. The specific aims of the proposed study are: 1) To evaluate Fg binding to ICAM-1 the resultant production of ET-1 and subsequent vasoconstriction during hypertension; 2) To determine the signaling pathway (ERK- and/or JNK-involved) for Fg-induced ET-1 production and the elevated vasoconstriction during hypertension; and 3) To determine the functional role of EC proteins altered by Fg binding in Fg-induced exocytosis of WPbs during hypertension. Hypertension-induced enhanced Fg binding to endothelial ICAM-1 (and alpha5beta1) the role of ERK (and JNK) signaling and the role of proteins altered by Fg binding to ECs in increased exocytosis of WPbs and production of ET-1 which causes enhanced vasoconstriction will be determined. Genetic (SHR) and non-genetic (DOCA-salt) rat hypertension models will be studied at early and established stages of hypertension to identify changes associated with the development and maintenance of hypertension. This study will delineate mechanisms of Fg-regulated production of ET-1 and the resultant increased vasoconstriction that exacerbates microcirculatory complications during hypertension.

project_terms:
Acetates;Age;Animals;Attenuated;Big Endothelin;Binding (Molecular Function);Blood;Blood Pressure;Cardiovascular system;Cerebrovascular Disorders;Confocal Microscopy;Control Animal;Deoxycorticosterone;Development;Dose;Endothelial Cells;Endothelin;Endothelin-1;Endothelium;Enzymes;Exocytosis;Extracellular Signal Regulated Kinases;F-Actin;Fibrinogen;Figs - dietary;Flow Cytometry;Genetic;Genetic Models;Hypertension;Inbred SHR Rats;Inbred WKY Rats;Integrin alpha5beta1;Integrins;Intercellular adhesion molecule 1;JUN gene;MALDI-TOF Mass Spectrometry;Maintenance;Mediating;Mitogen-Activated Protein Kinases;Mitogens;Modeling;Operative Surgical Procedures;Phosphorylation;Plasma;Production;Protein Kinase;Proteins;Proteome;Proteomics;Rattus;Reporting;Research Personnel;Resolution;Risk Factors;Role;SP600125;Signal Pathway;Signal Transduction;Small Interfering RNA;Sodium Chloride;Sprague-Dawley Rats;Staging;Surface;Time;Transfection;Two-Dimensional Polyacrylamide Gel Electrophoresis;Vascular Endothelium;Vascular constriction (function);Weibel-Palade Bodies;animal data;arteriole;base;high risk;inflammatory marker;inhibitor/antagonist;non-genetic;novel;programs;receptor;research study;response;stress-activated protein kinase 1


application_id: 7837596
project_number: 5R03HL096891-02
project_title: Pneumocystis jirovecii and macrophages in COPD
administering_ic: NHLBI
award_notice_date: 2010-04-15
opportunity_number: RFA-HL-08-008
application_type: 5
activity_code: R03
ic: HL
serial_number: 096891
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2009-05-11
project_end_date: 2011-10-30
study_section: ZHL1-CSR-H(M1)
contact_pi_person_id: 8968639
contact_pi: FEOLA, DAVID
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: Y
project_abstract:
DESCRIPTION (provided by applicant):   
  
Airway inflammation airway remodeling colonization with microorganisms and parenchymal destruction are hallmarks of chronic obstructive pulmonary disease (COPD). In addition to cigarette smoking infectious pathogens likely contribute to the decline in pulmonary function in COPD patients. The inflammatory process in patients with COPD displays a distinct pattern of inflammatory mediators and immune cells that are involved that are similar to the pattern seen in response to Pneumocystis jiroveci (PC). Evidence has now emerged on the importance of macrophage phenotype in COPD patients. Macrophages account for the majority of inflammatory cells recovered from bronchoalveolar lavage from COPD patients and are localized to sites of alveolar destruction. Further the IL-4/IL-13 alternatively activated macrophage phenotype (AAM) has been implicated in several chronic lung diseases. We propose in this study to evaluate the relationship between the AAM and PC in lungs of COPD patients in the Lung Tissue Research Consortium. In 3 Aims we will 1) correlate PC colonization with the presence of AAMs in lung tissue samples 2) determine through immunohistochemistry how the presence of PC correlates to the precise localization of macrophage phenotype and fibrosis and 3) determine how PC burden and AAMs correlate to clinical outcome measurements. This project will investigate a novel mechanism of pathogenesis which may provide targets for potential future therapeutic interventions for patients with COPD. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic obstructive pulmonary disease (COPD) affects 24 million Americans and causes chronic life- threatening lung disease. It has recently been described that Pneumocystis jiroveci (PC) infection may be an important factor in the progression of the disease. This project will investigate the hypothesis that PC infection worsens pulmonary fibrosis development in patients with COPD through induction of alternative macrophage activation. We have demonstrated in mouse models that PC polarizes the macrophage response toward this pro-fibrotic phenotype. Establishing a correlation between PC infection and alternative macrophage activation will lead to the identification of therapeutic interventions that possibly will slow the development of pulmonary fibrosis and functional decline in these patients. (End of Abstract)

project_terms:
Accounting;Acute;Affect;Aliquot;Alveolar;American;Animals;Area;Asthma;B-Lymphocytes;Binding (Molecular Function);Bronchoalveolar Lavage;CD8B1 gene;Carbon Monoxide;Cells;Characteristics;Chest;Chronic;Chronic Obstructive Airway Disease;Chronic lung disease;Cicatrix;Classification;Clinical;Collagen;Confocal Microscopy;Cystic Fibrosis;Data;Databases;Development;Diffuse;Disease Progression;European;Extracellular Matrix;Extracellular Matrix Proteins;Extrinsic allergic alveolitis;Fibronectins;Fibrosis;Future;Gene Proteins;Hamman-Rich syndrome;Human;IL8 gene;Immune;Immune response;Immunohistochemistry;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interleukin-13;Interleukin-4;Interleukin-6;Investigation;Lead;Life;Lung;Lung Capacity;Lung diseases;Macrophage Activation;Measurement;Organism;Outcome;Outcome Measure;Pathogenesis;Pathology;Patients;Pattern;Phenotype;Pneumocystis;Pneumocystis jiroveci;Prevalence;Process;Property;Pulmonary Emphysema;Pulmonary Fibrosis;Relative (related person);Reporting;Research;Risk;Role;Sampling;Sarcoidosis;Screening procedure;Serum;Severity of illness;Site;Societies;Structure of parenchyma of lung;Surface;Symptoms;T-Lymphocyte;Therapeutic Intervention;Tissue Sample;abstracting;airway inflammation;airway remodeling;alveolar destruction;cigarette smoking;disorder control;functional decline;macrophage;microorganism;mouse model;neutrophil;novel;pathogen;protein expression;public health relevance;pulmonary function;receptor;respiratory;response;tissue fixing

public_health_relevance:
Project NarrativeChronic obstructive pulmonary disease (COPD) affects 24 million Americans and causes chronic life-threatening lung disease. It has recently been described that Pneumocystis jiroveci (PC) infection may be animportant factor in the progression of the disease. This project will investigate the hypothesis that PC infectionworsens pulmonary fibrosis development in patients with COPD through induction of alternative macrophageactivation. We have demonstrated in mouse models that PC polarizes the macrophage response toward thispro-fibrotic phenotype. Establishing a correlation between PC infection and alternative macrophage activationwill lead to the identification of therapeutic interventions that possibly will slow the development of pulmonaryfibrosis and functional decline in these patients.


application_id: 7837572
project_number: 5U10NS058967-04
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2010-05-03
opportunity_number: RFA-NS-06-009
application_type: 5
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2012-04-30
study_section: ZNS1-SRB-K(41)
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal describes the establishment of a Neurological Emergencies Treatment Trials (NETT) Network Clinical Site Hub at the University of Kentucky Medical Center (UKMC) in Lexington Kentucky in response to NIH/NINDS RFA-NS-06-009. The overall goal of this proposal is to identify UKMC as an academic medical facility with regional affiliate partners adept in "the evaluation of treatments for patients with a broad spectrum of neurological emergencies." The NETT Clinical Site Hub at UKMC is founded upon an intra- institutional collaboration between physician faculty members of the Departments of Emergency Medicine Neurology and Neurosurgery. Regional affiliate medical care facilities aligned with UKMC include the Department of Veterans Affairs Medical Center/Cooper Drive Division (DVAMC/CDD) in Lexington and "spoke" community hospitals located in non-urban environments throughout Central and Eastern Kentucky. The following Specific Aims are proposed: 1) To demonstrate the existence of an infrastructure for patient recruitment in "large simple" clinical trials performed in acute-onset neurological disorders modeled by TBI drawing upon the resources of a Level 1 Trauma Center situated within a broadly-based geographical network of referring hospitals in non-urban settings and 2) To demonstrate the existence of an infrastructure for patient recruitment in clinical trials performed in acute-onset neurological disorders requiring Exception to Consent for Emergency Research.

project_terms:
Academic Medical Centers;Accident and Emergency department;Acute;Adult;Advanced Cardiac Life Support;Agreement;Air;Ambulances;American College of Surgeons;Brain;Caring;Cities;Clinical Trials;Collaborations;Communication;Community Hospitals;Consent;County;Disease model;Doctor of Medicine;Emergency Medicine;Emergency Situation;Emergency medical service;Emergency treatment;Enrollment;Environment;Evaluation;Faculty;Fire - disasters;Goals;Government;Head;Hospitals;Internet;Investigational Therapies;Kentucky;Medical;Medical Faculty;Medical center;Medicine;Neurological emergencies;Neurology;Operative Surgical Procedures;Patient Recruitments;Patients;Physicians;Positioning Attribute;Principal Investigator;Provider;Randomized;Rehabilitation therapy;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Population;Services;Speed (motion);Spinal Cord;Spinal cord injury;Trauma;Universities;University Hospitals;Urban Hospitals;Veterans;base;clinical research site;college;design;experience;meetings;member;nervous system disorder;neurosurgery;professor;response;trauma centers;treatment trial


application_id: 7837388
project_number: 2R56AI048850-06A1
project_title: Fatty acid binding proteins in macrophage function
administering_ic: NIAID
award_notice_date: 2009-05-21
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: AI
serial_number: 048850
suffix: A1
program_official: PEYMAN, JOHN A
project_start_date: 2000-12-01
project_end_date: 2010-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Fatty acid binding proteins FABPs have been identified as central regulators of both metabolic and
inflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobic
compounds enabling their diffusion within the cytoplasmic compartment. We have shown that
adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol
trafficking and inflammatory function in part via regulation of the activity of the peroxisome
proliferator-activated receptor ( (PPAR(). Macrophages and dendritic cells (DC) from FABP-
deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the
promotion of proinflammatory T cells responses during antigen presentation. FABP-deficient mice
are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall
the results of our research suggest that FABPs regulate a molecular switch between metabolic and
inflammatory pathways in macrophages and DC and as a consequence regulate both innate and
adaptive immune responses. We will continue our studies of these proteins through the pursuit of
the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs
affect inflammatory cytokine gene expression in macrophages and DC. We have found that FABP-
deficiency is accompanied by elevated activity of AMP-activated protein kinase (AMPK) and that
AMPK is a negative regulator of macrophage inflammatory function. Experiments will be performed
to determine the link between FABPs AMPK and PPAR( testing the hypothesis that FABP
regulation of energy stores regulates AMPK activity which in turn modulates inflammatory activity.
Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using
EAE as a model. This aim will include an evaluation of the specific contributions of T cell priming
and of the tissue environment towards the protection from EAE displayed by FABP-deficient mice.
Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with
exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in
leukocyte population and the association of diet-induced FABP expression with inflammatory
responsiveness. FABPs are considered potential therapeutic targets for a number of diseases. This
proposal is designed to gain a more complete understanding of how these proteins regulate immune
and inflammatory responses.

project_terms:
5'-AMP-activated protein kinase;Adipocytes;Adipose tissue;Affect;Animals;Antigen Presentation;Autoimmune Diseases;Autoimmune Process;Automobile Driving;Brain;Cells;Chronic;Cytokine Gene;Data;Dendritic Cells;Development;Diet;Dietary Fats;Diffusion;Disease;Encephalomyelitis;Environment;Epithelial;Evaluation;Exhibits;Experimental Autoimmune Encephalomyelitis;Fatty acid glycerol esters;Gene Expression;Genes;Glycogen Synthase Kinases;Immune;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intake;Interferons;Interleukin-17;Leukocytes;Link;Lipids;Metabolic;Modeling;Molecular;Mus;Nuclear;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Population;Proteins;Regulation;Research;Spinal Cord;T-Lymphocyte;Testing;Tissues;Transcriptional Activation;Wild Type Mouse;Work;cholesterol trafficking;cytokine;design;disorder risk;fatty acid-binding proteins;feeding;in vivo;mTOR protein;macrophage;receptor;research study;response;therapeutic target;transcription factor

public_health_relevance:
Recent work has shown that fatty acid binding proteins FABPs integrate metabolic and
inflammatory pathways and in doing so regulate immune responses. Therefore FABPs
may be useful targets for treatment of a wide variety of inflammatory and autoimmune
diseases. The targeting of FABPs for therapy underscores the need to have a very thorough
understanding of how FABPs function on both a cellular and whole animal level. This
proposal is designed to gain a more complete understanding of how FABPs regulate
inflammatory disease.


application_id: 7835781
project_number: 5R21ES016367-02
project_title: Priming of liver disease by arsenic exposure
administering_ic: NIEHS
award_notice_date: 2010-04-30
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: ES
serial_number: 016367
program_official: SHREFFLER, CAROL A
project_start_date: 2009-05-01
project_end_date: 2011-09-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Inorganic arsenic is a natural drinking water contaminant and a known hepatotoxin. However the exposure levels of arsenic required to cause overt liver damage may be higher than found in the US water supply. In preliminary studies it was shown that chronic exposure to arsenic at exposure levels that caused no overt hepatoxicity sensitized the liver to a subsequent inflammatory `hit' owing to injection of lipopolysaccharide (LPS). This new finding suggests that arsenic even at exposure levels that are not hepatotoxic per se may increase the risk of liver disease owing to a second hepatotoxic event. Based on these Preliminary Studies it is hypothesized that low-dose arsenic primes liver to a subsequent hepatotoxic insult. This hypothesis will be tested via the following specific aims. 1). To test the hypothesis that arsenic sensitizes to LPS-induced liver injury in the mouse. In the Preliminary Studies it was shown chronic exposure of arsenic in drinking water enhances hepatic inflammation and damage caused by LPS. However the drinking water concentration of arsenic used in this preliminary study is still higher than relevant to human exposure in the US. We will therefore test our hypothesis with lower more relevant water concentrations of arsenic. Specific subaims are: a) To determine the minimal low dose arsenic exposure conditions to cause sensitization to LPS. b) To identify potential mechanisms by which arsenic preexposure enhances liver damage caused by LPS. 2). To test the hypothesis that low-dose arsenic exposure sensitizes liver to hepatotoxicity in mouse models of non alcoholic fatty liver disease (NAFLD). A liver disease that is currently endemic to the US population is obesity-induced NAFLD. Here using minimal exposure conditions determined in Specific Aim 1 the hypothesis that low dose arsenic exposure will enhance chronic liver damage in established models of NAFLD will be tested. Specific subaims are: a) To determine the effect of arsenic on early intermediate and late stages of fatty liver diseases. b) To determine whether arsenic enhances the formation of progenitor cells and/or preneoplastic lesions in experimental NAFLD. Taken together these results will also establish new models of arsenic priming of liver disease in which new hypotheses and/or treatment regimens may be tested. Should arsenic cause such a priming effect the significance of this work to the US population is significant. Specifically such results would suggest that the relative risk of hepatic damage caused by arsenic exposure may have to be modified to take into account other mitigating factors such as type II diabetes and/or NAFLD. Exposure to arsenic in the drinking water is a major health concern. Our preliminary studies indicate that arsenic exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver possibly increasing the risk of serious chronic liver diseases (e.g. non-alcoholic fatty liver diseases). The project will develop a new model of arsenic exposure that will not investigate direct toxicity per se but rather test the hypothesis that arsenic exacerbates the response in established liver toxicity models.

project_terms:
Accounting;Acute;Animal Model;Animals;Arsenic;Biochemical;Chronic;Chronic Disease;Cirrhosis;Development;Disease;Dose;Environmental Exposure;Environmental Risk Factor;Epidemiology;Event;Exposure to;Fatty Liver;Fibrosis;Health;Hepatic;Hepatotoxicity;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Lesion;Lipopolysaccharides;Liver;Liver diseases;Malignant - descriptor;Malignant Neoplasms;Modeling;Mus;Non-Insulin-Dependent Diabetes Mellitus;Non-Malignant;Obesity;Physiological;Population;Regimen;Relative Risks;Risk;Risk Factors;Role;Staging;Stem cells;Stimulus;Testing;Toxic effect;Treatment Protocols;Water;Water Supply;Work;base;drinking water;exposed human population;hepatotoxin;mouse model;non-alcoholic fatty liver;pandemic disease;response


application_id: 7835687
project_number: 5R01CA105266-06
project_title: Ethnicity Breast Cancer Recurrence & Long-Term QOL
administering_ic: NCI
award_notice_date: 2010-05-06
application_type: 5
activity_code: R01
ic: CA
serial_number: 105266
program_official: O'MARA, ANN M
project_start_date: 2005-09-09
project_end_date: 2011-05-31
study_section: Epidemiology of Cancer Study Section[EPIC]
contact_pi_person_id: 6652159
contact_pi: BAUMGARTNER, KATHY B
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): This application proposes a follow-up study of the New Mexico Women's Health Study (NMWHS: 1992-1996) a statewide population-based case-control breast cancer study for survival recurrence and quality of life (QOL) approximately 14 years (y) post-diagnosis. The NMWHS included 1556 Hispanic (H) and non-Hispanic white (NHW) women. Women newly diagnosed with in situ or invasive breast carcinoma ascertained through the New Mexico Tumor Registry (NMTR) were eligible based on the following criteria: age 30-74y diagnosis year 1992- 1994; and New Mexico (NM) resident at diagnosis. All H cases were included and a 33% random sample of NHW cases was identified for inclusion. The sampling fraction for NHW cases was chosen to give a similar distribution to the H cases based on age and geographic distribution of H cases ascertained during an earlier 3-y period. Of the eligible cases participation rates were 68% (n=332) for H cases; and 77% (n=380) for NHW cases. Controls were recruited using a modified version of the Waksberg random digit-dialing method and were frequency-matched by ethnicity age-group and health planning district. Of the eligible controls participation rates were 76% (n=388) for H cases and 86% (n=456) for NHW cases. Mean age at diagnosis for cases was 54y compared to 53y for controls. In an initial review of a 10% (n=156) random sample of NMWHS participants only 9% of 142 classified as 'alive' were not located (deceased=14). Of the 'alive' group 82% were located within NM. Based on these results we estimate that there will be 670 subjects to be followed for survival 430 for recurrence (517 if deceased are included) and 969 for QOL assuming a 75% participation rate. An additional random 12.9% sample showed 93% still in NM. Recurrence will be ascertained through self-report and verified through medical records. New primaries will be ascertained through linkage with the NMTR. Mortality will be confirmed using the National Death Index. QOL measures will be based on a standardized questionnaire used in a previous breast cancer cohort study and conducted via telephone. The proposed follow-up study will provide a unique opportunity to evaluate factors influencing survival and recurrence in long-term breast cancer survivors and QOL compared to population-based controls. Most important the study will allow the comparison of H vs. NHW women for these outcomes and the interaction of ethnicity with other prognostic factors in an aging cohort. There are few studies of QOL in older long-term breast cancer survivors and no large studies that we are aware of that have compared QOL in cases with population-based controls. There are scant data comparing H with NHW women for these outcomes. The proposed study could have important implications for treatment of H vs. NHW women and long-term care of older breast cancer survivors.

