# projects

application_id: 7094159
project_number: 5R01AG024377-03
project_title: Characterization of the Sch9 Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2006-07-11
opportunity_number: RFA-AG-04-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 024377
program_official: CHATTERJI, MINKI
project_start_date: 2004-09-01
project_end_date: 2008-08-31
study_section: ZAG1-ZIJ-5(M3)
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT C
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Model eucaryotes including Saccharomyces cerevisiae are emerging as key elements for identifying genes that modulate longevity and aging and for determining molecular mechanisms of protein action in these processes. The S. cerevisiae Sch9 protein kinase plays a role in chronological life span but how it does so is unclear since upstream activators and downstream substrates remain unknown. We recently identified the first Sch9 substrate Lsp1 a negative regulator of the Pkc1-MAP kinase cascade. In Specific Aim 1 we will use the Lsp1 phosphopeptide sequence(s) to search for other substrates that may play roles in chronological life span. We will also determine the identity of two proteins that we have found to be phosphorylated in vitro by purified Sch9. Finally we will use biochemical approaches to search for other Sch9 substrates. Our other novel discoveries are that sphingolipid long chain bases (LCBs) activate Sch9 kinase activity in vitro and that LCB levels rise over 100-fold as cells pass from log to stationary phase. Based upon these results we seek to determine in Specific Aim 2 if LCBs regulate Sch9 activity in vivo thereby controlling chronological life span. In Specific Aim 3 we will determine if Lsp1 plays a role in chronological life span and whether or not it regulates the activity of Sch9. The same will be done for other Sch9 substrates identified in Aim 1. Finally in Specific Aim 4 we will determine if Lsp1 and a related protein Pil1 also a negative regulator of the Pkc1-MAP kinase cascade that terminates with the Slt2 protein kinase play a role in replicative life span. Slt2 has recently been shown to control replicative life span via phosphorylation of Sir3 a known regulator of life span. The results of these studies will establish a role for sphingolipids in life span regulation provide the first mechanistic insight into the control of chronological life span by Sch9 and generate new leads for understanding how Sch9 governs life span. Since Sch9 is a homolog of human Akt/PKB protein kinases our results may identify specific roles for Akts/PKBs in human aging and longevity.

project_terms:
Saccharomyces cerevisiae;aging;biological signal transduction;cell free system;cell growth regulation;cell senescence;chemical structure function;chromatography;enzyme activity;enzyme mechanism;enzyme substrate;fungal genetics;genetic models;immunoprecipitation;longevity;mass spectrometry;phosphopeptides;phosphorylation;protein kinase;protein protein interaction;protein sequence;protein structure function;reproduction;sphingolipids


application_id: 7094088
project_number: 5R01MH063726-05
project_title: Effect of Prior Effort on Reward Value
administering_ic: NIMH
award_notice_date: 2006-07-26
application_type: 5
activity_code: R01
ic: MH
serial_number: 063726
program_official: ROSSI, ANDREW F
project_start_date: 2002-09-15
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-1(01)S]
contact_pi_person_id: 7876951
contact_pi: ZENTALL, THOMAS R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-26
project_abstract:
DESCRIPTION (provided by applicant): The investigation in animals of behaviorthought to be characteristic of humans alone can serve to support the anevolutionary theory of similarity of behavior among species. More importantperhaps animal models of human behavior often encourage the identification ofsimpler accounts of human behavior than typically found in the psychologicalliterature. For example research with animals has forced the reexamination ofthe hypothesis that the ability demonstrate stimulus equivalence requiresverbal ability. It has also led to accounts of thephenomenon of transitive inference that are simpler than those proposed by manydevelopmental psychologists (e.g. propositional logic orthe linear representation of stimuli). In the present proposal we willinvestigate in animals a social psychological phenomenon that when found inhumans has been called "cognitive dissonance." More specifically "worth ethic"or "justification of effort" which can be described as the attribution ofgreater value to rewards that follow greater effort has been thought to dependon the human need to resolve the dissonance presumably engendered by theexertion of greater effort to obtain comparable rewards. We have found thatpigeons will demonstrate similar behavior (stimuli that follow a high effortresponse are preferred over those that follow a low effort response). Weinterpret that behavior in terms of a form of contrast which in this case canbe described as the relatively greater improvement in hedonic state experiencedbetween the end of the high effort response and the signal for reward. Wepropose to (1) examine the functional relation between effort and reward value(2) determine the source of the contrast (3) examine the generality of theeffect (4) distinguish experimentally between effort and delay toreinforcement (5) confirm that it is the value of the reward that is enhancedby prior effort and (6) determine why it is that even negative discriminativestimuli show this effect. The proposed research should have importantimplications for theories of cognitive dissonance as well as otherpsychological theories of human social behavior.

project_terms:
behavior test;behavioral /social science research tag;body physical activity;cognition;ethology;goal oriented behavior;motivation;pigeons;preference;psychic activity level;psychological models;reinforcer;social behavior;social psychology;stimulus /response


application_id: 7093507
project_number: 5R01HL074351-04
project_title: Late Preconditioning in Hypercholesterolemia
administering_ic: NHLBI
award_notice_date: 2006-06-16
application_type: 5
activity_code: R01
ic: HL
serial_number: 074351
program_official: SCHWARTZ, LISA
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 7372371
contact_pi: TANG, XIAN-LIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Late preconditioning (PC) provides sustained and powerful protection against both reversible and irreversible ischemia/reperfusion injury.  The underlying mechanisms of late PC have been extensively investigated in the hope of identifying new approaches to protect the ischemic myocardium.  Thus far however most studies have been undertaken in animal models in which ischemia was imposed in the absence of other disease processes.  Since pathologic conditions may interfere with the biochemical pathways that underlie late PC the PC response is likely to be modified by systemic diseases.  Therefore there is an urgent need to examine the PC response in the presence of concurrent clinically relevant abnormalities such as hypercholesterolemia (HC).  It has been well documented that HC impairs nitric oxide (NO) formation and that NO plays a critical role in late PC acting initially as a trigger and subsequently as a mediator of this phenomenon.  The overall objective of this proposal is to investigate the late PC response in the presence of HC.  Our fundamental hypothesis is that the cardioprotective effects of late PC are abrogated by HC and that this is caused by NO insufficiency both at the level of trigger (immediately after the PC stimulus) and at the level of mediator (24 h later).  We will first verify that both the anti-stunning and the anti-infarct effects of late PC are abolished in chronically-instrumented rabbits with HC; the dose dependent effects of HC will be established.  We will then examine the effect of HC on the generation of NO that triggers the signal transduction events that initiate the late PC response.  Furthermore we will determine whether HC blocks formation of NO from the inducible NOS which mediates the cardioprotection of late PC.  The role of ADMA disregulation and DDAH activity in impairing eNOS-dependent NO generation during HC will be investigated.  The role of tetrahydrobiopterin (BH4) deficiency in impairing the function of NO as a mediator of late PC will also be established.  The ability of supplemental L-arginine NO donors and exogenous BH4 to reinstate the late PC response in the presence of HC will be investigated.  This study will thoroughly test the concept that HC abrogates late PC by impairing the role of NO and will interrogate the underlying mechanisms.  The results may pave the way for therapeutic strategies aimed at restoring the late PC response in the clinically prevalent condition of HC.

project_terms:
JAK kinase;arginine;atherosclerosis;blood chemistry;cholesterol;cytoprotection;dosage;enzyme inhibitors;hypercholesterolemia;laboratory rabbit;myocardial ischemia /hypoxia;nitric oxide;nitric oxide synthase;nuclear factor kappa beta;nutrition related tag;pathogenic diet;protein kinase C;tetrahydrobiopterin;transcription factor


application_id: 7093176
project_number: 5U13GM058252-08
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2006-06-23
application_type: 5
activity_code: U13
ic: GM
serial_number: 058252
program_official: ECKSTRAND, IRENE A
project_start_date: 1998-09-01
project_end_date: 2009-06-30
study_section: Minority Programs Review Subcommittee B[MPRC-B]
contact_pi_person_id: 1859369
contact_pi: FRAZIER, DONALD T
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  The overall objective of this application is to continue our challenge to empower faculty at institutions with high minority enrollment to develop and submit competitive research proposals. Building on our past experience the competing renewal has three facets which will take place concurrently: 1) up-dating current modules (14) and the development testing and evaluation of two new internet course modules; 2) recruitment and training of participants through 5 workshops at remote sites and subsequent participation in the web-based course; 3) continuing evaluation of the training modules for the purpose of technological and content versions. Significant changes from the original program include moving the pre-course conference off-site to maximize the number of faculty participating from contiguous institutions and the introduction of machine language technology to aid in the editing and packaging of participants' grant writing efforts. At the conclusion of the initiative each participant should be both motivated and empowered to submit a competitive proposal. Thus our continuing partnership with NIGMS should improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and strengthen minority institution's overall research environment.

project_terms:
Internet;clinical research;computer assisted instruction;computer human interaction;cooperative study;ethnic group;health science research;human data;interactive multimedia;minority institution research support;role model;technical writing;training;workshop


application_id: 7093135
project_number: 5F31DA018476-02
project_title: Cocaine and Sucrose Cross-Sensitization in Rats
administering_ic: NIDA
award_notice_date: 2005-08-16
application_type: 5
activity_code: F31
ic: DA
serial_number: 018476
program_official: HOFFMAN, ALLISON
project_start_date: 2004-09-07
project_end_date: 2005-12-31
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8856992
contact_pi: KLEIN, EMILY D.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-07
project_abstract:
DESCRIPTION (provided by applicant):    
Because food and drugs activate some of the same areas of the brain it is hypothesized that the common ability to activate the mesolimbic dopamine system may underlie the observed relationship between substance abuse and eating disorders. The proposed experiments are based on a review of current literature and research in our laboratory that shows that rats previously exposed to cocaine demonstrate faster latencies to complete sessions on a fixed-ratio (FR) 30 schedule of reinforcement for sucrose than rats exposed to saline. It is hypothesized that exposure to cocaine sensitizes rats to the rewarding properties of sucrose and vice-versa. The first four proposed experiments will explore how previous cocaine exposure increases the value of sucrose as measured by an increased willingness to work for sucrose reward (Experiment 1) and increased consumption of sucrose (Experiments 2 & 3). Experiments 4 and 5 will examine whether exposure to sucrose produces cross-sensitization to cocaine. The findings of these experiments are intended to increase current understanding of how drug use affects the rewarding properties of natural reinforcers and how previous experience with natural reinforcers affects subsequent drug reward.

project_terms:
behavioral /social science research tag;behavioral habituation /sensitization;chordate locomotion;cocaine;comorbidity;conditioning;craving;cues;eating disorders;laboratory rat;limbic system;neurochemistry;neuropharmacology;nutrient intake activity;predoctoral investigator;psychopharmacology;reinforcer;substance abuse related behavior;substance abuse related disorder;sucrose