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


application_id: 7835549
project_number: 5R01DA002243-33
project_title: Degradation of Opioid Peptides
administering_ic: NIDA
award_notice_date: 2010-04-13
application_type: 5
activity_code: R01
ic: DA
serial_number: 002243
program_official: PUROHIT, VISHNUDUTT
project_start_date: 1978-09-30
project_end_date: 2012-04-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
project_abstract:
DESCRIPTION (provided by applicant):  The long-range objective of this project is to develop methods to modulate peptide hormone action through the peptidases that inactivate them. The focus of this application is to understand the contribution of three metallopeptidases insulysin neprilysin neprilysin-2 and a novel plasma membrane (3-endorphin cleaving enzyme to neuropeptide metabolism. The three specific aims are: 1. To study the allosteric properties of insulysin and its contribution to modulating physiological peptide levels. Insulysin which hydrolyzes a variety of peptides including (3-endorphin insulin and amyloid (3 peptides is allosterically regulated by both substrates (homotrophic effects) and by anions such as ATP (heterotrophic effects). The heterotrophic effectors switch the preference of the enzyme from cleaving relative large peptides like insulin amyloid (3-peptide and -3-endorphin to smaller peptides such as the dynorphins. 2. To study the contribution gate the relative contributions of neprilysin and neprilysin-2 to neuropeptide metabolism in the brain. 3. To isolate and characterize a newly found plasma membrane peptidase that degrades (3-endorphin. We propose to characterize this novel peptidase determine its tissue distribution as well as its substrate specificity. Relevence: Together these studies should contribute to our understanding of the involvement of a group of peptidases in the regulation of peptide action and may lead to new ways in which to modulate these activities in pathological states. For example one of the peptidases to be studied has recently been implicated in HIV dependent dementia in elderly affected individuals.

project_terms:
Affect;Allosteric Regulation;Amyloid;Anions;Binding Sites;Biochemical;Brain;Brain region;Cell Line;Cell membrane;Cleaved cell;Dementia;Drug or chemical Tissue Distribution;Dynorphins;Elderly;Endorphins;Enzymes;Goals;HIV;Hydrolysis;Individual;Insulin;Insulinase;Knockout Mice;Lead;Membrane;Metabolism;Metalloproteases;Methods;Neprilysin;Neuropeptides;Opioid;Opioid Peptide;Peptide Hydrolases;Peptide Metabolism;Peptides;Physiological;Progress Reports;Property;Regulation;Relative (related person);Reporting;Research Project Grants;Substrate Specificity;Techniques;Testing;cell type;in vivo;insight;macrophage;membrane activity;novel;peptide hormone;preference


application_id: 7834884
project_number: 1R01MD004598-01
project_title: Does Violence Against Women result in disparities in cancer care for women with b
administering_ic: NIMHD
award_notice_date: 2009-09-25
opportunity_number: RFA-MD-09-004
application_type: 1
activity_code: R01
ic: MD
serial_number: 004598
program_official: ALVIDREZ, JENNIFER L
project_start_date: 2009-09-25
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZMD1 PA (R4)]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant):  Violence against women (VAW) is defined by the United Nations as "any act of gender based violence that results in physical sexual or psychological harm or suffering to women." In Kentucky almost 40% of women had experienced some form of VAW in their lifetime. The frequency of VAW poses a serious public health challenge not only due to the prevalence but also the long term impact on women's health documented in an impressive body of literature. However very little research has explored the effect of lifetime VAW on cancer prevention and control. Kentucky has a high cancer burden with the highest cancer mortality rate of all US states. Incidence rates of cancer and the proportion of women diagnosed at a later stage are higher in the Appalachian region of Kentucky. VAW frequently co-occurs with social factors leading to health disparities including unemployment less education and minority race. Overall objectives of this project are to determine the extent to which VAW may explain noted disparities in cancer care based on women's race/ethnicity socioeconomic status access to health insurance or residence in high poverty and rural areas of Kentucky. Specific aims: To determine whether VAW is associated with disparities in breast cancer (aim 1) colorectal cancer (aim 2) and cervical cancer (aim 3) care outcomes to include not receiving cancer screening at recommended intervals being diagnosed with cancer at a later stage not receiving recommended cancer treatment including supportive/palliative care and poorer cancer specific survival among women diagnosed with these cancers in Kentucky and adjusting for relevant confounders including race socioeconomic status having health insurance rural residence and specific regions of high poverty (e.g. living in the Appalachian region of eastern Kentucky or the Delta region of western Kentucky). Methods: We propose a prospective cohort using the Kentucky Cancer Registry (KCR) as the source of 3150 breast cancer cases 1575 colorectal cancer cases and 525 cervical cancer cases. These 5250 women will be interviewed by phone to determine their lifetime exposure to VAW and comorbid conditions. These data will be linked with state level Medicare claims data for women completing phone surveys who are 65 or older. The Medicare claims data administered by the Center for Medicare and Medicaid Services include comprehensive coverage of medical services regardless of where the patients seek care in the nation which would allow the detailed examination of the proposed cancer care continuum: cancer screening stage at diagnosis treatment supportive or palliative care and survivorship. Both logistic regression and Cox proportional hazards modeling will be used to determine the role of VAW (by frequency duration severity and type) and socioeconomic attributes influencing disparities in cancer care. These associations will be investigated for each of the hypothesized five cancer care outcomes and by specific cancer. The mediating or moderating role of socioeconomic factors will also be explored using structural equation modeling. Relevance: This will be the first population-based cohort of the influence of VAW on the life course of cancer care in a state with high cancer burden and regions of extreme poverty. Findings will have significant public health impact in reducing disparities and improving cancer prevention and control in women.

project_terms:
Affect;Appalachian Region;Breast;Breast Cancer Treatment;Cancer Burden;Cancer Patient;Caring;Censuses;Cervical;Child;Choices and Control;Clinic;Colonoscopy;Colorectal;Colorectal Cancer;Consent;Cox Proportional Hazards Models;Data;Data Analyses;Data Set;Diagnosis;Diagnostic Neoplasm Staging;Divorce;Educational aspects;Ensure;Equation;Ethnicity aspects;Event;Exposure to;Family member;Fecal occult blood;Frequencies (time pattern);Funding;Gender;Geographic state;Grant;Health;Health Insurance;Healthcare;Human Papillomavirus;Incidence;Individual;Insurance Coverage;Intervention;Interview;Kentucky;Life;Life Cycle Stages;Link;Literature;Logistic Regressions;Low income;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Measures;Mediating;Medical;Medical Surveillance;Medicare;Medicare claim;Medicare/Medicaid;Methods;Minority;Modeling;Mortality Vital Statistics;Neighborhoods;Occult blood screen;Outcome;Outcomes Research;Palliative Care;Pap smear;Parents;Pathway interactions;Patient Self-Report;Patients;Pattern;Physicians;Positioning Attribute;Poverty;Prevalence;Psyche structure;Race;Recruitment Activity;Registries;Research;Research Personnel;Risk;Role;Rural;Schools;Screening for cancer;Screening procedure;Services;Severities;Smoke;Smoking Status;Socioeconomic Factors;Socioeconomic Status;Solutions;Source;Stage at Diagnosis;Staging;Surveys;Survivors;Telephone;Telephone Interviews;Texas;Time;Tumor stage;Unemployment;Uninsured;United Nations;United States Centers for Medicare and Medicaid Services;Violence;Woman;Women's Health;Work;base;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer therapy;care seeking;cohort;emotional abuse;experience;health disparity;improved;low socioeconomic status;malignant breast neoplasm;men;neoplasm registry;physical conditioning;population based;programs;prospective;psychologic;public health medicine (field);residence;rural area;social;socioeconomics;survivorship;tool;violence against women


application_id: 7834163
project_number: 3R01HL074219-05S1
project_title: Integrin Signaling In Vascular Cells
administering_ic: NHLBI
award_notice_date: 2009-07-16
application_type: 3
activity_code: R01
ic: HL
serial_number: 074219
suffix: S1
program_official: SRINIVAS, POTHUR R
project_start_date: 2009-07-15
project_end_date: 2010-06-30
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Abnormal vascular smooth muscle cell (SMC) growth and migration contributes to hypertension atherosclerosis and restenosis. SMC function is controlled by complex regulatory mechanisms which are governed in part by interactions with the extracellular matrix. Integrins the predominant receptors for the extracellular matrix activate adhesion-dependent signaling pathways and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. The objective of this application is to understand how integrin alphaVbeta3-dependent signaling influences SMC growth and migration. We observed that wild-type mice treated with an antibody-inhibitor of beta3-integrins but not beta3-integrin-deficient (beta3-/-) mice were protected from the development of intimal hyperplasia and have found differences in the properties of cultured wild-type and beta3-/- SMCs that may account for our in vivo observations. Based on our preliminary data we hypothesize that integrin alphaVbeta3- dependent intracellular signaling positively and negatively regulates SMC growth and migration thorough distinct pathways in stimulated and quiescent SMCs. The proposed studies will utilize genetic pharmacologic and RNA interference techniques to target integrin alphaVbeta3 in well-characterized cellular and animal models of SMC function. First we will identify alphaVbeta3-dependent pathways in stimulated SMCs. Our preliminary data indicates that alphaVbeta3 serves as a molecular switch to regulate Rho Family GTPase and control focal adhesion assembly. We will delineate the mechanism(s) responsible for GTPase regulation. Second based on our preliminary data we have identified a role for alphaVbeta3 in downregulation of p38MAPK during cellular quiescence. We will use the p38 MAPK pathway as a model to understand how alphaVbeta3-dependent pathways contribute to SMC quiescence. Third we will delineate the contribution of alphaVbeta3 to physiologic responses in cultured vessels and well-established mouse models of arterial injury. These results will provide specific insights into the function of SMC alphaVbeta3 in restenosis and atherosclerosis and may have broad implications for understanding alphaVbeta3 integrin function in angiogenesis osteoporosis and other disorders.

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


application_id: 7834091
project_number: 1RC1EY020442-01
project_title: CCR3: a molecular marker for neovascular AMD
administering_ic: NEI
award_notice_date: 2009-09-30
opportunity_number: RFA-OD-09-003
application_type: 1
activity_code: RC1
ic: EY
serial_number: 020442
program_official: SHEN, GRACE L
project_start_date: 2009-09-30
project_end_date: 2011-09-29
study_section: Special Emphasis Panel[ZRG1 CB-N (58)]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects as many Americans as all cancers combined and twice as many as Alzheimer's disease. The overwhelming cause of severe vision loss in AMD is choroidal neovascularization (CNV) the growth of abnormal blood vessels into the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A the majority of patients do not recover good functional vision and a significant fraction progress to legal blindness. This is due to the present inability to detect CNV before it invades the retina and causes structural and functional tissue damage. In new and exciting findings we are reporting the discovery of the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009): CCR3 a chemokine receptor best known for promoting eosinophil and mast cell trafficking is expressed in human choroidal endothelial cells in vivo only in the setting of CNV due to AMD. Targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo and was both superior to and safer than VEGF-A blockade. Non-invasive in vivo bioimaging using functionalized quantum dots targeting CCR3 detected CNV within the mouse choroid that had not yet invaded the retina and was invisible to fluorescein angiography. These findings define CCR3 as a novel specific molecular early diagnostic and therapeutic target in human CNV. In this proposal we will define the biological relationships between the CCR3/eotaxin axis and aging complement activation and oxidative stress to decipher how these established AMD pathogenetic factors regulate the neovascular progression of disease. We will also create and optimize new fluorescent optical bioimaging CCR3-targeting probes that can detect intrachoroidal "subclinical" CNV. These studies respond precisely to this Challenge Topic as they will illuminate how the immune system regulates this specific signature of the angiogenic switch in AMD and innovatively exploit it to enable prevention of vision loss by coupling early detection with targeted therapy. As such this proposal is perfectly aligned with the 5-year program goals of the NEI's Retinal Diseases strategic plan. It also advances the goals of the American Recovery and Reinvestment Act as it will if funded create or retain jobs for three individuals and provide economic benefits to third- party suppliers and vendors. We are committed to complete the program by the determined October 2010 deadline and are willing to complete quarterly reports pertaining to this project as outlined by NIH.   
  
PUBLIC HEALTH RELEVANCE: Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age- related macular degeneration (AMD) the leading cause of blindness among the elderly in the United States. Our recent discovery of CCR3 as the first molecule specifically expressed with human CNV and our exciting new finding that CCR3-targeting molecular imaging probes can detect CNV before retinal invasion support the investigation of CCR3 biology in AMD and optimization of bioimaging modalities. This proposal can transform the clinical practice paradigm by introducing an innovative bioimaging strategy that enables early detection of CNV for targeted therapy that can prevent vision loss. It also will advance the goals of the ARRA by creating or retaining multiple jobs and provide economic benefit to the University of Kentucky College of Medicine which has consistently served the Commonwealth of Kentucky as a principal force for economic development and third-party suppliers and vendors.

project_terms:
Accounting;Affect;Affinity;Age;Age related macular degeneration;Aging;Allergic;Alzheimer's Disease;American;Angiogenic Switch;Animal Model;Antibodies;Automobile Driving;Biodistribution;Biological;Biology;Blindness;Blood Vessels;Bruch's basal membrane structure;Cells;Choroid;Choroidal Neovascularization;Commit;Complement Activation;Coupled;Coupling;Diagnostic;Disease;Disease Progression;Dyes;Early Diagnosis;Economic Development;Economics;Elderly;Endothelial Cells;Eotaxin;Epidemic;Exudative age-related macular degeneration;Eye;FDA approved;Fab Immunoglobulins;Fluorescein Angiography;Funding;Future;Genetic;Goals;Grant;Growth;Human;Immune;Immune system;In Vitro;Individual;Intervention;Invaded;Investigation;Kentucky;Legal Blindness;Ligands;Malignant Neoplasms;Maps;Medicine;Modality;Molecular;Molecular Profiling;Molecular Target;Mus;Natural Immunity;Nature;Nonexudative age-related macular degeneration;Occupations;Optics;Outcome;Oxidative Stress;Panthera leo;Pathogenesis;Pathology;Patients;Pharmacotherapy;Photoreceptors;Plasma Proteins;Prevalence;Prevention;Quantum Dots;Recovery;Relative (related person);Reporting;Retina;Retinal;Retinal Diseases;Source;Specificity;Specimen;Staging;Strategic Planning;Structure of retinal pigment epithelium;Techniques;Testing;Tissues;United States;United States National Institutes of Health;Universities;Vascular Endothelial Growth Factor A;Vendor;Vision;Visual;aging population;angiogenesis;bioimaging;biomarker;chemokine receptor;clinical practice;college;cost;cytokine;eosinophil;imaging probe;improved;in vivo;innovation;legally blind;mast cell;molecular imaging;molecular marker;mouse model;nanocrystal;neovascular;novel;prevent;programs;public health relevance;response;therapeutic target;trafficking

public_health_relevance:
Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age-related macular degeneration (AMD) the leading cause of blindness among the elderly in theUnited States. Our recent discovery of CCR3 as the first molecule specifically expressed withhuman CNV and our exciting new finding that CCR3-targeting molecular imaging probes candetect CNV before retinal invasion support the investigation of CCR3 biology in AMD andoptimization of bioimaging modalities. This proposal can transform the clinical practice paradigmby introducing an innovative bioimaging strategy that enables early detection of CNV fortargeted therapy that can prevent vision loss. It also will advance the goals of the ARRA bycreating or retaining multiple jobs and provide economic benefit to the University of KentuckyCollege of Medicine which has consistently served the Commonwealth of Kentucky as aprincipal force for economic development and third-party suppliers and vendors.


application_id: 7832202
project_number: 3R21AG032567-02S1
project_title: Role of p62 in Protein Aggregation and Neurodegeneration in ALS
administering_ic: NIA
award_notice_date: 2009-09-29
opportunity_number: PA-06-181
application_type: 3
activity_code: R21
ic: AG
serial_number: 032567
suffix: S1
program_official: ST HILLAIRE-CLARKE, CORYSE
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-4 (O5)]
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
project_abstract:
DESCRIPTION (provided by applicant): This Competitive Revision application is in response to NOT-OD-09-058 "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." We request competitive supplement to our NIH grant R21AG032567 entitled "Role of p62 in Protein Aggregation and Neurodegeneration in ALS." 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. P62/Sequestosome 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. The central hypothesis to be tested in the parent R21 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 UPS and/or autophagy. We previously reported that p62 was co-localized with mutant SOD1 in the protein aggregates in spinal motor neurons in G93A SOD1 transgenic mice. Co-immunoprecipitation experiments showed that p62 specifically recognized mutant SOD1 but not the WT protein. Three specific aims were designed to test the hypothesis at the time. Aim 1 was to map the domains of p62 essential for recognizing and interacting with mutant SOD1. Aim 2  was to determine whether and how p62 mediated the autophagy activation induced by mutant SOD1. Aim 3 was to study how p62 would influence protein aggregation and ALS disease progression in vivo using p62 KO mice. We have largely accomplished the Aims 1 and 2 and are currently performing experiments proposed in Aim 3.  This Competitive Revision is built on the progress made in the R21 project and the new preliminary data suggesting that HDAC6 is likely an adaptor protein between p62 and mutant SOD1. In addition HDAC6 has been shown to play a critical role in autophagy activation and stress response. We thus propose to expand the parent R21 project to test a new hypothesis that HDAC6 is an adaptor protein mediating mutant SOD1-p62 interaction regulate the autophagic degradation of mutant SOD1 and mediate the stress response induced by mutant SOD1. Three new specific aims are proposed to test this hypothesis. Aim 1 is to dissect the detailed mechanism how HDAC6 functions as an adaptor between mutant SOD1 and p62.  Aim 2 is to determine the role of HDAC6 in aggregation and autophagic degradation of mutant SOD1.  Aim 3 is to study the significance of HDAC6 and p62 in mutant SOD1 induced stress response. Results from this study will provide invaluable insights into the role of HDAC6 and 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.  Relevance to the American Recovery & Reinvestment Act (ARRA): This application will create two new scientific researcher positions as soon as it is funded. Purchase of necessary equipment supplies and reagents for the proposed research will also stimulate the economy as intended by the ARRA.  
  
PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS Lou Gehrig's disease) is an age-related neurodegenerative disorder characteristic of the preferential motor neurons death. Mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) have been linked to a subset of familial ALS cases. Protein aggregates containing mutant SOD1 are a hallmark of familial ALS.  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. The parent R21 was to test the hypothesis that p62 could recognize misfolded mutant SOD1 and ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteins to the UPS and/or autophagy. We have largely accomplished the Aims 1 and 2 proposed in the parent R21 and are currently performing experiments proposed in Aim 3. Based on the progress and new preliminary results we propose to test the significance of an adaptor protein named histone deacetylase 6 (HDAC6) in mutant SOD1 protein degradation aggregation and neurotoxicity. The specific hypothesis to be tested in the expanded project is that HDAC6 is an adaptor protein mediating mutant SOD1-p62 interaction regulates the autophagic degradation of mutant SOD1 and mediates the stress response induced by mutant SOD1.  Results from this study will provide new insights into the role of HDAC6 and 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. Moreover this application will create two new scientific researcher positions as soon as it is funded. Purchase of necessary equipment supplies and reagents for the proposed research will also stimulate the economy as intended by the American Recovery & Reinvestment Act.

project_terms:
Adaptor Signaling Protein;Affect;American;Amyotrophic Lateral Sclerosis;Autophagocytosis;Cells;Cessation of life;Characteristics;Co-Immunoprecipitations;Data;Degradation Pathway;Disease Progression;Equipment and Supplies;Etiology;Failure (biologic function);Familial Amyotrophic Lateral Sclerosis;Funding;Genes;Grant;Life;Link;Lysosomes;Mediating;Molecular Chaperones;Motor Neurons;Mus;Mutation;Names;Nerve Degeneration;Neurodegenerative Disorders;Parents;Pathway interactions;Play;Positioning Attribute;Proteins;Publishing;Reagent;Recovery;Reporting;Request for Applications;Research;Research Personnel;Role;Series;Spinal;System;Testing;Time;Toxic effect;Transgenic Mice;Ubiquitin;United States National Institutes of Health;Work;age related;base;biological adaptation to stress;copper zinc superoxide dismutase;design;domain mapping;heat-shock factor 1;histone deacetylase 6;in vivo;inhibitor/antagonist;insight;multicatalytic endopeptidase complex;mutant;neurotoxicity;new therapeutic target;protein aggregate;protein aggregation;protein degradation;protein misfolding;protein transport;public health relevance;research study;response

public_health_relevance:
Project Narrative This Competitive Revision application is in response to NOT-OD-09-058 "NIH Announces theAvailability of Recovery Act Funds for Competitive Revision Applications." We request competitive supplementto our NIH grant R21AG032567 entitled "Role of p62 in Protein Aggregation and Neurodegeneration in ALS." Amyotrophic lateral sclerosis (ALS Lou Gehrig's disease) is an age-related neurodegenerative disordercharacteristic of the preferential motor neurons death. Mutations in the gene encoding copper-zinc superoxidedismutase (SOD1) have been linked to a subset of familial ALS cases. Protein aggregates containing mutantSOD1 are a hallmark of familial ALS. P62/Sequestome 1 (referred as p62 in this proposal) is a multifunctionalprotein involved in both of the two major protein degradation mechanisms: ubiquitin-proteasome system (UPS)and autophagy-lysosome pathway. The parent R21 was to test the hypothesis that p62 could recognizemisfolded mutant SOD1 and ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteinsto the UPS and/or autophagy. We have largely accomplished the Aims 1 and 2 proposed in the parent R21and are currently performing experiments proposed in Aim 3. Based on the progress and new preliminaryresults we propose to test the significance of an adaptor protein named histone deacetylase 6 (HDAC6) inmutant SOD1 protein degradation aggregation and neurotoxicity. The specific hypothesis to be tested in theexpanded project is that HDAC6 is an adaptor protein mediating mutant SOD1-p62 interaction regulates theautophagic degradation of mutant SOD1 and mediates the stress response induced by mutant SOD1. Results from this study will provide new insights into the role of HDAC6 and p62 in protein aggregationand neurodegeneration in ALS which will result in better understanding of ALS etiology and potential discoveryof new therapeutic target for ALS treatment. Moreover this application will create two new scientific researcherpositions as soon as it is funded. Purchase of necessary equipment supplies and reagents for the proposedresearch will also stimulate the economy as intended by the American Recovery & Reinvestment Act.


application_id: 7831192
project_number: 1RC1HL100239-01
project_title: Evaluation and Treatment of Skeletal Muscle Weakness in Critically Ill Patients
administering_ic: NHLBI
award_notice_date: 2009-09-30
opportunity_number: RFA-OD-09-003
application_type: 1
activity_code: RC1
ic: HL
serial_number: 100239
program_official: HARABIN, ANDREA L
project_start_date: 2009-09-30
project_end_date: 2011-08-10
study_section: Special Emphasis Panel[ZRG1 MOSS-C (58)]
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: Y
project_abstract:
DESCRIPTION (provided by applicant):  
Challenge Topic: 04-HL-108; Improving clinical outcomes in critically ill patients with respiratory failure. Over the past two decades a great deal has been learned about the basic physiology of the breathing muscles and a number of pathophysiological conditions including sepsis have been shown to rapidly produce severe respiratory muscle dysfunction in animal models of disease. Importantly these basic science studies have identified a number of pharmacological agents that appear capable of largely preventing or reversing the development of respiratory muscle dysfunction in animal models of disease. Unfortunately virtually none of these discoveries have been translated into clinical usage. In fact it is not even clear which hospitalized patients have respiratory muscle dysfunction how severe their dysfunction is and when this dysfunction develops during hospitalization. Based on our own observations however we believe severe respiratory muscle weakness develops in a large percentage of critically ill patients. If so administration of drugs designed to prevent the development of skeletal muscle weakness in this patient population should have a major impact on patient outcomes reducing the need for respiratory support shortening the duration of ICU and hospital stay and ultimately improving mortality. The purpose of the present proposal is to investigate these issues in detail to test our central hypothesis that respiratory muscle contractile dysfunction is a major contributor to respiratory failure in critically ill patients and to translate drug treatments for respiratory muscle dysfunction from the basic science laboratory to the intensive care unit. Aim 1 will systematically evaluate respiratory muscle strength in a large cohort of MICU patients using a state-of-the-art nonvolitional measure of diaphragmatic function namely assessment of the transdiaphragmatic twitch pressure elicited during bilateral phrenic nerve magnetic stimulation (twitch Pdi). Aim 2 will test the hypothesis that the development of skeletal muscle weakness in critically ill MICU patients can be attenuated by administration of two pharmacological agents (N-acetylcysteine and eicosopentanoic acid). We will compare skeletal muscle force and other outcome measures (duration of mechanical ventilation duration of ICU and hospital stay) in patients at risk for respiratory muscle weakness randomized to receive either placebo N- acetylcysteine (NAC) eicosopentanoic acid (EPA) or a combination of NAC and EPA. These experiments will provide the first comprehensive objective evaluation of the incidence severity and evolution of respiratory and limb skeletal muscle dysfunction in critically ill patients. In addition we will determine if it is possible to prevent the development of skeletal muscle weakness in critically ill patients via administration of two drugs (N-acetylcysteine and eicosopentanoic acid) previously shown in basic science studies to prevent respiratory muscle weakness in animal models of critical illness.

project_terms:
Acetylcysteine;Acids;Acute Disease;Adrenal Cortex Hormones;Animal Disease Models;Animal Model;Anterior;Arts;Attenuated;Basic Science;Bilateral;Blood gas;Breathing;Clinical;Critical Illness;Development;Diagnosis;Diaphragm (Anatomy);Drug Design;Evaluation;Evolution;Functional disorder;Goals;Hospitalization;Human;Hyperglycemia;Hypophosphatemia;Incidence;Institution;Intensive Care Units;Laboratories;Learning;Length of Stay;Limb structure;Magnetism;Measures;Mechanical ventilation;Mechanics;Mortality Vital Statistics;Muscle;Muscle Weakness;Muscle function;Outcome;Outcome Measure;Patients;Pharmaceutical Preparations;Physiological;Physiology;Placebos;Principal Investigator;Process;Randomized;Reporting;Respiratory Failure;Respiratory Mechanics;Respiratory Muscles;Respiratory System;Risk;Scientist;Sepsis;Severities;Skeletal muscle structure;Structure of phrenic nerve;Testing;Time;Translating;United States National Institutes of Health;Work;base;cohort;cost;improved;indexing;muscle strength;patient population;pressure;prevent;research study;respiratory

public_health_relevance:
These experiments will provide the first comprehensive objective evaluation of theincidence severity and evolution of respiratory and limb skeletal muscle dysfunction in criticallyill patients. In addition we will determine if it is possible to prevent the development of skeletalmuscle weakness in critically ill patients via administration of two drugs (N-acetylcysteine andeicosopentanoic acid) previously shown in basic science studies to prevent respiratory muscleweakness in animal models of critical illness.


application_id: 7829875
project_number: 3R01DA013519-09S1
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2009-09-28
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DA
serial_number: 013519
suffix: S1
program_official: APPEL, NATHAN M
project_start_date: 2009-09-30
project_end_date: 2012-09-29
study_section: Special Emphasis Panel[ZRG1 MDCN-C (95)]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519 titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. We request 2 years of support to expand the scope of our specific aims and accelerate the preclinical development of a clinical candidate for testing in human subjects. Recently we have identified a novel structure (GZ-793A) that was not described in the original funded application. Among all the compounds screened through the neurochemical assays focusing on compounds which potently and selectively interact with the vesicular monoamine transporter-2 (VMAT2) GZ-793A has exhibited the greatest potency and specificity in decreasing responding for intravenous methamphetamine. GZ-793A produced a complete blockade of methamphetamine self-administration (SA) in rats without any alteration in responding for sucrose i.e. it specifically decreases methamphetamine SA. The physicochemical properties of GZ-793A provides enhanced solubility and drugability relative to the majority of compounds initially proposed in the funded project. In this Competitive Revision Application we propose to optimize the chemical structure of GZ- 793A to ensure that several compounds of this promising new class are available as backups for the lead compound GZ-793A. We will evaluate this novel series of optimized compounds described in this Competitive Revision Application in the neurochemical assays to obtain a potent and selective VMAT2 inhibitor as additional structurally optimized lead compounds. These lead compounds will be evaluated in the methamphetamine SA assay following acute and repeated administration. We also propose to evaluate our current lead compound GZ-793A and the 3-4 additional lead compounds emerging from this research in comprehensive pharmacokinetic evaluations to assess their drugability as well as their ability to decrease methamphetamine SA following oral administration. Our goal by the end of the 2nd year of the Competitive Revision Application is to have identified a drugable orally bioavailable clinical candidate to move to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA. This project will stimulate the economy through the hiring of 4 additional postdoctoral fellows and 2 additional technical staff and through the procurement of additional equipment to conduct the studies. This project evaluating a complementary series of methamphetamine blockers will be completed within 2 years. Concurrently the parent grant will continue as originally proposed such that no budgetary changes for the remainder of the parent project are anticipated. The new funds will accelerate our productivity and allow us to pursue this new but related line of investigation toward the outcome of obtaining a clinical candidate for the treatment of methamphetamine abuse.  
  
PUBLIC HEALTH RELEVANCE: This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519 titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel structure (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model. We propose to optimize the chemical structure of GZ- 793A provide additional leads that are drugable orally-bioavailable clinical candidates and bring them to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA.

project_terms:
Acute;Affinity;Animal Model;Behavioral;Behavioral Assay;Binding (Molecular Function);Binding Sites;Bioavailable;Biological Assay;Biological Availability;Brain;Cell membrane;Chemical Structure;Chemicals;Clinical;Clinical Trials;Corpus striatum structure;Cyclic GMP;Cytosol;Databases;Development;Dopamine;Dose;Drug Kinetics;Ensure;Equipment;Evaluation;Exhibits;Experimental Designs;Funding;Future;Goals;Grant;Human;In Vitro;Individual;Intravenous;Investigation;Investigational New Drug Application;Ions;Kinetics;Lead;Light;Lobeline;Measures;Metabolism;Methamphetamine;Molecular Weight;Nature;Nicotine;Nicotinic Receptors;Oral;Oral Administration;Outcome;Parents;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase II Clinical Trials;Plasma;Postdoctoral Fellow;Preparation;Principal Investigator;Procedures;Process;Productivity;Property;Protein Binding;Proteins;Rattus;Recovery;Regulation;Relative (related person);Research;Rewards;Route;Running;Screening procedure;Self Administration;Series;Slice;Solubility;Source;Specificity;Structure;Structure-Activity Relationship;Sucrose;Synaptic Transmission;Synaptic Vesicles;Techniques;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;United States National Institutes of Health;Water;Work;analog;dihydrotetrabenazine;dopamine transporter;drug development;effective therapy;enantiomer;extracellular;functional group;human subject;in vitro Assay;in vivo;inhibitor/antagonist;methamphetamine abuse;methyllycaconitine;neurochemistry;new therapeutic target;noradrenaline transporter;novel;novel therapeutics;parent grant;parent project;pharmacophore;piperidine;pre-clinical;programs;public health relevance;response;safety study;scale up;serotonin transporter;uptake;vesicular monoamine transporter;vesicular monoamine transporter 2

public_health_relevance:
NARRATIVEThis Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 andNotice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as acompetitive supplement to our current R01 grant DA 13519 titled "Development of NovelTherapies for Methamphetamine Abuse" (FOA is PA07070). Currently there is no treatmentavailable for methamphetamine abuse. The overall objective of this project is to provide aclinical candidate for the treatment of methamphetamine abuse. Recently we identified a novelstructure (GZ-793A) which potently and selectively interacts with the vesicular monoaminetransporter-2 and exhibits potency and specificity in decreasing responding for intravenousmethamphetamine in an animal model. We propose to optimize the chemical structure of GZ-793A provide additional leads that are drugable orally-bioavailable clinical candidates and bringthem to comprehensive toxicological evaluation for preparation of an Investigational New Drugapplication (IND) to the FDA.


application_id: 7827997
project_number: 5T35DK072923-05
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2010-05-05
opportunity_number: PAR-04-090
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: PODSKALNY, JUDITH M,
project_start_date: 2006-05-01
project_end_date: 2011-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
This proposal describes a short-term summer training program for medical students focused on exposing students to career opportunities in basic and clinical research related to diabetes obesity endocrine disorders metabolic diseases and kidney diseases. This application addresses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The training program will include didactic instruction as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. These faculty have long-standing success in mentoring medical and graduate students and post-doctoral fellows. Students who have completed at least one year of medical school will be eligible to apply for this 10-week training program. Trainees will be selected based upon their academic performance letters of recommendation and matching their research interests and career goals with suitable mentors. We have been successful in recruiting students from minority rural and economically disadvantaged backgrounds. The students will participate in an established 10-week didactic summer program: "From Bench to Bedside: Introduction to Clinical Research" which included bioethics as well as Endocrine-specific seminars and journal clubs in basic and clinical research. Students will present posters of their research at the end of the program. The training program will begin with six trainees and increase to ten trainees as the program matures. Over the past 6 years the University of Louisville has increased its commitment to health science research and infrastructure graduate education and minority recruitment making this short-term training program for medical students particularly timely

project_terms:
Address;Bioethics;Clinical;Clinical Research;Diabetes Mellitus;Economically Deprived Population;Endocrine;Endocrine System Diseases;Environment;Faculty;Funding;Goals;Graduate Education;Hand;Instruction;Journals;Kidney Diseases;Letters;Medical;Medical Students;Mentors;Metabolic Diseases;Minority;Obesity;Performance;Postdoctoral Fellow;Recommendation;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Rural;Scientist;Structure;Students;Training;Training Programs;Universities;base;bench to bedside;career;experience;graduate student;health science research;interest;medical schools;posters;programs;skills;success


application_id: 7826766
project_number: 5R03DE019177-02
project_title: A Novel Murine Model of Chronic Inflammatory Periodontitus
administering_ic: NIDCR
award_notice_date: 2010-05-19
opportunity_number: PAR-07-418
application_type: 5
activity_code: R03
ic: DE
serial_number: 019177
program_official: BURGOON, PENNY W
project_start_date: 2009-07-01
project_end_date: 2012-09-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7130705
contact_pi: OZ, HELIEH S
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): There is accumulating evidence for an increasing incidence of chronic diseases in the human population. These diseases are generally complex with aspects of genetic control interacting with environmental stressors to trigger the symptoms of the diseases. Additionally many of these diseases clearly are manifested by chronic inflammation that contributes to loss of function of cells tissues or organs resulting in disease outcomes. It is also becoming more apparent in the post-genomic "personalized medicine" era that these diseases are observed in a subset of the population that present with "at risk" genotypes translating into phenotypic expression of disease. In this regard the chronic inflammation occurring in inflammatory bowel disease and rheumatoid arthritis have many similarities to the chronic immunoinflammatory response in the oral cavity that destroys the soft and hard tissues of the periodontium (i.e. periodontitis). Reactive oxygen species (ROS) are generated during inflammation particularly in regions of microbial challenge as an important protective mechanism for the host. However chronic production of the toxic reactive materials presents a situation where tissue damage and loss of function can occur related to a chronic inflammatory response. The project will focus on evaluating molecular aspects of inflammatory periodontal disease using a "chronic model" elicited by local administration of Trinitrobenzene sulfonic acid (TNBS) that elicits a localized chronic inflammatory response that undermines the integrity of the epithelium and upregulates ROS and a more "acute model" of ligature-induced periodontitis.. The objectives of this proposal will be to test the hypothesis that treatment of mouse models of chronic and acute inflammatory periodontitis with agents that regulate ROS production and function will decrease local inflammation and alveolar bone loss. The approach will be to treat mice with distinct antioxidants a cysteine prodrug 2-(RS)-n-propylthiazolidine- 4(R)-carboxylic acid (PTCA) and a glutathione (GSH) prodrug s-adenosylmethionine (SAMe) to interfere with molecular events elicited by ROS produced during inflammatory periodontal disease. These studies will use wild-type mice (Aim 1) and mice with a deficiency in superoxide dismutase (SOD1) as a major intrinsic molecule that protects against ROS damage. The implementation of the TNBS model of chronic inflammatory bone resorption and the ligature-model of acute inflammatory bone loss will enable comparison of contribution of ROS to osteoimmunological interactions in the oral cavity. We would predict that the experimental designs will demonstrate an important role for ROS in alveolar bone resorption and will enable identification of various gingival gene products that contribute to the local milieu reflecting this tissue destructive process. These findings should be exacerbated in the SOD1 knockout mice. The therapeutic strategies will also lay the ground work for more targeted control of ROS production as related to molecular pathways of host cell activation in the gingiva and osteoimmunologic linkages that result in alveolar bone resorption. The results will enable extended studies through R01 applications that will use these models to examine additional extrinsic antioxidants for controlling this disease as well as studies of the contribution of other intrinsic antioxidant components (ie. glutathione GST metallothionein) to establishing homeostasis in the periodontium. PUBLIC HEALTH RELEVANCE: Chronic inflammation of the oral cavity destroys the soft and hard tissues of the periodontium (ie. periodontitis) and causes tooth loss. These pathological changes can result from dysregulated production of reactive oxygen species. Specific aims for this proposal will examine targeted antioxidant therapies using mouse models of oral disease as a potential strategy for adjunctive management of human periodontitis.

project_terms:
Acute;Alveolar Bone Loss;Angioplasty Transluminal Percutaneous Coronary;Animal Model;Animals;Antioxidants;Biological Models;Bone Resorption;Carboxylic Acids;Cells;Characteristics;Chronic;Chronic Disease;Clinical;Complex;Crohn's disease;Cuprozinc Superoxide Dismutase;Cysteine;Data;Disease;Disease Outcome;Epithelium;Evaluation;Event;Experimental Designs;Genetic;Genomics;Genotype;Gingiva;Glutathione;Homeostasis;Human;Immune response;Inbred BALB C Mice;Incidence;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Knockout Mice;Lesion;Ligature;Literature;Medicine;Metallothionein;Modeling;Molecular;Molecular Probes;Mouth Diseases;Mucositis;Mucous Membrane;Mus;Oral;Oral cavity;Organ;Pathway interactions;Periodontal Diseases;Periodontitis;Periodontium;Play;Population;Process;Prodrugs;Production;Proteins;Reactive Oxygen Species;Rheumatoid Arthritis;Risk;Role;Seminal;Sulfonic Acids;Superoxide Dismutase;Symptoms;Testing;Therapeutic;Tissues;Tooth Exfoliation;Tooth Loss;Translating;Trinitrobenzenes;Variant;Wild Type Mouse;Work;alveolar bone;antioxidant therapy;bone loss;disorder control;environmental stressor;gastrointestinal;inflammatory bone resorption;loss of function;microbial;mouse model;mucosal site;novel;oral tissue;public health relevance;response

public_health_relevance:
NarrativesChronic inflammation of the oral cavity destroys the soft and hard tissues of the periodontium (ie. periodontitis)and causes tooth loss. These pathological changes can result from dysregulated production of reactive oxygenspecies. Specific aims for this proposal will examine targeted antioxidant therapies using mouse models of oraldisease as a potential strategy for adjunctive management of human periodontitis.