application_id: 7092569
project_number: 5R01DK067413-02
project_title: Insulin Control of Gene Transcription Through Sensitin
administering_ic: NIDDK
award_notice_date: 2006-06-09
application_type: 5
activity_code: R01
ic: DK
serial_number: 067413
program_official: BLONDEL, OLIVIER
project_start_date: 2005-07-15
project_end_date: 2009-06-30
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 1858075
contact_pi: VILLAFUERTE, BETTY C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Insulin resistance leading to type 2 diabetes generally involve defects in insulin signaling at the postreceptor level. Activation of the PI 3'-kinase to Akt pathway plays a significant role in insulin signaling but the events downtream of Akt are largely unknown. Recently we identified a novel Akt substrate which binds to the insulin-responsive elements (IREs) of insulin-like growth factor binding protein-3 (IGFBP-3) and other insulin-responsive genes. The IRE-binding protein "sensitin" cDNA encodes a 120 kDa cytoplasmic protein. After adding insulin the protein is cleaved to a 50 kDa fragment which localizes predominantly to the nucleus and transactivates IREs. PI 3'-kinase inhibition decreases both Ser/Thr phosphorylation and proteolysis of sensitin. Based on our preliminary data the long-term goal of our investigation is to employ the IRE of IGFBP-3 as a model system to delineate the signaling pathway by which insulin induces genomic effects through the action of a specific trans-acting factor sensitin that binds to the IRE. This application has the following aims: 1) To test the hypothesis that sensitin is subject to regulated phosphorylation by insulin using 2-D phosphomapping and mass spectrometry to localize residues of sensitin phosphorylated by insulin in HepG2 cells and the effect of phosphorylation on insulin-induced transcription assessed by mutational analysis. 2) To test the hypothesis that proteolytic cleavage of sensitin is required for transactivation of the IRE and the corollary hypothesis that nuclear translocation of sensitin is secondary to cleavage of the protein. We will identify the cleavage sites by microsequencing mutate the proteolytic domain to test its role in nuclear translocation and IRE transcription; and mutate the Akt phosphorylation site to determine if dephosphorylation prevents nuclear translocation or proteolysis of sensitin. 3) To determine the physiological significance of phosphorylation and proteolysis of sensitin in a rat diabetes model we will compare the phosphorylation and proteolysis of sensitin in vitro by hepatic cytosolic extracts from diabetic obese and lean control rats and determine whether sensitin mutation conferring protease- and phosphorylation-resistance increase the diabetes susceptibility of obese rats or worsen glucose control in diabetic rats. This study may lead to better understanding of insulin-regulated gene transcription and may provide insights into linked to the pathogenesis of type 2 diabetes mellitus.

project_terms:
binding proteins;body weight;cell line;diabetes mellitus genetics;gene mutation;genetic regulatory element;genetic strain;genetic susceptibility;genetic transcription;hormone regulation /control mechanism;insulin;insulin sensitivity /resistance;insulinlike growth factor;laboratory rat;liver metabolism;mass spectrometry;noninsulin dependent diabetes mellitus;nuclear transport;phosphorylation;protein localization;protein sequence;proteolysis;serine threonine protein kinase


application_id: 7092475
project_number: 2R01AA003624-27A1
project_title: Control of drug and ethanol metabolism
administering_ic: NIAAA
award_notice_date: 2006-05-05
opportunity_number: PA-05-074
application_type: 2
activity_code: R01
ic: AA
serial_number: 003624
suffix: A1
program_official: GENTRY, THOMAS
project_start_date: 1978-03-01
project_end_date: 2011-04-30
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
project_terms:
alcoholic fatty liver;alcoholism /alcohol abuse;biological signal transduction;blood lipoprotein biosynthesis;drug metabolism;ethanol;extracellular matrix;fibrin;gene induction /repression;genetically modified animals;inflammation;insulin;laboratory mouse;liver cirrhosis;liver disorder;liver function;liver metabolism;liver toxic disorder;metalloendopeptidases;metformin;pathologic process;plasminogen activator inhibitors;protein structure function;toxin metabolism;tumor necrosis factor alpha;very low density lipoprotein


application_id: 7092294
project_number: 5R01HL073089-04
project_title: The Role of Nebulin Isoforms in Thin Filament Assembly
administering_ic: NHLBI
award_notice_date: 2006-07-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 073089
program_official: EVANS, FRANK
project_start_date: 2003-08-04
project_end_date: 2008-07-31
study_section: Cardiovascular and Pulmonary Research A Study Section[CVA]
contact_pi_person_id: 7875119
contact_pi: MONCMAN, CAROLE L.
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: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant):  Crucial to our understanding of cardiac and skeletal muscle myofilament function or dysfunction during disease is an understanding of the events and interactions involved in myofilament assembly. The long term goal of this project is to elucidate these interactions. Essential to this work is defining key proteins and assessing their role in the structure. As an initial step in this research the roles of nebulin family members in the regulation and function of the actin based cytoskeleton will be analyzed. Nebulin and nebulette are large modular proteins associated with the thin filaments of skeletal muscle and cardiac muscle respectively. The defining element of the nebulin family members is the presence of a 35 residue repeat that serves as the basic actin binding motif for the family members. The organization of the repeat domain has led to the postulation that these proteins serve as blueprints for the architecture of the thin filaments during development. These proteins also contain 3 other domains an acidic N-terminal domain a linker domain and a Src homology 3 (SH3) domain. It is hypothesized that these other domains many of which are unique to each family member serve to regulate actin binding functions and target interactions of the nebulin modules to distinct subcellular locations. To test these hypotheses: 1) the linker domains of three nebulin family members (nebulin nebulette and Lasp 1) will be analyzed both in vivo and in vitro for actin binding activity and targeting functions dependent and independent of the nebulin modules; 2) the orientation of nebulette and the position of the linker and N-terminal domains will be mapped by immuno-electron microscopy; 3) the N-terminal domains of nebulette and nebulin will be examined for targeting and regulatory functions by examining the ability of this domain to interact with thin filaments in vivo and in vitro; and 4) chimeric nebulin-nebulette genes will be constructed and expressed in cardiomyocytes to evaluate the thin filament ruler hypothesis. This work will involve cellular and molecular biological techniques to alter gene expression in primary cultures of cardiac and skeletal muscle. Immunofluorescence and electron microscopy will be used to evaluate ultrastructural organization both in vitro and in vivo and biochemical and biophysical techniques to define molecular interactions. The results of this analysis will aid in our understanding of the roles of nebulin family members in the organization and functions of the thin filaments of striated muscle and to their roles in cytoskeletal dynamics. In addition information gained here will add to our knowledge of the roles of these proteins in normal and diseased states.