application_id: 7826611
project_number: 5R43CA138336-02
project_title: Tissue-Specific Mutagenesis in Rat as an In Vivo Tool for Colon Cancer Gene Disco
administering_ic: NCI
award_notice_date: 2010-06-21
opportunity_number: RFA-CA-08-011
application_type: 5
activity_code: R43
ic: CA
serial_number: 138336
program_official: WEBER, PATRICIA A
project_start_date: 2009-05-05
project_end_date: 2012-04-30
study_section: ZCA1-SRLB-Q(J1)
contact_pi_person_id: 1871056
contact_pi: RUIZ, JOSEPH C.
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: 2010-06-21
budget_end_date: 2012-04-30
project_abstract:
DESCRIPTION (provided by applicant): The outcome of this SBIR application will be a rat model of colorectal cancer (CRC) which can be used to discover new targets for colon cancer therapy. CRC rats will be produced using Transposagen's novel technology for introducing somatic mutations in rats. A number of germline and somatic mutations are known to contribute to the initiation and progression of both heritable and sporadic CRC but identifying the causative molecular and genetic defects involved in human CRC has proven difficult. Existing mouse models for CRC do not accurately model human disease. Rats more closely recapitulate the molecular cellular and pathologic characteristics of human CRC. Polyps in the rat unlike in the mouse progress to adenocarcinomas that are equivalent to stage T1 CRC in humans. Colon cancer induced in normal rats using known human carcinogens will spread to the liver indicating that the rat unlike the mouse may serve as a valuable model for CRC metastasis. The physical size of the rat also makes it much more amenable to endoscopy thus enabling polyp monitoring and real-time assessment of somatic mutations taking place in a single adenoma so that gate-keeper mutations can be more accurately discriminated from mutations involved in later stages of carcinogenesis. In Phase I of this application we will create and characterize three lines of transgenic rats: 1) rats exhibiting intestine-specific expression of a Cre recombinase using a VilCre transgene; 2) rats expressing a transposase (the enzyme responsible for transposon mobilization) gene under the direction of the ubiquitous ROSA26 promoter. A lox-stop-lox cassette will be used to restrict the expression of the transposase; 3) transgenic rats containing a gene trap donor transposon. Cre expression in tri-transgenic rats created by cross-breeding will trigger expression of the transposase which will then mobilize the gene trap transposon and insert it randomly throughout the genome. Importantly these mutations will occur in the intestine only because of the tissue-specific expression of the Cre recombinase. Our gene-trap will be capable of creating both null alleles (loss-of-function) and over-expressed transcripts (gain-of-function). A sequence-specific tag is used for mapping mutations an especially salient advantage compared to other random mutagenesis methods (such as chemical or radiation strategies) for rapid identification of tumor suppressors and oncogenes. In later Phase II work we will perform a full phenotypic analysis of the CRC phenotype of tri-transgenic rats and clone insertion sites to verify the efficacy of the model. The CRC rat model developed by our method of unbiased transposon mutagenesis in the intestine will likely identify novel cancer genes in a model of colon cancer that is more relevant to human CRC.

project_terms:
Adenocarcinoma;Alleles;Animal Model;Antineoplastic Agents;Atlas of Cancer Mortality in the United States;Biopsy;Biotechnology;Breeding;Cancer Etiology;Cancerous;Candidate Disease Gene;Carcinogens;Cessation of life;Chemicals;Collaborations;Colon Carcinoma;Colonoscopy;Colorectal Cancer;Complex;Data;Development;Diagnosis;Early Diagnosis;Endoscopy;Enzymes;Epithelial Cells;Exhibits;Gene Expression;Genes;Genetic;Genome;Germ-Line Mutation;Histopathology;Human;Human Characteristics;Human Pathology;Intestinal Mucosa;Intestinal Polyps;Intestines;Investigation;Jumping Genes;Lead;Lesion;Liver;Location;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Methods;Minnesota;Missouri;Modeling;Modification;Molecular;Molecular Abnormality;Molecular Analysis;Molecular Genetics;Monitor;Multipotent Stem Cells;Mus;Mutagenesis;Mutation;Neoplasm Metastasis;Oncogenes;Outcome;Pathologic;Penetrance;Pharmacologic Substance;Phase;Phenotype;Polyps;Promotor (Genetics);Radiation;Rat-1;Rattus;Request for Applications;Research Personnel;Resources;Risk;Rodent;Site;Skin Cancer;Sleeping Beauty;Small Business Innovation Research Grant;Somatic Mutation;Staging;Stem cells;System;Technology;Time;Tissues;Transcript;Transgenes;Transgenic Organisms;Transposase;Tumor Suppressor Genes;Universities;Wisconsin;Work;adenoma;base;biomarker;cancer initiation;cancer therapy;carcinogenesis;cost;gain of function;genetic risk assessment;human disease;in vivo;innovation;loss of function;medical schools;mouse model;new technology;novel;offspring;prototype;recombinase;therapeutic target;tool;transposon/insertion element

public_health_relevance:
Project Narrative Rats recapitulate the dietary genetic and pathological characteristics of human colon cancer moreaccurately than mice. In addition rats are more amenable to colonoscopy and biopsies because of their sizeand therefore are more convenient than mice for finding and studying the polyps and pre-cancerous lesionsthat lead to colon cancer. Here we propose a strategy using mobile DNA (or "jumping gene") technology in thismore relevant animal model to rapidly discover new cancer genes which may ultimately lead to betterassessment of genetic risk earlier diagnosis and new cancer drugs for humans.


application_id: 7826582
project_number: 5R01HL091893-03
project_title: The Platelet Secretory Machinery
administering_ic: NHLBI
award_notice_date: 2010-05-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 091893
program_official: SARKAR, RITA
project_start_date: 2008-05-01
project_end_date: 2012-04-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Secretion from activated platelets is thought to be a key step in hemostasis as well as in the post-thrombus sequellae of wound healing. Controlling platelet exocytosis offers a unique therapeutic opportunity to manipulate the microenvironment formed at the site of vascular damage. However our understanding of the machinery that facilitates platelet granule release is still not sufficient to identify valuable drug targets. Our proposed studies seek to rectify this by delineating the molecular events required for platelet secretion. From past reports it is clear that specific Soluble NSF Attachment Protein Receptors (v- and t-SNAREs) are required for platelet secretion. With this established our goals are now expanded to define the roles of secretion in hemostasis and to identify the mechanisms by which the exocytosis machinery is regulated. Two Specific Aims are proposed: 1) To assess the role of the v-SNARE VAMP-8 in platelet function. Our work demonstrated that VAMP-8/endobrevin is required for platelet exocytosis. Aim 1 will complete the characterization of this v-SNARE's role using specific experiments to define the in vivo and in vitro phenotypes of VAMP-8-/- platelets. Other experiments will address the sub-platelet distribution of VAMP-8 and characterize its interacting partners. 2) To identify and characterize the SNARE regulators that interact with and control the syntaxin t-SNAREs in platelets. Past studies assigned roles for SNAP-23 syntaxin 2 and 4. This aim focuses on defining roles for known t-SNAREs regulators and identifying novel ones. The syntaxin-regulators Munc18 Munc13 DOC2 and tomosyn will be studied using biochemical techniques and a permeabilized platelet secretion assay. The experiments will expand our understanding of how these proteins mediate SNARE pairing and subsequent membrane fusion. In summary the information gained from this proposal will identify new therapeutic targets to control hyperactive platelets and will provide diagnostic reagents to determine why hypoactive platelets are defective. PUBLIC HEALTH RELEVANCE: Strokes and heart attacks are major killers in the United States. In both cases the damage is caused by a loss of blood flow usually because a blood clot has formed in the wrong place. Understanding all aspects of clot formation is critical to treating this problem. This application focuses on one aspect of clot formation platelets. Specifically this application focuses on how platelets secrete components needed for clot formation. This work is of critical important because it will direct the development of future therapeutic agents needed to decrease the risk of spurious clot formation.

project_terms:
Address;Adhesions;Agonist;Alpha Granule;Atherosclerosis;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Clot;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Categories;Cause of Death;Cell membrane;Cells;Cellular biology;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;DAB2 gene;Data;Defect;Development;Diagnostic Reagent;Disease;Drug Delivery Systems;Event;Exocytosis;Family;Future;Goals;Hemorrhage;Hemostatic function;In Vitro;Inflammation;Knowledge;Lead;Learning;Lysosomes;Mediating;Membrane Fusion;Membrane Proteins;Molecular;Molecular Target;Mouse Strains;Mus;Myocardial Infarction;Pathology;Pathway interactions;Phenotype;Physicians;Platelet Activation;Play;Process;Protein Secretion;Proteins;Recombinant Proteins;Regulation;Reporting;Research;Risk;Role;SNAP receptor;Signal Transduction;Site;Stimulus;System;Techniques;Therapeutic;Therapeutic Agents;Thrombosis;Thrombus;Time;United States;VAMP-2;Work;Wound Healing;base;design;extracellular;falls;in vivo;in vivo Model;insight;neurotransmitter release;new therapeutic target;novel;outcome forecast;programs;protein protein interaction;public health relevance;research study;response;soluble NSF attachment protein;stroke;syntaxin;syntaxin-2;target SNARE proteins;therapeutic target;vesicular SNARE proteins


application_id: 7825411
project_number: 5R01GM087735-02
project_title: Mass Informatics of Two Dimensinoal Gas Chromatography Time-of-flight Mass Spectr
administering_ic: NIGMS
award_notice_date: 2010-05-05
opportunity_number: PAR-07-344
application_type: 5
activity_code: R01
ic: GM
serial_number: 087735
program_official: LYSTER, PETER
project_start_date: 2009-05-01
project_end_date: 2013-04-30
study_section: Enabling Bioanalytical and Biophysical Technologies Study Section[EBT]
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
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
project_abstract:
DESCRIPTION (provided by applicant): High-throughput omics analysis platforms provide important new technical capabilities to analyze complex biological fluids for disease markers. A particularly important platform for metabolomics is two-dimensional gas chromatography time-of- flight mass spectrometry (GCxGC/TOF-MS) that provides both high precision and extended capacity for molecular detection. However data analysis from this platform is not developed for high sample numbers or for detection of the very large numbers of analytes that this technology detects (more than 1500 per biofluid sample). We will develop an informatics platform for accurate and efficient analysis of data generated from GCxGC/TOF-MS analyses through the following specific aims: (1) Mass informatics for differential metabolomics (2) Interactive visual analysis of metabolite correlation networks and (3) Informatics analysis tools integration. The biological information that our system will deliver is regulation of altered metabolites that relate to phenotypic differences between groups of samples. This information will enable assessment of human health and wellness and will have a direct impact on public health. In the context of existing collaborations our initial large scale application focus will be analyses of metabolomic profiling data from plasma samples of patients with breast and prostate cancer compared with control subjects. Broadly speaking our informatics tools will facilitate efforts in the metabolomics community to perform comparative metabolite profiling with high precision and high volume on the powerful GCXGC-TOF-MS platform. The project consists of the development of algorithms for assessment of metabolite identification accuracy alignment of spectra and normalization of datasets. Separate algorithms will be developed to distinguish specific molecules that are observed to be different between different sample cohorts and to provide a statistical significance context for each differentially expressed molecule. An additional group of algorithms will be developed to enable interactive visual analysis of metabolite correlation networks. Deliverables from this project will include provision of independent software modules that can be remotely invoked via web services and an integrated web-based data analysis pipeline for GCxGC/TOF-MS data. PUBLIC HEALTH RELEVANCE: High-throughput molecular omics analysis platforms provide important new technical capabilities to analyze complex biological fluids for disease markers. A particularly important platform for metabolomics is two-dimensional gas chromatography time-of- flight mass spectrometry (GCxGC/TOF-MS) that provides both high precision and extended capacity for molecular detection. This approach usually uses a short polar column after the main analytical column. Typically the second column is operated at a higher temperature than the first column. The metabolites co-eluted from the first GC column are further separated in the second column because of the difference of column temperature and the chromatography matrix. The further separated metabolites are directed to a high capacity time-of-flight mass spectrometry system for detection. Two- dimensional gas chromatography offers significant advantages for analysis of complex samples including: an order-of-magnitude increase in separation capacity significant increase in signal-to-noise ratio and dynamic range and improvement of mass spectral deconvolution and similarity matches. Since GCWGC/TOF-MS can provide more and accurate information it represents powerful tool for the analysis of small molecule metabolites in complex biological systems. However data analysis from this platform is not developed for high sample numbers or for detection of the very large numbers of analytes that this technology detects (more than 1500 per biofluid sample). We will develop a set of computational algorithms for accurate and efficient analysis of data generated from GCxGC/TOF-MS analyses through the following specific aims: (1) Mass informatics for differential metabolomics (2) Interactive visual analysis of metabolite correlation networks and (3) Informatics analysis tools integration. The biological information that our system will deliver is regulation of altered metabolites that relate to phenotypic differences between groups of samples. This information will enable assessment of human health and wellness and will have a direct impact on public health. A direct application of this type of information is metabolite biomarker discovery in clinical biomedical research. In the context of existing collaborations our initial large scale application focus of the developed mass informatics system will be analyses of metabolomic profiling data from human plasma samples of patients with breast cancer and human multiple myeloma compared with corresponding control subjects. With the raw instrument data as input information our informatics tools will perform a series of data mining and discover the metabolites present in the sample and also provide their regulation information. These informatics tools will facilitate efforts in the metabolomics community to perform comparative metabolite profiling with high precision and high volume on the powerful GCXGC-TOF-MS platform. The project consists of the development of algorithms for assessment of metabolite identification accuracy alignment of spectra and normalization of datasets. Separate algorithms will be developed to distinguish specific molecules that are observed to be different between different sample cohorts and to provide a statistical significance context for each differentially expressed molecule. An additional group of algorithms will be developed to enable interactive visual analysis of metabolite correlation networks. Deliverables from this project will include provision of independent software modules that can be remotely invoked via web services and an integrated web-based data analysis pipeline for GCxGC/TOF-MS data.

project_terms:
Algorithms;Area;Biological;Biomedical Research;Blood;Breast;Chromatography;Clinical;Collaborations;Communities;Complex;Complex Mixtures;Computational algorithm;Computer software;Data;Data Analyses;Data Files;Data Set;Detection;Development;Disease;Disease Marker;Emerging Technologies;Equilibrium;Gas Chromatography;Health;High temperature of physical object;Human;Informatics;Internet;Investigation;Liquid substance;Malignant Neoplasms;Malignant neoplasm of prostate;Marketing;Mass Fragmentography;Mass Spectrum Analysis;Measures;Medicine;Metabolic;Methods;Mission;Modeling;Modification;Molecular;Monitor;Multiple Myeloma;Noise;Online Systems;Output;Pathway Analysis;Patients;Pattern Recognition;Plasma;Preventive;Probability;Process;Regulation;Relative (related person);Research Personnel;Residual state;Running;Sampling;Secure;Series;Services;Signal Transduction;Simulate;Solutions;Source;Speed (motion);Statistical Models;System;Technology;Temperature;Testing;Time;Urine;Variant;Visual;Work;base;biomarker;clinically relevant;cohort;comparative;complex biological systems;data mining;direct application;graphical user interface;human data;improved;instrument;instrumentation;interest;liquid chromatography mass spectrometry;malignant breast neoplasm;metabolomics;open source;programs;public health medicine (field);public health relevance;small molecule;software systems;tool;two-dimensional

public_health_relevance:
High-throughput molecular omics analysis platforms provide important new technicalcapabilities to analyze complex biological fluids for disease markers. A particularlyimportant platform for metabolomics is two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS) that provides both high precision andextended capacity for molecular detection. This approach usually uses a short polarcolumn after the main analytical column. Typically the second column is operated at ahigher temperature than the first column. The metabolites co-eluted from the first GCcolumn are further separated in the second column because of the difference of columntemperature and the chromatography matrix. The further separated metabolites aredirected to a high capacity time-of-flight mass spectrometry system for detection. Two-dimensional gas chromatography offers significant advantages for analysis of complexsamples including: an order-of-magnitude increase in separation capacity significantincrease in signal-to-noise ratio and dynamic range and improvement of mass spectraldeconvolution and similarity matches. Since GCGC/TOF-MS can provide more andaccurate information it represents powerful tool for the analysis of small moleculemetabolites in complex biological systems.However data analysis from this platform is not developed for high sample numbers orfor detection of the very large numbers of analytes that this technology detects (morethan 1500 per biofluid sample). We will develop a set of computational algorithms foraccurate and efficient analysis of data generated from GCxGC/TOF-MS analysesthrough the following specific aims: (1) Mass informatics for differential metabolomics(2) Interactive visual analysis of metabolite correlation networks and (3) Informaticsanalysis tools integration. The biological information that our system will deliver isregulation of altered metabolites that relate to phenotypic differences between groups ofsamples. This information will enable assessment of human health and wellness andwill have a direct impact on public health. A direct application of this type of informationis metabolite biomarker discovery in clinical biomedical research. In the context ofexisting collaborations our initial large scale application focus of the developed massinformatics system will be analyses of metabolomic profiling data from human plasmasamples of patients with breast cancer and human multiple myeloma compared withcorresponding control subjects.With the raw instrument data as input information our informatics tools will perform aseries of data mining and discover the metabolites present in the sample and alsoprovide their regulation information. These informatics tools will facilitate efforts in themetabolomics community to perform comparative metabolite profiling with high precisionand high volume on the powerful GCXGC-TOF-MS platform. The project consists of thedevelopment of algorithms for assessment of metabolite identification accuracyalignment of spectra and normalization of datasets. Separate algorithms will bedeveloped to distinguish specific molecules that are observed to be different betweendifferent sample cohorts and to provide a statistical significance context for eachdifferentially expressed molecule. An additional group of algorithms will be developed toenable interactive visual analysis of metabolite correlation networks. Deliverables fromthis project will include provision of independent software modules that can be remotelyinvoked via web services and an integrated web-based data analysis pipeline forGCxGC/TOF-MS data.


application_id: 7825373
project_number: 5R01CA120606-04
project_title: Patient Navigation for Cervical Cancer in Appalachia
administering_ic: NCI
award_notice_date: 2010-04-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 120606
program_official: KOBRIN, SARAH
project_start_date: 2007-06-01
project_end_date: 2012-04-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Over the past five decades mortality rates from cervical cancer have decreased by approximately 75%. This reduction is largely attributable to the Pap smear and improvements in treatment. Despite this encouraging reduction certain groups of women have not experienced significant benefits and remain at disproportionate risk of death from cervical cancer. Among these women are those living in rural areas particularly middle aged and older women who live in rural Appalachia. This population continues to have among the highest cervical cancer mortality rates and efforts to address this problem have fallen short of their objectives. To reduce the unequal and unnecessary burden from cervical cancer experienced by rural Appalachian women we propose to undertake a community-based patient navigator (PN) intervention in partnership with local public health departments. In this proposed project we intend to develop administer and evaluate a plan for effective utilization of lay health workers as PNs in local health department cervical cancer screening programs. The aims are: 1) to improve understanding of the barriers to follow-up experienced by women with abnormal Pap test results; 2) in conjunction with designated nurse case managers to recruit train and utilize lay health workers as PNs in local health departments' cervical cancer screening and follow-up treatment programs; and 3) with extensive input from women who do not follow-up after abnormal results and through the development of a PN program to increase the proportion of patients who are adherent with recommendations for timely abnormal Pap test follow-up. The project will be conducted in 26 public health departments in rural southeastern Kentucky. A lagged design will be used in which the health departments will be randomized to intervention or delayed intervention groups. A total of 858 patients will be enrolled in the project 429 in the intervention group and 429 in the delayed intervention group. Patients who do not keep scheduled follow-up appointments for abnormal Pap smear results will be eligible and referred to PNs and enrolled. Assessment will occur in face-to-face interviews at baseline and again at two points after the intervention.

project_terms:
Address;Adherence (attribute);Aftercare;Appalachian Region;Appointment;Breast;Cancer Burden;Case Management;Case Manager;Cervical Cancer Screening;Cessation of life;Communities;County;Dependence;Development;Disease;Enrollment;Funding;Health;Health Personnel;Health Promotion;Institution;Intervention;Interview;Kentucky;Life;Literature;Malignant neoplasm of cervix uteri;Medicaid;Modeling;Mortality Vital Statistics;Nurses;Pap smear;Patients;Population;Randomized;Recommendation;Recruitment Activity;Risk;Role;Rural;Rural Population;Schedule;Screening procedure;Services;Test Result;Training;Treatment Cost;Woman;Women's Group;Work;age group;base;cancer prevention;design;experience;falls;follow-up;group intervention;high risk;improved;innovation;middle age;older women;outreach program;prevent;programs;public health medicine (field);rural area;treatment program;willingness


application_id: 7825344
project_number: 5R01DK080327-03
project_title: Effects of fish oil on inflammation and metabolic syndrome
administering_ic: NIDDK
award_notice_date: 2010-04-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080327
program_official: STATEN, MYRLENE A
project_start_date: 2008-05-01
project_end_date: 2013-04-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity and type 2 diabetes are conditions characterized by a state of chronic low-grade inflammation due largely to an increase in adipose tissue inflammation brought about by infiltrating macrophages. Drugs such as thiazolidinediones (TZDs) improve insulin sensitivity via activation of PPAR-gamma and there is much evidence that PPAR3 agonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease fish oils (I-3 fatty acids) activate PPAR3 and demonstrate anti-inflammatory properties. This is a translational research study intended to examine the mechanism for many of the beneficial effects of fish oils on metabolic syndrome in humans. We plan to treat insulin resistant subjects with fish oils and the following hypotheses. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. We plan to examine the circulating levels of cytokines as well as the levels of cytokines and macrophages in adipose tissue biopsies of subjects who are treated with 4 g/day of I-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue and we will determine whether I-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPAR3 and/or by changes in membrane composition that affect signal transduction functions. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR3 inhibitor and we will measure PPAR3 responses such as the secretion of HMW adiponectin and macrophage apoptosis. In addition we will determine whether I-3 fatty acids induce changes in recruitment of inflammatory receptors such as toll-like receptor 4 (TLR4) and TNF1 Receptor 1 (TNFR1) to membrane rafts. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid and an improvement in muscle insulin signal transduction. Before and after treatment with fish oils insulin sensitivity will be measured along with intramyocellular lipid and genes or proteins involved in insulin action and muscle lipid oxidation.  Project Narrative: The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.

project_terms:
24-thiazolidinedione;Adipocytes;Adipose tissue;Affect;Aftercare;Agonist;Animal Feed;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Arachidonic Acids;Biopsy;Blood specimen;Cardiovascular system;Cell Adhesion Molecules;Chronic;Complex;Coronary;Coronary heart disease;Development;Diabetes Mellitus;Disease Progression;Epidemic;Event;Fasting;Fatty Acids;Fish Oils;Generations;Genes;Health Benefit;Heart Diseases;Human;Hyperglycemia;In Vitro;Incidence;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-6;Life;Lipids;Literature;Measures;Mediating;Mediator of activation protein;Membrane;Metabolic syndrome;Molecular Weight;Muscle;Muscle Cells;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Hormone Receptors;Obesity;Omega-3 Fatty Acids;Organ;PPAR gamma;Parents;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Process;Production;Property;Protein Isoforms;Proteins;Rattus;Reactive Oxygen Species;Risk Factors;Series;Serum;Signal Transduction;Source;Syndrome;Thiazolidinediones;Translational Research;Triglycerides;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Western World;adiponectin;carbohydrate metabolism;cytokine;feeding;high risk;immunoregulation;improved;inflammatory marker;inhibitor/antagonist;insulin secretion;insulin sensitivity;insulin signaling;macrophage;oxidation;receptor;research study;response;toll-like receptor 4

public_health_relevance:
Project Narrative The incidence of obesity metabolic syndrome and diabetes is rising in epidemic proportions in the Western world and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.


application_id: 7824861
project_number: 7R37DK039176-21
project_title: Regulation of lipoprotein lipase in adipocytes
administering_ic: NIDDK
award_notice_date: 2009-06-22
application_type: 7
activity_code: R37
ic: DK
serial_number: 039176
program_official: HAFT, CAROL R
project_start_date: 1988-09-01
project_end_date: 2011-06-30
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-02-01
project_abstract:
DESCRIPTION (provided by applicant): The mechanism of LPL regulation is complex and we have focused on the translational regulation of LPL which occurs in response to diabetes and in response to hormones such as thyroid hormone and epinephrine. LPL translation is controlled by an RNA binding complex that forms in response to epinephrine and binds to the 3'UTR of the LPL mRNA resulting in an inhibition of LPL translation. One component of this complex is a member of the A-Kinase Anchoring Protein (AKAP) family which tethers PKA to specific cellular sites. AKAP121 contains a consensus KH RNA binding region and is a component of the RNA binding complex. Additional studies have characterized the region on the LPL mRNA that binds the AKAP- PKA complex and demonstrated that transgenic mice expressing LPL without the proximal 3'UTR upregulate LPL at the translational level. Therefore we plan to examine LPL translation regulation by studying both the RNA binding complex and the LPL mRNA. Hypothesis 1. LPL translation is regulated by an RNA binding complex which interacts with a specific motif on the LPL 3'UTR. This RNA binding complex depends on specific sequence elements of PKA AKAP149 and possibly other components. Aim 1. Examine AKAP149/121 interactions with other elements of the PKA complex. Aim 2. Determine whether AKAP targeting to ER or mitochondria is important in LPL translation inhibition. Aim 3. Will the introduction of AKAP149 confer LPL translational inhibition by PKA in a non-adipose cell? Aim 4. Is the increase in LPL that accompanies hypothyroidism due to changes in AKAP expression? Aim 5. Identify LPL 3'UTR sequence elements that alter the interaction with the RNA binding complex. Hypothesis 2. By preventing the interaction between the RNA binding complex with the LPL 3'UTR LPL will become unresponsive to epinephrine and adipose tissue will accumulate more lipid diverting lipid from other insulin target organs yielding improved insulin sensitivity. Aim 6. Examine the phenotype of a transgenic mouse that expresses LPL lacking the proximal 3'UTR. Will this cause lipid partitioning into adipose tissue and improve insulin sensitivity? Aim 7. Examine insulin sensitivity and other phenotypic features of d-AKAP1 knockout mice. Relevance. LPL is a central enzyme in lipid metabolism: the enzyme is expressed by adipocytes and muscle cells and hydrolyzes the triglyceride core of plasma VLDL and chylomicrons. LPL is an important adipogenic enzyme in adipose tissue and abnormalities in LPL result in inefficient lipoprotein metabolism leading to atherosclerosis especially in patients with diabetes.

project_terms:
3' Untranslated Regions;A kinase anchoring protein;Abbreviations;Accounting;Acetates;Adipocytes;Adipose tissue;Atherosclerosis;Binding (Molecular Function);Blood capillaries;Brown Fat;Capillary Unspecified;Catabolism;Chylomicrons;Complex;Consensus;Cyclic AMP-Dependent Protein Kinases;Development;Diabetes Mellitus;Elements;Endoplasmic Reticulum;Endothelium;Enzymes;Epinephrine;Epitopes;Esterified Fatty Acids;Gene Expression Regulation;Homologous Gene;Hormones;Human;Hydrolysis;Hypothyroidism;Insulin;Knock-out;Lead;Lipids;Lipoproteins;Metabolism;Mice Knockout;Mice Transgenic;Mitochondria;Mus;Muscle Cells;Nucleotides;Organ;Patients;Phenotype;Physiological;Plasma;Protein Family;Protein Overexpression;Proteins;RNA Binding;RNA Splicing;RNA Messenger;RNA-Binding Proteins;Regulation;Research Personnel;Site;Thyroid Hormones;Tissues;Transgenes;Translational Regulation;Translational Repression;Translations;Triglycerides;Triiodothyronine;Untranslated Regions;Very low density lipoprotein;base;genetic manipulation;improved;insulin sensitivity;lipid metabolism;lipoprotein lipase;member;prevent;programs;protein expression;response


application_id: 7824860
project_number: 1RC1DK087456-01
project_title: Slit2-mediated expansion of primitive hematopoietic stem cell populations for tra
administering_ic: NIDDK
award_notice_date: 2010-03-15
opportunity_number: RFA-OD-09-003
application_type: 1
activity_code: RC1
ic: DK
serial_number: 087456
program_official: WRIGHT, DANIEL G
project_start_date: 2010-03-15
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZRG1 VH-D (58)]
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Funding Agency: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Challenge Area - (11) Regenerative Medicine Specific challenge topic - 11-DK-101 Promote regeneration and repair in the digestive system liver pancrease kidneys hematologic and urological system. 3. Project Title: Slit2-mediated expansion of primitive hematopoietic stem cell populations for transplantation and hematopoietic recovery Hematopoietic Stem Cells (HSCs) integrate signals from the niche with cell intrinsic regulatory programs to maintain the endogenous HSC pool. Regulation of stem cell-niche interactions influences the entire lymphohematopoietic system and ultimately the organism making characterization of these pathways fundamental to the pursuit of novel therapeutic interventions involving adult stem cells. Based on natural variation in absolute numbers of HSCs in inbred mice we initiated a forward genetic study that revealed a quantitative trait locus on chromosome 5 (Chr5) linked to the determination of HSC numbers in C57B/L6 (B6) and DBA/2 (D2) mice. Phenotypic analysis of strains congenic for the chromosome 5 QTL confirmed that D2 alleles in that region produce a 2.4-fold increase in HSC numbers while B6 alleles confer a 1.7-fold decrease in HSCs. We performed microarray and RT-PCR analysis to identify candidate HSC-regulatory genes in the Chr5 QTL region based on gene expression patterns. We found that a single transcript Slit2 was differentially expressed at a significant level and positively correlated to HSC numbers. A retrovirus was used to stably infect B6 bone marrow cells which normally do not express Slit2 with a Slit2-containing GFP vector. Infected cells were transplanted into B6 hosts and expanded in vivo for 12 weeks ensuring reconstitution of the complete hematopoietic hierarchy within the GFP+ fraction. In vitro quantification demonstrated that ectopic expression of Slit2 produces a 4-fold increase in HSC numbers relative to an empty vector control. These results provide evidence that Slit2 is a novel regulator of murine hematopoiesis and a potential target for therapeutic intervention in the treatment of a variety of human diseases. Given the pivotal role of Slit/Robo signaling in cell-cell interactions and known antagonism of the CXCL12/CXCR4 axis we predict that Slit2- mediated regulation of HSCs is accomplished by alterations in HSC-niche interactions. Proposed studies will determine how Slit2 expression influences HSCs within the niche to promote expansion of the HSC pool and how Slit2 expression is regulated in HSCs. We propose three aims: The first is to determine the mechanisms by which SLIT2 regulates stem cell number. Self-renewal is of particular interest. The second is to determine how the differential expression of the Slit2 gene is regulated with particular focus on transcription factor binding. The third aim will examine the therapeutic potential of modulating Slit2 expression. A mouse knockout model will be employed. The effects on stem cell localization within the bone marrow will be determined using imaging techniques.  
   
PUBLIC HEALTH RELEVANCE:  This proposal investigates the role of Slit2 in regulating the number and location of hematopoietic stem cells within the bone marrow. In three specific aims we will investigate the mechanism(s) by which Slit2 regulates stem cell number with special  
attention to self-renewal. In the second aim we will investigate the mechanism(s) by  
which Slit2 expression is regulated in hematopoietic cells. In the third aim the therapeutic  
potential of altering Slit2 expression will be investigated in a knockout mouse model and  
using imaging techniques to localize stem cells in the bone marrow.

project_terms:
5' Untranslated Regions;A Mouse;Alleles;American;Architecture;Area;Attention;Autoimmunity;Binding (Molecular Function);Binding Sites;Biological Assay;Bone Marrow;Bone Marrow Cells;Breeding;Cell Communication;Cell Count;Cell Death;Cell physiology;Cells;Chromosomes Human Pair 5;Computer Simulation;Congenic Strain;Core Facility;CpG Islands;Defect;Drosophila sli protein;Ectopic Expression;Engraftment;Ensure;Equilibrium;Funding Agency;GTP Binding;Gene Expression;Generations;Genes;Genetic;Genetic Polymorphism;Genome;Goals;Healthcare;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Homing;Imagery;Imaging Techniques;In Vitro;In-Migration;Inbred Mouse;Indium;Kentucky;Kidney;Knock-out;Knockout Mice;Link;Liver;Location;Luciferases;Mediating;Methylation;Migration Assay;Modeling;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Natural regeneration;Organism;Pancreas;Pancrease;Pathway interactions;Pattern;Physiological;Process;Promotor (Genetics);Quantitative Trait Loci;Recombinants;Recovery;Regenerative Medicine;Regulation;Regulator Genes;Relative (related person);Reporter;Retroviridae;Reverse Transcriptase Polymerase Chain Reaction;Role;Signal Pathway;Signal Transduction;Stem cells;System;Testing;Therapeutic;Therapeutic Intervention;Transcript;Transgenic Mice;Transgenic Organisms;Transplantation;Universities;Variant;adult stem cell;base;cancer therapy;clinically relevant;congenic;gastrointestinal system;human disease;improved;in vivo;interest;method development;mouse model;novel;novel therapeutic intervention;programs;public health relevance;reconstitution;repaired;self-renewal;sodium bisulfite;stem;stem cell niche;stem cell population;transcription factor;urologic;vector;vector control

public_health_relevance:
PROJECT NARRATIVEThis proposal investigates the role of Slit2 in regulating the number and location ofhematopoietic stem cells within the bone marrow. In three specific aims we willinvestigate the mechanism(s) by which Slit2 regulates stem cell number with specialattention to self-renewal. In the second aim we will investigate the mechanism(s) bywhich Slit2 expression is regulated in hematopoietic cells. In the third aim the therapeuticpotential of altering Slit2 expression will be investigated in a knockout mouse model andusing imaging techniques to localize stem cells in the bone marrow.


application_id: 7824216
project_number: N01PC54403-16-0-1
project_title: Surveillance Epidemiology and End Results (SEER) Program - Kentucky
administering_ic: NCI
project_start_date: 2005-08-01
project_end_date: 2010-07-31
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI) is an authoritative source of information on cancer incidence and survival in the United States. SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 26 percent of the US population. SEER coverage includes 23 percent of African Americans 40 percent of Hispanic Americans 42 percent of American Indians and Alaska Natives 53 percent of Asians and 70 percent of Hawaiian and Pacific Island Americans. The current SEER data maintained at NCI includes records on 5.4 million cancers. The database serves as important resource for reporting on the burden of cancer and is utilized by researchers both within and outside of NCI for the purpose of conducting descriptive epidemiologic studies.
The SEER Program is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. 
The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. The SEER Program has among its objectives: 
1. To assemble and report on a periodic basis estimates of cancer incidence.
2. To monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 
3. To provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 
4. To identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 
5. To serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as problems related to the operation of the SEER Program.


application_id: 7824144
project_number: N01DA68866-10-0-1
project_title: Development & Manufacture of Pharmaceutical Products for Addiction Treatment
administering_ic: NIDA
project_start_date: 2006-09-17
project_end_date: 2010-09-17
contact_pi_person_id: 8538852
contact_pi: MURTY, RAM B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of this contract is to carry out the development & manufacture of pharmaceutical preparations to be used in the medications develoopment program of the National Institute on Drug Abuse (NIDA) for addiction treatment.


application_id: 7822693
project_number: 5R01EB007556-05
project_title: Fabricated Microvascular Networks
administering_ic: NIBIB
award_notice_date: 2010-04-26
opportunity_number: PAR-06-504
application_type: 5
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;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;design;implantation;in vivo;indexing;insight;lithography;research study;scaffold;tool


application_id: 7822378
project_number: 3R01AA014623-04S1
project_title: Zinc and Alcohol-Induced Oxidative Liver Injury
administering_ic: NIAAA
award_notice_date: 2009-06-10
opportunity_number: PA-02-035
application_type: 3
activity_code: R01
ic: AA
serial_number: 014623
suffix: S1
program_official: OROSZ, ANDRAS
project_start_date: 2005-08-10
project_end_date: 2010-05-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 6870954
contact_pi: ZHOU, ZHANXIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Alcoholic liver disease (ALD) is a major health problem but well-established and effective forms of therapy are lacking. Our long-term goal is to develop therapeutic agents that effectively correct the fundamental cellular disturbances resulting from excessive alcohol consumption. A number of hypotheses regarding the mechanisms by which alcohol causes cell injury have been suggested with oxidative stress being a leading putative etiologic factor. Thus antioxidant therapy has gained increasing attention in prevention of ALD. Zinc is an essential trace element with potent antioxidant functions. Cellular zinc homeostasis is regulated by metallothionein (MT). The MT-bound zinc can be released under oxidative stress condition. Hepatic zinc depletion in liver has long been noted in alcoholic liver disease. A mechanistic link between hepatic zinc depletion and cell injury however has not been established. This project proposes to test the hypothesis that hepatic zinc depletion is a critical mediator in alcohol-induced oxidative stress thus zinc supplementation should attenuate alcohol-induced oxidative liver injury. A novel MT-null (MT-KO) mouse model along with wild type 129/Sv mice will be chronically fed liquid alcohol diet. The specific aims are as follow: (1) To define the importance of hepatic zinc depletion in the development of ALD the effect of dietary zinc deficiency and its supplementation on hepatic zinc status and oxidative liver injury will be determined in mice after chronic alcohol exposure: (2) To evaluate the therapeutic potential of zinc in controlling ALD the effects of dietary zinc supplementation on alcohol-induced liver injury in mice previously exposed to alcohol will be examined; (3) To determine whether zinc protects against ALD through inhibition of oxidative stress the effects of dietary zinc supplementation on ROS accumulation ROS-generating and ROS-scavenging systems in the liver will be analyzed in mice after chronic alcohol exposure; (4) To understand the molecular mechanisms by which zinc inhibits alcohol-induced oxidative stress the effects of dietary zinc supplementation on gene expression in the liver will be determined by DMA microarray and Real-Time RTPCR. The effects of zinc on the activities of zinc finger transcription factors also will be examined. These studies will provide fundamental understanding of the role of zinc in the pathophysiology of ALD and pave the way to novel therapeutical approaches to prevention and treatment of this disease.