project_terms:
SDS polyacrylamide gel electrophoresis;actin binding protein;binding sites;cardiac myocytes;complementary DNA;gene expression;genetically modified animals;green fluorescent proteins;immunoelectron microscopy;laboratory mouse;laboratory rabbit;microfilaments;muscle proteins;myocardium;polymerase chain reaction;protein isoforms;protein protein interaction;protein structure function;striated muscles;tissue /cell culture;western blottings


application_id: 7092252
project_number: 5R25DA011388-08
project_title: Girls in Drug Abuse Science
administering_ic: NIDA
award_notice_date: 2006-07-05
opportunity_number: PAR-99-076
application_type: 5
activity_code: R25
ic: DA
serial_number: 011388
program_official: SASEK, CATHRINE
project_start_date: 1998-09-30
project_end_date: 2010-06-30
study_section: ZDA1-MXG-S(16)
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Developing scientists is a priority of the National Institutes of Health the National Institute on Drug Abuse and this continuation project. The overall aim of this competing continuation application for a Science Education Drug Abuse Partnership Award Project (SEDAPA) is to extend the development and implementation of a curriculum and manual for high school young women to middle school girls in sixth to eighth grade who live in rural Appalachian Kentucky. The specific aims for the project are: (1) To increase the scientific technological and interpersonal knowledge as well as skills of participating middle-school girls ages 11 to 15 from rural Appalachian Kentucky; (2) To increase the knowledge of parents and middle schoolteachers on gender equity strategies and teaching techniques to increase the science participation of middle school girls in rural Appalachian Kentucky; (3) To develop and disseminate a model curriculum to enhance science as well as drug abuse research in rural Appalachian Kentucky; and (4) To develop and disseminate a guide for "Promoting Gender Equity in the Classroom" to enhance science education in rural and Appalachian areas. This competing continuation application focuses on 120 rural Appalachian Kentucky girls entering the sixth grade from 21 rural counties; 120 to 240 parents of these girls; and at least 30 rural middle school teachers from the same 21 rural counties. Project Summer Institutes Saturday Sessions and scientific as well as community mentoring opportunities will continue for participating girls. For this competing continuation application younger girls (middle school) will be targeted; workshops for parents and teachers will be added; 21 rather than 14 rural counties will be included; current project participants will be involved as mentors; Chris in Drug Abuse Science Clubs will be added; the Kentucky Department of Education along with project staff will work to promote Gender Equity in all middle schools in Kentucky; and the replication manual will be expanded for girls in grades 6 to 8 to produce a complete and comprehensive manual across grades 6 to 12 for replication in other rural and Appalachian areas.

project_terms:
adolescence (12-20);clinical research;community;curriculum;drug abuse education;education evaluation /planning;educational resource design /development;female;gender difference;handbook;health disparity;human subject;medically underserved population;parents;questionnaires;rural area;secondary schools;teacher;teaching


application_id: 7092176
project_number: 5F30NS048716-03
project_title: Reconstruction of the nigrostriatal pathway
administering_ic: NINDS
award_notice_date: 2006-06-30
opportunity_number: PA-01-100
application_type: 5
activity_code: F30
ic: NS
serial_number: 048716
program_official: SIEBER, BETH-ANNE
project_start_date: 2004-07-01
project_end_date: 2007-12-31
study_section: ZNS1-SRB-M(01)
contact_pi_person_id: 7789861
contact_pi: ZIEMBA, KRISTINE S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The long-term objective of this research proposal is to develop a means to reconstruct the neural circuit that degenerates in Parkinson's disease (PD) - that is the nigrostriatal pathway. While current therapy (levadopa treatment) for PD may alleviate symptoms for a while there is still no way to halt or reverse the neurodegeneration. Since 1% of the population over the age of 65 is affected by PD and the prevalence increases with increasing age research into better therapies and an eventual cure for PD is important for our aging population. Cellular replacement is not a new idea in PD research but this proposal differs from most previous efforts by attempting an anatomically and physiologically correct reestablishment of the nigrostriatal pathway effecting a more complete behavioral recovery. Molecular cues to guide growth of dopaminergic neurons will be identified in vitro and adenoviral vectors will be used to express these molecules between the substantia nigra (SN) and the striatum in hemiparkinsonian rats. When dopaminergic neurons are subsequently transplanted into the SN their axons should grow along the growth-supportive pathway ending in the striatal target. Success will be evaluated with detailed histological and behavioral analyses.

project_terms:
Adenoviridae;Parkinson&apos;s disease;behavior test;brain derived neurotrophic factor;chemokine;corpus striatum;electron microscopy;laboratory rat;nervous system regeneration;nervous system transplantation;neuroanatomy;neuronal guidance;neurons;neurotrophic factors;nonhuman therapy evaluation;predoctoral investigator;psychomotor function;substantia nigra;transfection /expression vector


application_id: 7092021
project_number: 5R01NS039254-07
project_title: Tat-mediated brain endothelial cell dysfunction
administering_ic: NINDS
award_notice_date: 2006-06-30
opportunity_number: PAS-03-165
application_type: 5
activity_code: R01
ic: NS
serial_number: 039254
program_official: NUNN, MICHAEL
project_start_date: 2000-04-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-AARR-A(07)M]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AIDS /HIV neuropathy;AIDS therapy;HIV infections;biological signal transduction;biological transport;blood brain barrier;brain cell;brain disorders;cell line;gene expression;human tissue;inflammation;laboratory mouse;oxidation reduction reaction;peroxisome proliferator activated receptor;tissue /cell culture;vascular endothelium;virus infection mechanism;virus protein