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


application_id: 7821380
project_number: 5R01CA129967-02
project_title: Amplification of tumor hypoxic responses by MIF-dependent HIF stabilization
administering_ic: NCI
award_notice_date: 2010-02-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129967
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2009-05-01
project_end_date: 2014-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has the grim distinction of being one of the most prognostically unfavorable human cancers. It has been suggested that low oxygen tensions within PDAC tumors contribute significantly to its metastatic potential and chemotherapeutic resistance. Hypoxia-inducible factors (HIFs) transcribe gene products that contribute to metabolic adaptation neo-angiogenic potential metastatic spread and therapeutic resistance. We recently discovered that macrophage migration inhibitory factor (MIF) one of the oldest cytokines ever described is elevated in PDAC patient's plasma and induced by hypoxia-induced HIF-1a-dependent transcription in pancreatic cancer cells. Intriguingly MIF was found to reciprocally modulate hypoxia- induced HIF-1a stabilization. Several human PDAC cell lines transfected with siRNA against MIF recapitulate MIF-/- fibroblasts in defective hypoxia-induced HIF-1a stabilization and subsequent HIF-dependent transcription. Moreover MIF-deficient PDAC cells display defective xenograft tumor outgrowth less HIF-1a and significantly reduced microvascular density than MIF-containing xenografts. Finally our results indicate that MIF promotes HIF-1a stability by functionally regulating a subunit of the COP9 signalosome CSN5 in repressing a unique HIF-1-specific ubiquitin E3 ligase. Our central hypothesis is that MIF overexpression in pancreatic adenocarcinoma lesions acts to modulate either the levels or activity of free CSN5 that in turn serves to repress or mask a unique oxygen-independent ubiquitin E3 ligase specific for HIF-1a. Studies outlined in this application seek to identify the contribution and requirements for MIF in PDAC growth pathophysiology and hypoxic adaptation. We will additionally delineate the precise mechanisms and molecular determinants involved in MIF-dependent HIF-1 stabilization. In order to fulfill the stated objectives of this application the following experimental aims are proposed: 1) Elucidate the basic mechanism by which MIF contributes to hypoxia-induced HIF-1a stabilization 2) Define the molecular determinants and effectors of HIF-1 degradation in MIF-deficient cells and 3) Determine if MIF contributes to pancreatic ductal adenocarcinoma growth pathophysiology and hypoxic adaptation. PUBLIC HEALTH RELEVANCE: All solid tumors require microenvironmental adaptation throughout tumorigenesis. One of the hallmarks of this adaptive response is the development of intratumoral hypoxia that stimulates HIF-directed expression of pro-angiogenic/metastatic gene products. Our findings establish that one of these gene products MIF is elevated in the plasma of a subset of pancreatic cancer patients. We further describe a unique functional inter-relationship between the extracellular cytokine/growth factor MIF and the transcription factor HIF-1a in pancreatic ductal adenocarcinoma (PDAC) cells. This point is demonstrated by our data showing that cells lacking MIF exhibit defective hypoxia and PHD inhibitor-induced HIF-1a stabilization and subsequent transcription of metabolic and angiogenic gene products. More importantly xenograft mouse models of PDAC tumorigenesis reveal that MIF-deficient tumor outgrowth HIF-1a expression and tumor-associated angiogenesis are severely impaired when compared to cells containing MIF. Because HIF expression contributes directly to tumor aggressiveness and cancers of the pancreas are reportedly very hypoxic it is likely that MIF functionally contributes to tumor maintenance environmental adaptation and ultimately prognosis of pancreatic adenocarcinoma patients.

project_terms:
Ablation;Adenocarcinoma Cell;Apoptosis;Binding (Molecular Function);Biochemical;Cancer Patient;Cell Line;Cells;Complement;Complex;Cullin Proteins;Data;Development;Disease Progression;Exhibits;Fibrinogen;Functional disorder;Gene Targeting;Genetic;Genetic Transcription;Growth;Growth Factor;Human;Hypoxia;Hypoxia Inducible Factor;Image;In Situ Nick-End Labeling;In Vitro;In-Migration;Injection of therapeutic agent;JAB1 protein;Laboratories;Lesion;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Masks;Mediating;Metabolic;Migration Inhibitory Factor;Molecular;Mus;Mutant Strains Mice;Neoplasm Metastasis;Nude Mice;Oxygen;Oxygen measurement partial pressure arterial;PECAM1 gene;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathology;Pathway interactions;Patients;Pimonidazole;Plasma;Post-Translational Protein Processing;Proteins;Relative (related person);Resistance;Role;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Staining method;Stains;Subgroup;TP53 gene;Therapeutic;Transgenes;Transgenic Mice;Tumor Burden;Vascular Endothelial Growth Factors;Work;Xenograft procedure;angiogenesis;base;cancer cell;cell motility;cytokine;density;environmental adaptation;extracellular;fibroblast migration inhibitory factor;human cancer mouse model;hypoxia inducible factor 1;in vivo;inhibitor/antagonist;mouse model;neovascularization;novel;outcome forecast;overexpression;pancreatic neoplasm;phenylpyruvate tautomerase;prevent;protein degradation;public health relevance;response;transcription factor;tumor;tumor progression;tumor xenograft;tumorigenesis;ubiquitin ligase;ubiquitin-protein ligase


application_id: 7818520
project_number: 3R01DE009761-17S1
project_title: Bacterial Proteinases in Periodontal Disease
administering_ic: NIDCR
award_notice_date: 2009-09-25
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DE
serial_number: 009761
suffix: S1
program_official: LUNSFORD, DWAYNE
project_start_date: 2009-09-25
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-K (95)]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN 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
project_abstract:
DESCRIPTION (provided by applicant): We have recently identified a novel protein secretion pathway (proposed to be a Type IX Secretion System; T9SS) employed by periodontopathogens including Porphyromonas gingivalis Prevotella intermedia and Tannerella forsythia to secrete a number of virulence factors. Progress on our current parent R01 grant has revealed the presence of 3 to 5 new essential components participating in the gingipains secretion pathway utilized by P. gingivalis. Interestingly a large number of the newly identified genes along with those already reported apparently encode for putative integral outer membrane (OM) beta-barrel proteins. The requirement of several beta-barrel OM proteins for secretion is unique for T9SS and sets this OM translocation apparatus apart from eight other known secretion system in Gram-negative bacteria. In this application responding to NOT-OD-09-058 (Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) we will: (i) verify transmembrane topology of integral OM beta-barrel proteins; (ii) investigate the subcellular location of other proteins essential for gingipains secretion; (iii) determine the secretome of P. gingivalis P. intermedia and T. forsythia which is dependent on T9SS (iv) perform an initial characterization on proteases of T. forsythia bearing unique domain structure which are most likely secreted via T9SS.  
  
PUBLIC HEALTH RELEVANCE: The results of these proposed studies should yield important information on unique proteases of T. forsythia which may function as virulence factors and shade light on a novel pathway for the protein secretion by P. gingivalis T. forsythia and P. intermedia. This insight may enable the design of antibodies or chemical compounds to block the export of multiple virulence factors from major periodontopathogens which in the long term may revolutionize treatment and prophylaxis of periodontal disease.

project_terms:
Antibodies;Bacteria;Biogenesis;C-terminal;Cell surface;Chemicals;Complex;Cytoplasm;Environment;Eukaryotic Cell;Extracellular Protein;Forsythia;Funding;Genes;Genome;Gram-Negative Bacteria;Grant;Individual;Light;Location;Membrane;Membrane Proteins;Messenger RNA;Molecular Chaperones;Parents;Pathogenesis;Pathway interactions;Peptide Hydrolases;Peptide Signal Sequences;Periodontal Diseases;Porphyromonas gingivalis;Prevotella intermedia;Process;Properdin;Prophylactic treatment;Protein Secretion;Proteins;Recovery;Reporting;Research;Structure;Surface;System;Tertiary Protein Structure;United States National Institutes of Health;Virulence Factors;appendage;beta barrel;design;extracellular;fimbria;insight;novel;pathogen;periodontopathogen;periplasm;proteinase In;public health relevance

public_health_relevance:
The results of these proposed studies should yield important information on unique proteases of T.forsythia which may function as virulence factors and shade light on a novel pathway for the proteinsecretion by P. gingivalis T. forsythia and P. intermedia. This insight may enable the design ofantibodies or chemical compounds to block the export of multiple virulence factors from majorperiodontopathogens which in the long term may revolutionize treatment and prophylaxis ofperiodontal disease.


application_id: 7813880
project_number: 3R01DE019243-02S1
project_title: Mathematical Model of Parotid Acinar Differentiation
administering_ic: NIDCR
award_notice_date: 2009-09-21
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DE
serial_number: 019243
suffix: S1
program_official: BURGOON, PENNY W
project_start_date: 2009-09-21
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZDE1 JH (30)]
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
project_abstract:
DESCRIPTION (provided by applicant): This application is in response to NOT-OD-09-058 titled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." This Competitive Revision application proposes an additional Specific Aim for the original R01 project. The long term goal of our project is to define the development of signaling networks that induce differentiation of cells into mature salivary serous acinar cells. Millions of patients suffer loss of salivary gland function due to Sjogren's syndrome or radiation therapy. Understanding the differentiation of salivary cells is a necessary step to enable the restoration of diseased or destroyed parotid salivary tissue. Our overall hypothesis for the parent project is that a mathematical model can identify key regulatory pathways that control parotid acinar cell differentiation. The goal of the existing project is to develop IPA-based mathematical and statistical models that will identify gene networks which cause terminal differentiation of parotid acinar cells. The dynamical mathematical models will serve to generate hypotheses which will be reiteratively tested and the model will be repeatedly refined by the incorporation of new data. Both Affymetrix microarrays and miRNA arrays are being used to create biological networks with Ingenuity Pathway Analysis and Genespring programs. These networks are used to create coupled Ordinary Differential Equation (ODE) models to describe the process of differentiation. A difficulty in any biological modeling project is finding the appropriate networks. Specific Aim #1R for this Competitive Revision proposes to develop an unbiased statistical approach to derive genetic networks from array data. The approach is based on recently developed methods for genetic network discovery based on algebraic analysis of the statistically significant interactions in the mathematical network without the need of precisely fitting all the model parameters. This novel method is based on two recent publications by the Co-PI Dr. Rempala where it is shown to be highly robust against misclassification and capable of correctly identify the network from noisy and incomplete data. The new modeling component will be supported by generating additional microarray results to use for training and validation as well as RT-PCR and transfection studies to validate the derived network. The additional statistical and biological results will add a new dimension to the original project and will speed progress in defining the molecular pathways that drive cytodifferentiation of parotid acinar cells. In addition the unbiased statistical approach to discovering biological networks will be applicable to study of other tissues and pathologies.  
  
PUBLIC HEALTH RELEVANCE:  The overall goal of this research is to define the molecular mechanisms which control differentiation of cells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer from salivary gland dysfunction due to Sj"gren's Syndrome radiation therapy or xerostomia due to essential medications. This research is a necessary foundation for developing new technologies such as gene transfer therapy and biologics for treating or alleviating the oral symptoms of xerostomia.

project_terms:
Acinar Cell;Address;Algorithms;American;Biological;Biological Models;Biological Response Modifier Therapy;Calibration;Cell Differentiation process;Computer Simulation;Coupled;Data;Development;Dimensions;Equation;Foundations;Functional disorder;Funding;Gene Transfer;Genes;Genetic;Goals;Hybrids;Methods;MicroRNAs;Modeling;Molecular;Muscle;Natural regeneration;Network-based;Neurons;Oral;Parotid Gland;Pathology;Pathway Analysis;Pathway interactions;Patients;Pharmaceutical Preparations;Process;Publications;Radiation therapy;Recovery;Regulation;Regulatory Pathway;Research;Reverse Transcriptase Polymerase Chain Reaction;Salivary;Salivary Glands;Serous;Signal Pathway;Signal Transduction;Sjogren's Syndrome;Speed (motion);Statistical Models;Symptoms;Syndrome;Testing;Tissues;Training;Transfection;United States National Institutes of Health;Validation;Xerostomia;base;cell type;computer based statistical methods;genome-wide;mathematical model;network models;new technology;novel;parent grant;parent project;parotid cell;programs;public health relevance;research study;response;restoration;salivary acinar cell;salivary cell;tool

public_health_relevance:
Project Narrative. The overall goal of this research is to define the molecular mechanisms which control differentiation ofcells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer fromsalivary gland dysfunction due to Sjgren's Syndrome due to radiation therapy or to medication-inducedxerostomia. This research is a necessary foundation to for developing new technologies such as gene transfertherapy and biologics for treating or alleviating the oral symptoms of xerostomia.


application_id: 7813836
project_number: 5R21CA141190-02
project_title: Regulation of immune reactions by synthetic thioglucans
administering_ic: NCI
award_notice_date: 2010-05-13
opportunity_number: PA-06-400
application_type: 5
activity_code: R21
ic: CA
serial_number: 141190
program_official: WELCH, ANTHONY R
project_start_date: 2009-05-01
project_end_date: 2012-04-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 1865667
contact_pi: VETVICKA, VACLAV
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The major objective of this proposal is to develop characterize and test new synthetic version of a natural immunomodulator 2-glucan. Natural products useful in preventing and/or treating disease have been studied for a long time. Despite promising clinical trials and lack of understanding of their mechanism dampened enthusiasm. Natural glucans are large molecules with a low affinity for CR3 and have undesirable side effects because their large size enables them to cross-link CR3 stimulating a strong release of proinflammatory cytokines. Unfortunately it has not been possible to generate small fragments of natural 2- glucan in a reproducible manner. The mechanisms of glucan actions were never fully established. The novel aims of our project involve: 1) synthesis of new never before tested thioglucans; 2) comprehensive evaluation of cytokine stimulation; 3) the understanding of the absorption mechanisms leading to oral treatment for clinical practice; 4) evaluation of genomic. Aim #1 To design and synthesize new class of oligosaccharides. Main goal is to optimize chemical structures of oligo-2-(13)-glucans in order to improve stimulation of the immune system by: 1) increasing stability of oligoglucans so that the probability of interactions between the immunostimulating agent and its receptor also increases; and 2) inducing better molecular interactions between glucans and their receptors present on immunocompetent cells. Aim #2 Determine the biological characteristics of small synthetic thioglucans. This goal will be achieved using four approaches: 1) evaluate their binding to the CR3 and Dectin-1 receptor; 2) determine their effects on induction of 13 different cytokines; 3) evaluation of the absorption and tissue distribution of orally administered glucans; and 4) comparing gene expression profiles between glucan-treated and untreated cells using microarray technology and evaluation of possible signaling pathways. Data from the proposed project will provide crucial understanding of the correlation between structure of quantitatively novel thioglucans and their effects on immune reactions as well as important new information on the mechanisms by which glucans affect the cells. This project thus may lead to the new tumor therapy. PUBLIC HEALTH RELEVANCE: b-Glucan is a well-known biological response modifier that has been used as adjuvant therapy for cancer since 1980 mostly in Japan. b-Glucans also enhance innate host defense against certain bacteria yeast and viral pathogens. In addition glucans are considered to be important prophylaxis against irradiation. In summary b-glucan might be the most important natural immunomodulator. In this project we propose to prepare improved synthetic oligosaccharides based on glucans and to characterize their biological properties. Based on our preliminary data we hypothesize that these oligosaccharides will be more active and will overcome intrinsic problems with natural b-glucans that make them undesirable as drugs.

project_terms:
Adjuvant Therapy;Adverse effects;Affect;Affinity;Bacteria;Binding (Molecular Function);Biologic Characteristic;Biological;Biological Factors;Biological Response Modifiers;Cells;Charge;Chemical Structure;Clinical Trials;Complement Receptor;Complex Mixtures;Data;Disease;Drug or chemical Tissue Distribution;Evaluation;Experimental Models;Gene Expression;Genomics;Glucans;Goals;Host Defense;Human;Immune;Immune system;Immunocompetent;Immunomodulators;Infection;Japan;Lead;Leukocytes;Macrophage-1 Antigen;Malignant Neoplasms;Membrane;Microarray Analysis;Molecular Profiling;Molecular Weight;Mus;Natural Killer Cells;Oligonucleotides;Oligosaccharides;Oral;Pharmaceutical Preparations;Polymers;Probability;Property;Prophylactic treatment;Protozoa;Reaction;Recording of previous events;Regulation;Research;Signal Pathway;Solubility;Structure;Testing;Time;Viral;Yeasts;absorption;base;cancer therapy;clinical effect;clinical practice;crosslink;cytokine;dectin 1;design;improved;irradiation;macrophage;neutrophil;novel;pathogen;prevent;public health relevance;receptor;tumor

public_health_relevance:
Narrative b-Glucan is a well-known biological response modifier that has been usedas adjuvant therapy for cancer since 1980 mostly in Japan. b-Glucans alsoenhance innate host defense against certain bacteria yeast and viral pathogens.In addition glucans are considered to be important prophylaxis againstirradiation. In summary b-glucan might be the most important naturalimmunomodulator. In this project we propose to prepare improved synthetic oligosaccharidesbased on glucans and to characterize their biological properties. Based on ourpreliminary data we hypothesize that these oligosaccharides will be more activeand will overcome intrinsic problems with natural b-glucans that make themundesirable as drugs.


application_id: 7812703
project_number: 3R42AA015475-03S1
project_title: Potential anti-relapse drugs: a plant genomics approach
administering_ic: NIAAA
award_notice_date: 2009-09-28
opportunity_number: PA-09-081
application_type: 3
activity_code: R42
ic: AA
serial_number: 015475
suffix: S1
program_official: EGLI, MARK
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZAA1 DD (01)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol-induced neurodegeneration and the consequent dementia are important therapeutic targets in alcoholism. However because alcohol-induced neurotoxicity has different mechanisms during the presence of alcohol and during its withdrawal these are difficult targets for pharmacotherapy. Based on preclinical research two types of neuroprotective compound potent anti-oxidants and agonists at alpha7 nicotinic receptors for acetylcholine (nicAChRs) are agents which seem particularly well-suited to this therapeutic challenge. As part of a minor specific aim in the original phase 2 STTR project ("Anti-relapse agents a plant genomics approach")  we have discovered a novel natural product from the native plant Solidago nemoralis which has both of these characteristics and which is highly protective against alcohol-induced toxicity in simple cell culture models. This is tentatively identified as a methyl quercetagetin and there are no previous reports of compounds from this plant species or with similar quercetin-like structures being active at alpha7-nicAChRs or against this type of neurotoxicity. The original project (which focused on anti-relapse properties) was not designed to investigate neuroprotective activity. Under the program NOT-OD-09-058 "NIH announces the availability of Recovery Act funds for competitive revision applications" we now propose to pharmacologically characterize this compound further and to evaluate its therapeutic potential against the neurotoxic effects of alcohol both in in vitro models and in a developmental rodent model in vivo. In addition to this conventional approach we also propose to use a selection procedure based on the cytoprotective anti-oxidant properties of this compound to generate mutant plant cell cultures which overproduce this activity. This was not a part of the original proposal because we had no idea that we would discover a structure which combined these properties! This supplement will enable us to employ two postdoctoral researchers to cover the additional research and will enable us to accelerate the investigation of this novel neuroprotective agent in alcoholism. The development of novel medications for alcoholism is a stated priority for NIAAA and for NIH.  
  
PUBLIC HEALTH RELEVANCE: Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications The dementia associated with alcoholism is a major but largely unrecognized clinical problem probably rivaling Alzheimer's Dementia in incidence in the USA. There are no recognized treatments and this probably impacts the low rate of diagnosis of the condition. Basic research suggests that two types of pharmacological activity are of most potential therapeutic value and somewhat serendipitously we have discovered a natural product molecule which appears to have both of these properties. This proposal is to characterize this molecule more fully and to begin to evaluate its potential as a neuroprotective drug in alcoholism. Since ultimately the best treatment for alcoholism is a marked reduction in consumption we envisage this product being used as a part of a pharmacotherapeutic and behavioral program aimed at abstinence or at a reduction of alcohol consumption from pathological levels.

project_terms:
Abstinence;Address;Affinity;Agonist;Alcohol consumption;Alcohol withdrawal syndrome;Alcohol-Induced Neurotoxicity;Alcoholism;Alcohols;Alzheimer's Disease;Antioxidants;Basic Science;Behavioral;Binding (Molecular Function);Biological Assay;Biological Factors;Carbon;Cell Culture Techniques;Cell Line;Cells;Characteristics;Chemicals;Clinical;Column Chromatography;Complex;Consumption;Data;Dementia;Development;Diagnosis;Flavonoids;Funding;Genomics;Harvest;Hippocampus (Brain);Human;Incidence;Investigation;Ligands;Measures;Methods;Minor;Modeling;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;National Institute on Alcohol Abuse and Alcoholism;Neonatal;Nerve Degeneration;Neuroblastoma;Neurons;Neuroprotective Agents;Oxidants;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Phase;Plants;Population;Positioning Attribute;Procedures;Property;Protons;Quercetin;Rattus;Recovery;Relapse;Reporting;Research;Research Personnel;Resistance;Rodent Model;Scheme;Small Business Technology Transfer Research;Solidago;Structure;Testing;Therapeutic;Time;Toxic effect;United States National Institutes of Health;Withdrawal;alcohol effect;alcoholism therapy;alpha-bungarotoxin receptor;base;chemical synthesis;design;drug relapse;fluoromethyl 22-difluoro-1-(trifluoromethyl)vinyl ether;in vitro Model;in vivo;in vivo Model;inhibitor/antagonist;member;methyl group;mutant;neonate;neuroprotection;neurotoxic;neurotoxicity;novel;pre-clinical research;prevent;programs;public health relevance;radioligand;receptor;sephadex;therapeutic target

public_health_relevance:
Project narrativeNotice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery ActFunds for Competitive Revision ApplicationsThe dementia associated with alcoholism is a major but largely unrecognized clinical problem probablyrivaling Alzheimer's Dementia in incidence in the USA. There are no recognized treatments and this probablyimpacts the low rate of diagnosis of the condition. Basic research suggests that two types of pharmacologicalactivity are of most potential therapeutic value and somewhat serendipitously we have discovered a naturalproduct molecule which appears to have both of these properties. This proposal is to characterize thismolecule more fully and to begin to evaluate its potential as a neuroprotective drug in alcoholism. Sinceultimately the best treatment for alcoholism is a marked reduction in consumption we envisage this productbeing used as a part of a pharmacotherapeutic and behavioral program aimed at abstinence or at a reductionof alcohol consumption from pathological levels.


application_id: 7812207
project_number: 5K01NR010239-03
project_title: Older Mothers and Adult Daughters: High Blood Pressure Self Management Behaviors
administering_ic: NINR
award_notice_date: 2010-04-08
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: NR
serial_number: 010239
program_official: HUSS, KAREN
project_start_date: 2008-05-01
project_end_date: 2012-04-30
study_section: Nursing Science Review Committee[NRRC(40)]
contact_pi_person_id: 8639560
contact_pi: SHAWLER, CELESTE
other_pis: Not Applicable
congressional_district: 03
department: NONE
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 NURSING
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in American women. Kentucky ranks as the 6 highest state in the nation for heart disease among women. This program of research will advance the initiatives of Healthy People 2010 by assisting women to develop self management behaviors to reduce and moderate hypertension a major risk factor for heart disease. The long-term aim of this program of research is to determine the causal relationships of inner strength perceived control and quality of the relationship of older mothers and their adult daughters so that nursing interventions can be developed to improve cardiovascular self management behaviors and health related quality of life. The specific aim of this longitudinal predictive study is to determine the impact of inner strength perceived control and the quality of the relationship of older mothers and their adult daughters on blood pressure self management behaviors and health related quality of life. To achieve these goals the candidate has designed a comprehensive training program with experienced nurse researchers who will facilitate the development of the candidate's expertise in the theoretical perspectives of chronic illness management specifically blood pressure self management and health related quality of life. The candidate will complete formal coursework and planned interactions and meetings with mentors and consultants. In addition the candidate will participate in on-going research seminars prepare and submit scientific publications and present at scientific sessions. Mentors will be Dr. Debra Moser Professor U. of Kentucky and Dr. Neville Strumpf Professor U. of Pennsylvania. The proposed training and research environments are: the College of Nursing and Sanders Brown Center on Aging at the U. of Kentucky Lexington Kentucky; Hartford Center for Geriatric Nursing Excellence: U. of Pennsylvania Philadelphia Pennsylvania; and U. of Louisville School of Nursing Louisville Kentucky. The candidate will apply the knowledge gained from the training program to develop a program of research designed to enhance blood pressure self management behaviors of older women with hypertension. The aims of the proposed study are to: (1) Use dyadic analysis to examine the direct (i.e. 'actor') and indirect (i.e. 'partner') effects of mothers' and daughters' inner strength on the outcomes of self management strategies for blood pressure and health related quality of life in both mothers and daughters measured at baseline and 6 months later and to determine whether there are significant changes over time in the outcomes; (2) To determine using dyadic analysis whether perceived control mediates the relationship between inner strength and outcomes in mothers and daughters; (3) To determine using dyadic analysis whether the mother-daughter relationship mediates the relationship between inner strength and outcomes in mothers and daughters; (4) To determine using dyadic analysis if there is a significant relationship between perceived control and quality of the mother-daughter relationship. The findings from this study will be used to support a program of theory-based nursing intervention studies designed to increase blood pressure self management behaviors of mother-daughter dyads when the older woman is diagnosed with hypertension. The adult daughter may or may not be diagnosed with hypertension and the study is designed to compare relationships whether or not daughters are diagnosed with hypertension. Previous work by the candidate demonstrated that inner strength was a key concept for older women and their adult daughters in managing health crisis. The candidate plans to further examine the significance of inner strength and modifiable health behaviors of older women with hypertension.

project_terms:
Adult;Adult Children;Aerobic;Age;Aging;American;Behavior;Blood;Blood Pressure;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Characteristics;Cholesterol;Chronic Disease;Cognitive;Comorbidity;Daughter;Development;Diagnosis;Diet;Discipline of Nursing;Eating;Educational aspects;Elderly;Environment;Exhibits;Fatty acid glycerol esters;Geriatric Nursing;Goals;Health;Health behavior;Healthy People 2010;Heart Diseases;Heart failure;Hypertension;Intake;Intervention;Intervention Studies;Kentucky;Killings;Knowledge;Life;Measures;Mediating;Mentors;Mothers;Myocardial Infarction;Nurses;Outcome;Pennsylvania;Philadelphia;Physical activity;Prevention;Prevention strategy;Primary Prevention;Prophylactic treatment;Publications;Quality Control;Recording of previous events;Research;Research Design;Research Personnel;Research Training;Risk;Risk Factors;School Nursing;Secondary Prevention;Self Management;Sodium;Time;Training Programs;United States;Weight;Woman;Work;base;college;design;experience;fruits and vegetables;health related quality of life;improved;lifestyle intervention;meetings;nursing intervention;older women;physical conditioning;prevent;professor;programs;stroke;theories


application_id: 7812204
project_number: 5R01HL083122-04
project_title: Prostanoid-dependent abdominal aortic aneurysm formation
administering_ic: NHLBI
award_notice_date: 2010-05-06
application_type: 5
activity_code: R01
ic: HL
serial_number: 083122
program_official: TOLUNAY, ESER
project_start_date: 2007-05-01
project_end_date: 2013-04-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8351945
contact_pi: LOFTIN, CHARLES DAVID
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Our recent report together with our preliminary studies show that genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) reduces the incidence and severity of AAAs in mice chronically infused with angiotensin II (Angll). Furthermore significant COX-2 expression is increased in AAAs as compared to the uninvolved aorta. Our preliminary studies also show that the expression of the PGE2 receptor EP4 is significantly increased in aneurysmal tissue. However the role of the prostanoid receptors in AAA formation is not clearly defined. The long-term objectives of this proposal are to elucidate mechanisms by which prostanoids contribute to AAAs. We propose the hypothesis that COX-2 participates in all stages of Angll- induced AAA development through preferential synthesis of PGE2 and TXA2 which specifically activate EP4 and TP receptors respectively. This hypothesis is based on previous observations that a) Explant cultures from human AAAs express significant levels of COX-2. b) PGE2 contributes to vascular pathology by increasing expression and/or activation of matrix metalloproteinases and inducing smooth muscle cell apoptosis. c) TXA2 increases adhesion molecule expression and contributes to influx of macrophages in the vessel wall. Therefore we propose the following specific aims: 1) Determine the role of COX-2 at multiple stages of AAA formation. These studies will use mice genetically deficient in COX-2 as well as the COX-2- specific inhibitor celecoxib. 2) Determine the effect of genetic deficiency of the prostanoid receptors EP4 and TP on AAA formation. These studies will provide a mechanistic view of the role of COX-2-dependent prostanoids and will provide insight into the development of novel therapeutics for AAAs. The objectives of the proposed studies are to identify new treatments for abdominal aortic aneurysms (AAAs). AAAs are a life-threatening disease which afflict approximately 5% of the male population over the age of 65 and once the disease has formed there is an increased chance for rupture of the aorta an event which most people do not survive. The cause of aortic aneurysms in humans is not known but is thought to involve inflammation within the wall of the aorta. Therefore we will use an animal model of this disease to determine the mechanisms by which this disease occurs in humans. These studies are important as they will help identify non-surgical treatments for this disease in humans.

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


application_id: 7810738
project_number: 5R01HL071010-08
project_title: Mechanism of Vascular Remodeling in Hyperhomocysteinemia
administering_ic: NHLBI
award_notice_date: 2010-03-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 071010
program_official: ERSHOW, ABBY
project_start_date: 2002-06-01
project_end_date: 2012-03-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Elevated plasma levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) cause vascular disease. The long-term objective of this project is to understand the mechanism of vascular remodeling in HHcy. Studies from the previous funding period showed that there is an inverse relationship between plasma Hcy and levels of peroxisome proliferators activated receptor (PPAR) a nuclear receptor which ameliorates vascular endothelial dysfunction. The central hypothesis of this competitive renewal application is that Hcy decreases thioredoxin peroxiredoxin increases NADH oxidase mtNOS activity and reactive oxygen species (ROS) in mitochondria in a gene dose-dependent manner. ROS transduces metalloproteinase activation causing thickening (fibrosis) of the basement membrane rendering ineffective endothelial nitric oxide synthase (eNOS) and promotes endothelial-smooth muscle disconnection/uncoupling by antagonizing PPARy activity. The specific aims to address the central hypothesis are as following: Specific Aim #1: To determine whether by rendering ineffective PPARy Hcy decreases mitochondrial thioredoxin peroxiredoxin increases NADH oxidase mtNOS activity and ROS. The PPARy agonist ciglitazone will be administered to wild type (WT) cystathione (3 synthase (CBS) knockout heterozygote and homozygote (i.e. CBS +/+ CBS - /+ and CBS -/-) PPARy-/+ iNOS-/- p47-/- MMP-9-/- and double knockout mice. Aortic PPARy activity will be measured by EMSA. Levels of mitochondrial ROS will be measured using 2 7-dichlorofluorescein in continuous assay. Peroxiredoxin thioredoxin and NADH oxidase will be measured in situ by Western blot and RT-PCR analyses. Specific Aim #2: To determine whether Hcy increases metalloproteinase activity decreases the elastin/collagen ratio and causes fibrosis by antagonizing PPARy. Metalloproteinase TIMP elastin and collagen will be measured in situ by novel 2-D zymography reverse-zymography real-time RT- PCR and Western blot analysis. Specific Aim #3: To determine whether Hcy attenuates vascular function by increasing iNOS and rendering eNOS ineffective by antagonizing PPARy. Aortic contractile response will be measured. The novelty of this proposal is that it elucidates the mitochondrial mechanism of oxidative stress and vascular remodeling by Hcy. This study will provide new insights into the mechanism of arterial remodeling and will have therapeutic ramifications for vessel wall disease.

project_terms:
3-nitrotyrosine;9-deoxy-delta-9-prostaglandin D2;Abbreviations;Acetylcholine;Address;Agonist;Aorta;Arachidonic Acids;Attenuated;Basement membrane;Biological Assay;Blood Vessels;Blood flow;Bradykinin;Breeding;Caliber;Collagen;Cystathionine;Disease;Disintegrins;Dose;EMSA;Eicosatrienoic Acid;Elastin;Electrodes;Endothelin-1;Extracellular Matrix;Fibrosis;Fluorescein;Fluoresceins;Functional disorder;Funding;Gelatin;Gelatinase A;Gelatinase B;Genes;Genetic;Goals;Heterozygote;Homo;Homocysteine;Homocystine;Homozygote;Hydroxyeicosatetraenoic Acids;Hyperhomocysteinemia;In Situ;Knock-out;Knockout Mice;Leukotriene B4;Matrix Metalloproteinases;Measures;Mediating;Metalloproteases;Mitochondria;Mus;NADH;NADH oxidase;NF-kappa B;NG-Nitroarginine Methyl Ester;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitroprusside;Nuclear;Nuclear Receptors;Oxidation-Reduction;Oxidative Stress;Peroxisome Proliferator-Activated Receptors;Plasma;Polymerase Chain Reaction;Proteomics;RXR;Reactive Oxygen Species;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Smooth Muscle Myocytes;Smooth muscle (tissue);Stress;Structure;Superoxide Dismutase;Therapeutic;Thick;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Tissues;Vascular Diseases;Vascular remodeling;Western Blotting;arginine methyl ester;arterial remodeling;ciglitazone;ciprofibrate;human AKAP13 protein;human NOS3 protein;in vivo;insight;mouse model;novel;peroxiredoxin;pressure;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;vascular endothelial dysfunction;vasoactive agent


application_id: 7810667
project_number: 5P30NS051220-05
project_title: Core--Pharmacokinetics and Biomarker
administering_ic: NINDS
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9005
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
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: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Research Centers
project_abstract:
The proposed core facility will include a single large room . It will be used for the analysis of the levels of experimental compounds in various biofluids (plasma CSF urine) and tissues (brain spinal cord) in normal or injured rats or mice. For this purpose we will transfer the Shimadzu HPLC with ESA Coulichem electrochemical detector to the Core. However a new state of the art HPLC system with autosampler and electrochemical UV/Vis fluorescence and light scattering detectors is requested in the grant budget for year 4. Secondly the core will be used for carrying out the bioanalytical work associated with exploration of various pathophysiological biomarkers. A major focus will be on the measurement of isoprostanes using GC-MS.The recently purchased Shimadzu GC-MS will be moved to this facility. A microplate reader for protein assays and ELISAs that will be moved to this core. In addition we will continue working on the potential of CSF alpha-spectrin measurements carried out by immunoblot or ELISA. Most of the latter will take place in Dr. Hall's laboratory space outside of the core. In addition all animal surgeries injury procedures and sample collection will take place in the Animal Surgery and TBI/SCI Model Core facility. The Pharmacokinetics & Biomarker Core will only be used for bioanalytical work.

project_terms:
Acute;Affect;Animal Model;Animals;Arachidonic Acids;Arts;Biological Assay;Budgets;Center Core Grants;Cerebrospinal Fluid;Clinical;Clinical Trials;Core Facility;Cytoskeletal Proteins;Detection;Doctor of Philosophy;Dose;Drug Kinetics;Enzyme-Linked Immunosorbent Assay;Evaluation;Faculty;Family;Fluorescence;Free Radicals;Funding;Gas Chromatography;Grant;High Pressure Liquid Chromatography;Immunoblotting;Injury;Intervention;Investigation;Isoprostanes;Laboratories;Lipid Peroxidation;Measurable;Measurement;Measures;Modeling;Monitor;Mus;Neuroprotective Agents;Operative Surgical Procedures;Plasma;Postdoctoral Fellow;Procedures;Process;Proteins;Protocols documentation;Rattus;Reader;Research;Research Personnel;Spectrin;Spinal Cord;System;Techniques;Technology;Testing;Time;Tissues;Translations;Urine;Work;alpha Spectrin;biomarker;brain tissue;detector;injured;light scattering;member;neuroprotection;sample collection;spinal cord and brain injury;urinary;veterinary science


application_id: 7810666
project_number: 5P30NS051220-05
project_title: Core--Microscopy Image Analysis and Stereology
administering_ic: NINDS
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9004
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Research Centers
project_abstract:
As proposed the Microscopy Image Analysis & Stereology Core would be created as an independent core completely separated from the existing Microscopy Facility at this institution. The core would however be equipped with current in-house equipment made available by SCoBIRC faculty including two Olympus Provis AX70 Fluorescence Microscopes (Image Pro interfaced via MagnaFire Digital Camera) Olympus BX 41 with Video Camera Olympus BX 50 Epifluorescent Microscope (Bioquant Stereology package + 3D topographer interfaced with MagnaFire Digital Camera & Optronics Video Camera) Nikon E400 teaching microscopy with DAGE Video Camera. Specifically the proposed Microscopy Image Analysis & Stereology Core will combine the existing equipment which is currently scattered among various NINDS-funded investigators' laboratories with the additional new equipment and dedicated technical oversight. It would also place all these facilities under one administrative structure. Accordingly the proposed core requests the provision of a senior technician who will oversee the use of the image analysis and stereology equipment as well as the desired confocal microscope.

project_terms:
Calendar;Center Core Grants;Educational process of instructing;Equipment;Faculty;Funding;Grant;Guidelines;Housing;Image;Image Analysis;Institution;Laboratories;Microscope;Microscopy;Research;Research Personnel;Schedule;Specific qualifier value;Structure;Supervision;Time;Training;digital;fluorescence microscope;spinal cord and brain injury


application_id: 7810665
project_number: 5P30NS051220-05
project_title: Core-Behavioral Testing
administering_ic: NINDS
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9003
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Research Centers
project_abstract:
SCI Testing Paradigms: Gross locomotor skill will be assessed during open field walking with the 21-point Basso Beattie and Bresnahan (BBB) locomotor recovery scale. The horizontal ladder (Columbus Instruments) will be used to examine hindlimb locomotor function and interlimb coordination. Specific kinetic and kinematic parameters of overground locomotion will be studied and analyzed using a runway device previously described (Muir et al. 1996; Muir and Whishaw 1999). For assessment of sensory function animals will be examined using von Frey hairs for testing tactile sensation and Hargreaves' test for nociception (Stoelting Instruments). The grip strength meter (TSE Systems) is a recently developed apparatus that measures the gripping strength of the front or hind paw of either rats or mice. Blood pressure monitors (Columbus Instruments) will also be required in order to study changes in blood pressure and heart rate in a model of autonomic dysreflexia. TBI Testing Paradigms: The Morris water maze is a well accepted procedure for studying functional deficits and recovery of function following TBI and one room of the Core will be dedicated. Animals will also be tested on additional paradigms including the rotarod test (Columbus Instruments) balance beam and the grip strength meter.