application_id: 7091595
project_number: 5F31AI061829-03
project_title: Expression and Cleavage of the Hendra Virus F Protein
administering_ic: NIAID
award_notice_date: 2006-07-24
application_type: 5
activity_code: F31
ic: AI
serial_number: 061829
program_official: HERNANDEZ, MILTON J
project_start_date: 2004-07-02
project_end_date: 2007-07-01
study_section: Special Emphasis Panel[ZRG1-ONC-O(29)L]
contact_pi_person_id: 7879247
contact_pi: CRAFT, WILLIE W
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-02
project_abstract:
DESCRIPTION (provided by applicant):  Hendra Virus (HeV) is a recently identified paramyxovirus that has been identified as a P4 pathogen and added to the DHHS Select Agents list and the NIAID Priority Pathogens list. Like other paramyxovirus fusion proteins the Hendra Virus F protein (HeV F) has been demonstrated to promote viral membrane fusion. HeV F is synthesized as a precursor protein F0 which is cleaved into the F1 and F2 subunits (Michalski et al. 2000). This processing has been demonstrated to be essential for fusogenic activity in other viral systems. The HeV F protein appears to undergo incomplete processing with a substantial amount being incorporated into virions in the uncleaved state. The goals of these investigations are to characterize the proteolytic processing of HeV F protein and to determine how the cleavage state of the protein affects fusogenic activity. Specific aim 1 will examine the expression and cleavage state of HeV F on the cellular surface and analyze the nature of this uncleaved protein. Experiments in aim 2 will determine the amino acid residues that are key to proper proteolytic processing. Finally the effect that uncleaved HeV F protein on the surface has on the fusogenic activity will be analyzed in aim 3.

project_terms:
Nipah virus;biotin;confocal scanning microscopy;emerging infectious disease;equine morbillivirus;gene expression;mutant;predoctoral investigator;protein binding;protein localization;protein structure function;proteolysis;site directed mutagenesis;transfection;trypsin;virion;virus infection mechanism;virus protein


application_id: 7091504
project_number: 5R01HL058686-06
project_title: Chemosensitivity of Tachykinin-containing Lung Afferents
administering_ic: NHLBI
award_notice_date: 2006-06-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 058686
program_official: NOEL, PATRICIA
project_start_date: 1998-04-01
project_end_date: 2009-06-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Vagal bronchopulmonary C-fiber sensory nerves play an important role in regulating airway functions. Hypersensitivity of these afferents is believed to be involved in the manifestation of airway hyperresponsiveness associated with mucosal injury a prominent feature of asthma. During airway inflammatory reaction a number of low molecular weight highly cationic proteins are secreted by inflammatory cells such as eosinophils that infiltrate into the airways. It is well documented that the release of these proteins can induce mucosal injury and airway hyperresponsiveness. Our recent studies have established the first direct evidence demonstrating an intense and sustained effect of both human eosinophil granule-derived and synthetic cationic proteins on vagal bronchopulmonary C-fiber endings. However the mechanism underlying both the initial stimulatory and the sustained sensitizing effects of cationic proteins on these sensory nerves is poorly understood. Our central hypothesis is that the cationic charge carried by these proteins acts on the airway mucosa triggering the release of certain inflammatory mediators that in turn exert potent effects on the C-fiber terminals. The mast cells located in the airway mucosa probably play an important role in the interaction between cationic proteins and sensory endings. Sensitization of these afferents can then lead to airway hyperresponsiveness via both cholinergic reflex pathways and tachykininergic mechanisms. Single-fiber and whole-cell patch-clamp recording techniques will be employed to measure the activity of bronchopulmonary C fibers in anesthetized rats and in isolated neurons respectively. The results obtained from this study should provide critical information for gaining new insights into the mechanisms underlying the airway hyperresponsiveness induced by cationic proteins.

project_terms:
C fiber;action potentials;asthma;carbon dioxide tension;chemical hypersensitivity;electrophysiology;enzyme activity;hydrogen ions;inflammation;laboratory rat;lung injury;mucosa;neuropharmacology;ozone;prostaglandin endoperoxide synthase;tachykinin;vagus nerve;voltage /patch clamp


application_id: 7091452
project_number: 5R01AG024950-03
project_title: Aging stem cells and their microenvironment
administering_ic: NIA
award_notice_date: 2006-07-05
opportunity_number: RFA-AG-04-008
application_type: 5
activity_code: R01
ic: AG
serial_number: 024950
program_official: WILLIAMS, JOHN
project_start_date: 2004-09-30
project_end_date: 2009-07-31
study_section: ZAG1-ZIJ-7(O1)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most if not all of the body's organ systems show the effects of aging. It is now increasingly apparent that homeostatic maintenance of organ function owes to cellular renewal derived ultimately from stem cells. Therefore aging stem cells may critically impact maintenance of normal organ function. Adult stem cells in all organs studied rely on micro environmental cues from supporting stroma to modulate if not direct stem cell replication differentiation and quiescence. This proposal investigates the effect of aging on both stem cells and the microenvironment. Using hematopoietic stem cells as a model we test the hypothesis that the number of stem cells available in bone marrow affects that organ's capacity to supply blood and immune cells during aging. Quantitative trait loci (QTL) affecting natural variation in stem cell numbers in mice have been mapped and congenic strains have been generated in which independent effects of the loci can be studied. Efforts underway to identify the genes responsible for the QTL will identify molecular pathways important in regulating stem cell numbers and the effect of aging on them. Effects of age on the stem cell microenvironment will focus on two essential functions. The first is to capture stem cells from the circulating blood. Stem cells are in a natural state of flux between the marrow and blood with evidence that this pathway is bidirectional. Homing of stem cells to the marrow is the first critical step in stem cell transplantation in the treatment of hematologic and non-hematologic malignancies. As more and older patient's become candidates for transplant the effects of age on homing are largely unexplored. Lastly clinical science has found ways to dramatically alter the flux of stem cells from the marrow microenvironment into the blood in a process called mobilization. Despite its widespread use in harvesting stem cells for transplantation the basic mechanisms are not only incompletely understood the effects of aging are uncharted. We will use mouse models to test the hypothesis and the flux of stem cells both to and from the marrow is altered in aging.

project_terms:
aging;apoptosis;bioinformatics;cell migration;cell proliferation;flow cytometry;gene expression;genetic regulation;genetically modified animals;hematopoietic stem cells;laboratory mouse;longitudinal animal study;microarray technology;quantitative trait loci;telomerase;telomere;transfection /expression vector


application_id: 7091189
project_number: 1R01AG026307-01A1
project_title: Repetitive Thought Stress and Immunity in Older Adults
administering_ic: NIA
award_notice_date: 2006-07-13
opportunity_number: PA-05-027
application_type: 1
activity_code: R01
ic: AG
serial_number: 026307
suffix: A1
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2011-04-30
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
anxiety;behavior test;behavioral /social science research tag;clinical research;cortisol;emotional adjustment;human old age (65+);human subject;immunosenescence;influenza;influenza vaccines;interleukin 6;interview;longitudinal human study;marriage /marital status;memory;patient oriented research;physiologic stressor;psychological aspect of aging;psychological stressor;quality of life;saliva;social behavior;stress


application_id: 7090696
project_number: 5R01HL070911-03
project_title: Sleep and Sleep Disorders in Children
administering_ic: NHLBI
award_notice_date: 2006-07-12
application_type: 5
activity_code: R01
ic: HL
serial_number: 070911
program_official: TWERY, MICHAEL
project_start_date: 2004-07-15
project_end_date: 2008-05-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1959297
contact_pi: MOLFESE, DENNIS L
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): The goal of this research is to investigate the effects of sleep restriction and sleep prolongation on cognitive processes in preschool and school-age children as measured by event-related potentials (ERPs). Children throughout the USA frequently face mild sleep restrictions due to a host of pressures - demands of homework school activities peer interactions family activities - that reduce the number of hours of sleep children experience from day-to-day or week-to-week. Such changes can impact the child's ability to attend to classroom studies or other areas that place additional cognitive processing demands on the child. To pursue this goal 480 children half females from 4 through 8 years of age will participate in a number of cognitive tasks while their brain electrical activity is recorded. It is anticipated that changes in the topographic recordings of brain electrical patterns across the scalp will change as a function of sleep deprivation and sleep prolongation. Such changes will be characterized by latency shifts that reflect the rapidity in which the brain responds to information. Analyses will also attempt to localize the hypothesized sources within the brain where information is processed. This work will greatly enhance knowledge concerning the role sleep plays in brain and behavior and can lead to the development of a means to identify children potentially at cognitive risk because of chronic sleep restrictions. This is an important first step in minimizing potential negative risks of sleep restriction on cognitive development during the childhood years.

project_terms:
actigraphy;brain electrical activity;children;clinical research;cognition;electroencephalography;electromyography;electrooculography;evoked potentials;human subject;middle childhood (6-11);polysomnography;preschool child (1-5);sleep;sleep disorders


application_id: 7090642
project_number: 5R01HL073693-04
project_title: HIV protease inhibitors marcophage function/estrogen
administering_ic: NHLBI
award_notice_date: 2006-06-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 073693
program_official: MCDONALD, CHERYL
project_start_date: 2003-07-09
project_end_date: 2008-06-30
study_section: AIDS and Related Research 6[AARR-6]
contact_pi_person_id: 1859333
contact_pi: WILSON, MELINDA E
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Protease inhibitor therapy has greatly increased the lifespan of individuals infected with the human immunodeficiency virus (HIV). Unfortunately one of the deleterious side effects of protease inhibitor therapy is dyslipidemia which is known to be closely associated with development of atherosclerosis. The development of atherosclerosis is a multifactorial process in which macrophage lipid metabolism plays a central role. In the healthy population premenopausal women have a lower incidence of atherosclerosis as compared to men. Women on protease inhibitor therapy however have similar dyslipidemia as men on protease inhibitor therapy suggesting that the cardioprotective effects of estrogen are lost. Additionally preliminary studies in mice show that female mice have significantly fewer atherosclerotic lesions accompanied by a reduced disruption of lipid metabolism in macrophages. Therefore this proposal will test the hypothesis that the gonadal steroid estrogen modulates the effects of HW protease inhibitors on macrophage lipoprotein metabolism and thus atherosclerotic lesion formation. Aim 1 will determine the ability of 17??estradiol to suppress HIV protease inhibitor-induced macrophage sterol accumulation. We will use the human monocyte/macrophage cell line THP-1 to define the effects 17??estradiol on the HIV protease inhibitors ritonavir and amprenavir induced alterations of CD36 expression and CD36-dependent function by measuring lipoprotein uptake and cholesterol efflux. Aim 2 will investigate potential mechanisms by which 17??estradiol prevents macrophage dysfunction induced by HW protease inhibitors. An estrogen receptor antagonist will be administered to THP-1 cells to assess the role of estrogen receptors in the regulation of the scavenger receptor CD36 expression and function in the presence of ritonavir and/or amprenavir. We wilt also examine the expression and function of peroxisome proliferating activated receptor gamma (PPAR?) and PPAR? mRNA following estrogen treatment. Aim 3 will determine if 17??estradiol alters the development of atherosclerotic lesions induced by HW protease inhibitors in vivo. We will examine the atherosclerotlc lesion size and lipid metabolism in peritoneal macrophages from intact LDL receptor null mice as well as ovariectomized and estrogen replaced female mice. To determine if estrogen receptors are needed in vivo LDL receptor null mice will be crossed with estrogen receptor null mice to determine if the estrogen receptors are required for estrogen to prevent atheroscterotic lesions and macrophage dysfunction following HIV protease inhibitor treatment. The data obtained from these studies will be critical to enhancing our understanding of the actions of estrogen in the cardiovascular system as well as estrogen function during HIV infection and protease inhibitor therapy.