project_terms:
Animals;Area;Autonomic Dysreflexia;Blood Pressure;Blood Pressure Monitors;Calendar;Center Core Grants;Core Facility;Devices;Electronics;Ensure;Equilibrium;Esthesia;Evaluation;Funding;Future;Guidelines;Hair;Heart Rate;Hindlimb;Human Resources;IACUC;Individual;Kinetics;Laboratories;Letters;Locomotion;Locomotor Recovery;Measures;Modeling;Mus;National Institute of Neurological Disorders and Stroke;Neurologic;Operative Surgical Procedures;Pain Measurement;Procedures;Protocols documentation;Qualifying;Rattus;Recovery of Function;Reporting;Research;Research Personnel;Rotarod Performance Test;Schedule;Sensory;Surgical Injuries;System;Tactile;Testing;Time;United States National Institutes of Health;Walking;Work;Writing;animal care;base;behavior test;central nervous system injury;grasp;instrument;kinematics;meter;morris water maze;research study;skills;spinal cord and brain injury


application_id: 7810664
project_number: 5P30NS051220-05
project_title: Core--Animal surgery and TBI /SCI model
administering_ic: NINDS
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9002
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Research Centers
project_abstract:
The Animal Surgery & TBI/SCI Model Core will be available to all members of the center and theirstudents and technicians. Services provided by this core will include: assistance in performing 1) traumatic brain injury using one of the standard closed head injury models (controlled cortical impact fluid percussion Marmarou diffuse impact-acceleration); 2) spinal cord injury (NYU device IH 0400 device OSU device). The facility will be designed to handle both rats and mice with the stipulation that only one species will be present at any given surgery appointment. The core facility will also provided assistance in post-injury animal welfare and care including bladder expression following SCI.

project_terms:
Acceleration;Animal Welfare;Animals;Appointment;Bladder;Caring;Center Core Grants;Closed head injuries;Core Facility;Devices;Diffuse;Injury;Liquid substance;Modeling;Mus;Operative Surgical Procedures;Percussion;Rattus;Research;Services;Spinal cord injury;Students;Traumatic Brain Injury;controlled cortical impact;design;member;spinal cord and brain injury


application_id: 7810663
project_number: 5P30NS051220-05
project_title: Core--Bioinformatics
administering_ic: NINDS
opportunity_number: PAR-02-059
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9001
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Research Centers
project_abstract:
The Bioinformatics Center Core facility will provide an administrative and organizationalframework to support and coordinate Center research cores and related activities and to facilitate increased collaboration among investigators. In addition the Core will maintain a secure server to store and archive scientific data from each of the Center cores and investigators and will provide ongoing support and further development of the existing SCIgenes database.

project_terms:
Archives;Bioinformatics;Center Core Grants;Collaborations;Core Facility;Data;Databases;Development;Reporting;Research;Research Personnel;Secure;spinal cord and brain injury


application_id: 7809531
project_number: 5P01NS058484-03
project_title: Animal
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 9001
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Although multiple lines of experimental evidence implicate calpains in the process of secondaryneurodegeneration following traumatic brain injury (TBI) little is understood about the downstream actions ofcalpains in the injured brain and how these pathways might differ in focal and diffuse TBI. In addition toelucidating novel targets and cellular pathways for calpains in the injured brain the Program will evaluateseveral novel strategies to inhibit posttraumatic calpain activation including enhancing activity of calpastatinknocking out the calpain I isoform and administering small molecule inhibitors. The overall goal of theAnimal Core (Core B) is to facilitate the Program's investigations of calpain-mediated neuropathology andevaluations of calpain inhibitory therapeutic strategies in mouse models of focal and diffuse TBI. To thisendthe Core will perform three specific functions in support of Program objectives: 1) produce consistentpredictable focal or diffuse traumatic brain injuries in mice to be further evaluated in Projects 1 2 and 3 andin Core C 2) provide reliable unbiased assessments of posttraumatic cognitive and motor function in brain-injured and control mice for evaluation of strategies to reduce posttraumatic calpain activation pursued inProjects 1 2 and 3 and 3) maintain and expand as necessary colonies of human calpastatinoverexpressing mice calpastatin deficient mice calpain I knockout mice and cyclophilin D deficient mice foruse in Projects 1 and 3 and Core C. Through these three major functions the Animal Core will increase theefficiency of the Program by reducing redundancy in training personnel and resources and will enhance theability of Projects and Cores to directly compare data by minimizing variability. In addition the Core willprovide behavioral assessments under blinded conditions and will provide centralized management oftransgenic and knockout mouse resources vital to the Program's scientific interests. The activities of theCore are essential to the successful completion of the scientific goals of the Program.

project_terms:
Adult;Animals;Behavior assessment;Behavioral;Blinded;Brain;Brain Injuries;Breeding;Calpain;Calpain I;Cell Culture Techniques;Cognitive;Craniocerebral Trauma;Data;Diffuse;Drops;Evaluation;Female;Generations;Genotype;Goals;Human;Human Resources;Individual;Injury;Investigation;Knock-out;Knockout Mice;Life;Literature;Maintenance;Mediating;Modeling;Monitor;Motor;Mus;Nerve Degeneration;Neurologic Dysfunctions;Operative Surgical Procedures;Pathway interactions;Performance;Procedures;Process;Program Efficiency;Protein Isoforms;Reagent;Research Personnel;Resources;Schedule;Survivors;Testing;Therapeutic;Time;Tissue Harvesting;Training;Transgenic Mice;Transgenic Organisms;Traumatic Brain Injury;Weight;brain pathway;calpastatin;cellular targeting;cognitive function;cohort;controlled cortical impact;cyclophilin D;functional outcomes;grasp;in vivo;inhibitor/antagonist;injured;insight;interest;memory retention;morris water maze;mouse model;neuropathology;novel;novel strategies;overexpression;preclinical evaluation;pregnant;programs;research study;sharing data;small molecule;therapeutic target;treatment strategy


application_id: 7809529
project_number: 5P01NS058484-03
project_title: Newer small molecule calpain inhibitors for TBI
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0002
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
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: 2009-05-01
budget_end_date: 2010-04-30
funding_mechanism: Non-SBIR/STTR
project_abstract:
Considerable experimental evidence now supports a critically important pathophysiological role for thecalcium-activated protein-degradative enzyme calpain in the secondary injury process that follows traumaticbrain injury (TBI). This has suggested that that early treatment with a calpain-inhibiting drug should be ableto reduce post-TBI secondary injury to brain tissue and thus facilitate neurological recovery and survival.Accordingly several small molecule calpain inhibitors have been discovered. A few of these have beentested in rodent TBI models and have shown some promise in terms of either a decrease in calpain-mediated proteolytic damage in the injured brain tissue or an improvement in neurological recovery.However none of the available calpain inhibitors have been systematically studies in TBI models so thattranslation of their effects into clinical development would be possible. Thus the overall goal of this projectis to carefully examine the ability of 5 carefully selected calpain inhibitors including three newer compoundsto be able to effectively inhibit post-traumatic cytoskeletal proteoytic degradation mitochondrial dysfunctionand neurodegeneration and to improve neurological recovery. The 5 compounds will first be screened fortheir ability to inhibit calpain activation in normal mice in a dose-related fashion (Aim 1). The most effectivecompounds will be advanced into testing for their cytoskeletal (Aim 2) mitochondrial (Aim 3) andneuroprotective effects (Aim 4) in a diffuse and a focal TBI model. One of the 5 compounds selected is adual inhibitor of calpain proteolytic degradation and free radical-induced lipid peroxidation. The lattersecondary injury process is known to enhance calpain activation by causing impairment of neuronal calciumhomeostatic mechanisms. As a result the increase in intracellular calcium exacerbates calpain activation.Therefore a dual inhibitor or calpain and lipid peroxidation would be expected to be more effective than aeither type of compound alone. In addition to looking at the dose-related benefits of early administration of acalpain inhibitor or a dual calpain inhibitor/lipid peroxidation inhibitor in two different TBI models thetherapeutic efficacy window and the optimum duration of treatment will be explored. The resulting data willaddress the overall hypothesis that calpain inhibition is a practical neuroprotective therapeutic approach anddefine how best to design anti-calpain therapy so that future clinical trials in TBI patients are enabled.

project_terms:
AK 295;Acute;Address;Animals;Antioxidants;Attenuated;Behavioral;Brain;Brain Injuries;Calcium;Calpain;Calpain I;Cathepsins;Cell Culture Techniques;Cell Death;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Collaborations;Conceptions;Cysteine Protease;Cytoskeletal Proteins;Data;Development;Diffuse;Dose;Early treatment;Enzymes;Evaluation;Excision;Failure (biologic function);Free Radicals;Functional disorder;Future;Goals;Hand;Hour;Human Resources;Impairment;Infarction;Injury;Intravenous;Knock-out;Laboratories;Laboratory Research;Lead;Lipid Peroxidation;Lipids;Measures;Mediating;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurons;Outcome;Oxygen;Papain;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Phosphatidylethanolamine Binding Protein;Plasma;Play;Preparation;Principal Investigator;Process;Promotor (Genetics);Property;Proteins;Proteolysis;Proteomics;Recovery;Relative (related person);Reporting;Research;Research Personnel;Rodent;Role;Running;Sampling;Screening procedure;Series;Solubility;Spectrin;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Traumatic Brain Injury;Treatment Efficacy;Treatment Protocols;Work;apoptosis inducing factor;base;biomarker;brain tissue;calpain inhibitor;calpastatin;caspase;comparative;design;improved;in vivo;inhibitor/antagonist;injured;innovation;intraperitoneal;knockout animal;lipid peroxidation inhibitor;mitochondrial dysfunction;mouse model;neurological recovery;neuroprotection;novel;overexpression;oxidative damage;prevent;programs;protective effect;protective efficacy;research study;response;small molecule;therapeutic target;treatment duration;water solubility


application_id: 7808237
project_number: 1F31DE020240-01
project_title: AI-2-dependent quorum sensing in Aggregatibacter actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2009-09-18
opportunity_number: PA-07-002
application_type: 1
activity_code: F31
ic: DE
serial_number: 020240
program_official: FRIEDEN, LESLIE A
project_start_date: 2009-12-01
project_end_date: 2012-11-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9851704
contact_pi: NOVAK, ELIZABETH ANN
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): Dental plaque is a complex oral biofilm comprised of a diverse microbial community which necessitates that bacteria coordinate their behavior and function based on the environment and other organisms in the biofilm. In the oral pathogen Aggregatibacter actinomycetemcomitans this intimate cell-to- cell communication potentially occurs via the quorum sensing circuit dependent upon the soluble signaling molecule autoinducer-2 (AI-2). Previous results suggest that the response circuits of A. actinomycetemcomitans differ from the established paradigms for AI-2 signaling. Thus we hypothesize that the AI-2-mediated quorum sensing response circuit in A. actinomycetemcomitans is tailored towards the specific survival strategies employed by this organism in the oral biofilm and contributes to its in vivo persistence and virulence through AI-2 regulation of iron acquisition. To address this hypothesis we will further characterize the molecular mechanisms of AI-2-dependent quorum sensing in A. actinomycetemcomitans. Our first specific aim is to determine the importance of AI-2-dependent quorum sensing in the persistance and virulence of A. actinomycetemcomitans. Since periodontal diseases are mixed bacterial infections of the oral cavity it is theorized that populational shifts in the biofilm that leads to overrepresentation of certain organisms rather than their absence or presence is a major contributing factor to the onset and progression of oral diseases. Using the Baker model of periodontitis we will determine if AI-2-mediated quorum sensing is important in vivo during single infections with either wild type or AI-2 receptor-deficient strains of A. actinomycetemcomitans. Our second specific aim is to identify the component that links AI-2 detection to downstream gene regulation. Initial studies suggest that the two- component system QseBC may link detection and gene regulation. To address our hypothesis we will determine if QseBC regulates biofilm formation in A. actinomycetemcomitans. This will be accomplished by constructing QseBC mutants and analyzing their ability to form biofilms in vitro. We will also determine if QseBC influences the expression of AI-2-regulated genes such as iron acquisition by utilizing quantitative PCR.   
  
Public Health Relevance: Determining the extra- and intracellular physiologic roles of AI-2 will provide rationale for the development of novel quorum sensing inhibitors as a way to prevent the growth of A. actinomycetemcomitans biofilms associated with oral diseases as well as other diseases (e.g. cardiovascular disease). Furthermore innovative methods to control biofilm formation in the oral cavity would have a major impact on healthcare costs

project_terms:
Actinobacillus actinomycetemcomitans;Address;Bacteria;Bacterial Infections;Behavior;Cardiovascular Diseases;Cell Communication;Cell physiology;Cells;Communication;Communities;Complex;Dental Plaque;Detection;Development;Disease;Environment;Escherichia coli;Event;Exhibits;Gene Expression Regulation;Genes;Goals;Growth;Health Care Costs;In Vitro;Infection;Iron;Link;Mediating;Methods;Microbial Biofilms;Modeling;Molecular;Mouth Diseases;Onset of illness;Operon;Oral cavity;Organism;Outcome;Periodontal Diseases;Periodontitis;Physiological;Porphyromonas gingivalis;Regulation;Research;Role;Salmonella;Signal Transduction;Signaling Molecule;System;Therapeutic Intervention;VAI-2;Vibrio;Virulence;base;extracellular;in vivo;inhibitor/antagonist;innovation;microbial;microbial community;mutant;novel;oral biofilm;oral pathogen;periplasm;prevent;public health relevance;quorum sensing;receptor;response;uptake


application_id: 7808198
project_number: 1F30HL099272-01
project_title: Regulation of Lysolipid Signaling by Autotaxin-Integrin Interactions on Platelets
administering_ic: NHLBI
award_notice_date: 2010-01-08
opportunity_number: PA-08-021
application_type: 1
activity_code: F30
ic: HL
serial_number: 099272
program_official: SARKAR, RITA
project_start_date: 2010-05-01
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1 F10A-S (20)]
contact_pi_person_id: 9792683
contact_pi: FULKERSON, ZACHARY
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:
Address;Adhesions;Animals;Aspirin;Binding (Molecular Function);Biological Assay;Blocking Antibodies;Blood Circulation;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Catalysis;Cell Adhesion;Cell physiology;Cells;Coagulation Process;Data;Disease;Endothelial Cells;Enzymes;Event;Family;G-Protein-Coupled Receptors;GTP-Binding Proteins;Generations;Genetic;Glycerophospholipids;Hemorrhage;Hydrolysis;Immunologics;In Vitro;Inflammation;Injury;Integrin Binding;Integrins;Laboratories;Lipids;Lymphocyte;Lysophosphatidic Acid Receptors;Lysophosphatidylcholines;Lysophospholipids;Measures;Mediator of activation protein;Membrane;Metabolism;Molecular;Molecular Conformation;Muscle Cells;Muscle function;Mutation;Myocardial Infarction;Names;Pharmaceutical Preparations;Physiological;Plavix;Production;Protocols documentation;RGD (sequence);Regulation;Role;Signal Transduction;Signaling Molecule;Site;Smooth muscle (tissue);Surface;System;Testing;Therapeutic;Thrombosis;Variant;Vitronectin;Work;alkylglycerophosphoethanolamine phosphodiesterase;base;experience;extracellular;in vivo;inhibitor/antagonist;insight;lysophosphatidic acid;migration;new therapeutic target;novel;nuclease;phosphoric diester hydrolase;receptor;small molecule;somatomedin B;stroke;therapeutic development;tool


application_id: 7808073
project_number: 3R01AR045617-08S1
project_title: Intracellular signaling during skeletal muscle hypertrophy
administering_ic: NIAMS
award_notice_date: 2009-09-28
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AR
serial_number: 045617
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2009-09-28
project_end_date: 2011-09-27
study_section: Special Emphasis Panel[ZRG1 MOSS-B (95)]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Several studies have established that signaling through mTOR is necessary for growth of adult skeletal muscle. The general objective of the parent grant (AR45617) is to define the molecular mechanisms whereby mechanical events and growth factors mediate the intracellular activation of mTOR signaling and protein synthesis during skeletal muscle hypertrophy. The experiments described in this competitive revision will expand the scope of the work proposed in the parent grant with the pursuit of the role of REDD2/ddit4l a novel negative regulator of mTOR/TORC1 signaling. The overall hypothesis is that targeted disruption of REDD2 expression in adult skeleletal muscle will result in increased mTOR activity increased protein synthesis and greater growth. Expression of REDD2 is highly and uniquely enriched in adult skeletal muscle in mice rats and humans. Recent experiments in my lab have determined that expression of REDD2 is quickly and significantly down-regulated in both human and mouse muscle in response to hypertrophic stimuli. Using in vitro approaches we have also determined that REDD2 functions as a negative regulator of mTOR signaling in muscle cells. These new observations expand the scope of our current project on mTOR signaling and skeletal muscle. In addition they suggest that REDD2 may play a critical role in modulating the signaling activity through mTOR with downstream effects on protein synthesis and skeletal muscle hypertrophy. To address the hypothesis of this competitive revision we propose the following two specific aims: Specific Aim 1. To determine the molecular mechanism(s) by which REDD2 inihibits mTOR/TORC1 signaling in response to mechanical strain in myotubes in vitro. Specific Aim 2. To determine the role of loss of function of REDD2 in adult skeletal muscle in vivo on mTOR/TORC1 signaling rates of protein synthesis and muscle size. The objectives of this competitive revision are consistent with the goals of the announcement NOT-OD-09-058 and are three-fold. Our first objective is to expand our current research program (AR45617) with studies on the role of REDD2 in the regulation of skeletal muscle signaling during hypertrophy. The second objective is to hire new personnel to accomplish the research goal and third is to invest in the generation of a new mouse model floxed REDD2 that is essential for this work and will contribute to the field of skeletal muscle research.   
  
PUBLIC HEALTH RELEVANCE: The goals of this project are to pursue our understanding of a novel skeletal muscle specific molecule REDD2 which contributes to the regulation of growth/anabolic pathways in adult skeletal muscle. The results from these studies provide novel insight and potentially a new target molecule for pursuing therapeutic strategies to facilitate muscle growth and/or attenuate muscle wasting associated with disuse aging bed rest and cachexia.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Adult;Age;Aging;Attenuated;Bed rest;Biogenesis;Cachexia;Clinical;Cyclin D1;Development;Event;Exercise;Generations;Genetic Recombination;Goals;Growth;Growth Factor;Health;Human;Human Resources;Hypertrophy;IGF1 gene;In Vitro;Insulin;Link;Maintenance;Mechanics;Mediating;Molecular;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Outcome;Pathway interactions;Phosphotransferases;Play;Principal Investigator;Process;Protein Biosynthesis;Proteins;Quality of life;Rattus;Regulation;Research;Resistance;Role;Signal Pathway;Signal Transduction;Signaling Protein;Sirolimus;Skeletal muscle structure;Stimulus;Striated Muscles;TSC1 gene;Techniques;Testing;Therapeutic;Time;Translational Regulation;Work;c-myc Genes;cdc Genes;in vivo;in vivo Model;insight;knock-down;loss of function;mTOR protein;molecular site;mouse model;muscle form;muscle hypertrophy;neuromuscular activity;novel;overexpression;parent grant;programs;public health relevance;research study;response;skeletal muscle growth;small hairpin RNA;wasting

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Esser Karyn A.Project Narrative:The goals of this project are to pursue our understanding of a novel skeletal muscle specific molecule REDD2which contributes to the regulation of growth/anabolic pathways in adult skeletal muscle. The results fromthese studies provide novel insight and potentially a new target molecule for pursuing therapeutic strategiesto facilitate muscle growth and/or attenuate muscle wasting associated with disuse aging bed rest andcachexia.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