project_terms:
HIV infections;amprenavir;atherosclerosis;biological signal transduction;confocal scanning microscopy;estrogen receptors;estrogens;genetically modified animals;human immunodeficiency virus;hyperlipidemia;laboratory mouse;lipid metabolism;low density lipoprotein receptor;macrophage;peroxisome proliferator activated receptor;polymerase chain reaction;protease inhibitor;protein localization;receptor expression;ritonavir;scavenger receptor;tissue /cell culture;western blottings


application_id: 7090595
project_number: 5U10EY010403-13
project_title: OCULAR HYPERTENSION TREATMENT STUDY (OHTS)
administering_ic: NEI
award_notice_date: 2006-09-20
opportunity_number: EY93-01
application_type: 5
activity_code: U10
ic: EY
serial_number: 010403
program_official: EVERETT, DONALD F
project_start_date: 1994-01-01
project_end_date: 2008-12-31
study_section: Vision Research and Training Committee[VSN]
contact_pi_person_id: 6517188
contact_pi: SOLTAU, JOERN B
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This is an application to become a participating Clinical Center int he         Ocular Hypertension Treatment Study (OHTS).  The complete details of the        OHTS rationale design and methods are contained in the OHTS Manual of         Procedures.                                                                                                                                                     This proposal provides complete documentation of the ability of the             Department of Ophthalmology and Visual Sciences of the University of            Louisville College of Medicine to screen large numbers of ocular                hypertensive patients and to enroll at lease 50 eligible patients over a        24-month period.                                                                                                                                                Documentation is provided of the capabilities of the proposed investigators     and their staff for performance of the study in accordance with the details     of the OHTS Manual of Procedures.                                                                                                                               The chairman of the Department of Ophthalmology and Visual Sciences is an       investigator and has committed the resources of the department to this          study.  In addition all fellowship-trained glaucoma specialists in the         Louisville community are co-investigators and are committed to the success      of this study.  This unanimous support represents the strength of the           commitment of the Department of Ophthalmology and the glaucoma community in     Louisville to the Ocular Hypertension Treatment Study.  Patients will be        drawn from two general eye clinics three glaucoma sub-specialty practices      and d large health maintenance organization.                                                                                                                    By conducting this study in the kentucky Lions Eye Research Institute           (KLERI) we ensure that we will have ample facilities and personnel for the     protocol.  We have space dedicated for clinical research.  We have              experienced personnel to cross cover the study personnel.  The clinical         coordinator/technician is experienced in ophthalmic photography and will be     trained to back up our ophthalmic photographer.  We have a study                coordinator working on other projects who will be crossed-trained to back       up the clinical coordinator/technician.

project_terms:
African American;beta antiadrenergic agent;carbachol;chemoprevention;clinical trials;cooperative study;disease /disorder proneness /risk;dosage;drug administration routes;drug adverse effect;early diagnosis;epinephrine;eye disorder chemotherapy;eye fundus photography;eye pharmacology;glaucoma;glaucoma test;human subject;human therapy evaluation;intraocular pressure;longitudinal human study;mass screening;medical complication;miotic;optic disk;pilocarpine;prognosis;statistics /biometry;therapy compliance;vision disorders;visual fields


application_id: 7090184
project_number: 2R01AA012895-04A1
project_title: Mechanisms of Alcohol Tolerance and Priming in Humans
administering_ic: NIAAA
award_notice_date: 2006-09-22
application_type: 2
activity_code: R01
ic: AA
serial_number: 012895
suffix: A1
program_official: WITT, ELLEN
project_start_date: 2000-12-01
project_end_date: 2010-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
alcoholic beverage consumption;alcoholism /alcohol abuse;behavioral /social science research tag;clinical research;cognition;disease /disorder proneness /risk;human subject;impulsive behavior;judgment;locus of control;reinforcer;self medication;substance abuse related behavior


application_id: 7090133
project_number: 5R01HL072410-04
project_title: IL-6 in late preconditioning
administering_ic: NHLBI
award_notice_date: 2006-06-12
application_type: 5
activity_code: R01
ic: HL
serial_number: 072410
program_official: SCHWARTZ, LISA
project_start_date: 2003-07-01
project_end_date: 2009-06-30
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 7035773
contact_pi: DAWN, BUDDHADEB
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this proposal is to elucidate the cellular and molecular mechanisms underlying the late phase of preconditioning (PC). Recent studies have shown that the generation of NO and the activation of the JAK-STAT pathway are necessary for the development of late PC while iNOS and COX-2 act as obligatory mediators of protection. Our fundamental hypothesis is that the mechanism for the delayed antiapoptetic and infarct-sparing effects of both ischemia- and NO donor-induced late PC involves IL-6- dependent signaling via the JAK-STAT and ERK-C/EBP pathways which leads to upregulation of myocardial iNOS and COX-2. This study will utilize a broad multidisciplinary approach that will encompass the fields of integrative physiology protein chemistry molecular biology and gene targeting. All studies will be carried out in an established mouse model of late PC. In Aim 1 the role of IL-6 in the genesis of ischemia-induced and NO donor-induced late PC will be conclusively verified using IL-6-/- mice. The effects of IL-6 on cardiomyocyte apoptosis as well as infarct size will be examined. The role of IL-6Ralpha in augmenting the protective effects of IL-6 will be determined in IL-6alpha overexpressing transgenic mice. Aim 2 will systematically investigate the activation of the JAK-STAT pathway by IL-6 and its role in the development of protection against apoptosis and infarction. Using STAT1-/- mice and a novel cardiac-specific STAT3-/- mouse the role of specific STAT protein(s) will be conclusively identified. Aim 3 will examine IL-6- dependent ERK-C/EBP signaling in relation to the development of protection against apoptosis and infarction. The role of this pathway in both ischemic and NO donor PC will be conclusively established by the use of C/EBPbeta-/- mice. Aim 4 will elucidate the role of IL-6-activated JAK-STAT and ERK-C/EBP pathways in inducing myocardial iNOS 24 h later. Aim5 will determine the role of COX-2 induction via the IL-6-ERKC/ EBP axis in the mediation of delayed protection against apoptosis and infarction. COX-2-/- mice will be used to obtain conclusive results. This proposal will yield important new information regarding the antiapoptotic and delayed cardioprotective effects of IL-6 and its role in the induction of myocardial iNOS and COX-2 obligatory mediators of late PC. This information may eventually lead to the development of novel therapeutic strategies to protect the heart in patients with ischemic heart disease.

project_terms:
JAK kinase;apoptosis;cardiac myocytes;cardiovascular disorder prevention;cytoprotection;enhancer binding protein;enzyme activity;enzyme induction /repression;gel mobility shift assay;genetically modified animals;interleukin 6;laboratory mouse;mitogen activated protein kinase;myocardial infarction;myocardial ischemia /hypoxia;nitric oxide;nitric oxide synthase;prostaglandin endoperoxide synthase


application_id: 7089986
project_number: 5R15CA106248-02
project_title: Logistic joinpoint regression model in cohort studies
administering_ic: NCI
award_notice_date: 2006-05-19
opportunity_number: PA-03-053
application_type: 5
activity_code: R15
ic: CA
serial_number: 106248
program_official: TIWARI, RAM C
project_start_date: 2005-07-01
project_end_date: 2007-12-31
study_section: Biostatistical Methods and Research Design Study Section[BMRD]
contact_pi_person_id: 7726328
contact_pi: REMPALA, GRZEGORZ A
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
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): In studying trend data such as cancer mortality and incidence data one is frequently concerned with detecting a change in recent trend. The ability to identify such changes in a cohort is an important problem for both retrospective and prospective cohort studies when looking for disease patterns. The proposed research seeks to develop a method to broaden the applicability of the join point regression model in detecting changes in disease trends. Specifically we shall consider the extension of the simple Gaussian joinpoint regression model to logistic regression with K responses and possibly non-homogenous dispersion parameters. We shall derive and implement with the software the method for estimation and testing of the model parameters on the basis of the conditional maximum likelihood. Since the location of the joinpoints (change points) in the model is unknown the method would employ the iterative conditional maximization algorithm in seeking the solutions of the likelihood equations. In order to test the validity of the final model as well as to assess the significance of the final set of detected change points we shall sequentially apply the parametric bootstrap method. The conditions for consistency and general appropriateness of all the resulting estimation and testing procedures in our setting shall be also derived. Additionally we shall compare via simulation studies the performance of the joinpoint logistic regression model versus that of penalized splines (P-splines) and multivariate adaptive regression splines (MARS) models. Finally we shall also apply the developed model to the longitudinal dataset on cancer mortality among the members of the Louisville VC cohort of now retired chemical workers up until 1996. The dataset is available via the University of Louisville Health Surveillance Program. Using the joinpoint logistic regression model we shall determine the pattern of longitudinal changes (time change-points) in the cohort cancer occurrences as compared with the state reference population adjusting for the temporal clustering of the disease in the different production areas. The use of the Louisville VC cohort data shall allow us to illustrate our approach in an innovative application to monitoring occupational diseases and to compare its effectiveness with that of the standard methodology in view of the multiplicity of different analysis of this dataset available in the literature.

project_terms:
chemical carcinogenesis;clinical research;computer program /software;computer simulation;human data;human mortality;industry;longitudinal human study;mathematical model;model design /development;neoplasm /cancer;neoplasm /cancer epidemiology;occupational disease /disorder


application_id: 7089883
project_number: 5R01NS046242-03
project_title: Structure/Function of N-ethylmaleimide Sensitive Factor
administering_ic: NINDS
award_notice_date: 2006-07-03
application_type: 5
activity_code: R01
ic: NS
serial_number: 046242
program_official: TALLEY, EDMUND M
project_start_date: 2004-09-20
project_end_date: 2008-06-30
study_section: Synapses, Cytoskeleton and Trafficking Study Section[SYN]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):   
The homohexameric N-ethylmaleimide Sensitive Factor (NSF) is a key element in most physiologically important vesicular trafficking and exocytosis events (i.e. neurotransmission hemostasis immune responses). As an AAA ATPase NSF acts as a "protein helicase" unwinding spent SNARE (SNAP receptor) complexes after they have mediated membrane fusion. Dysfunction of NSF leads to stark phenotypes such as paralysis or growth arrest. NSF protomers have three contiguous domains (NSF-N NSF-D1 and NSF-D2); each contributes uniquely to activity. Despite our advances little is known about which structural elements are required for NSF to bind its adaptor protein alpha SNAP (Soluble NSF Attachment Proteins) and to use the chemical energy from ATP hydrolysis to disassemble SNARE complexes. This proposal's Specific Aims focus on these key unanswered questions. The Aims are: 1) To determine which structural features of NSF-N are required for SNAP-SNARE complex binding and SNAP-mediated stimulation of the ATPase activity of NSF. 2) To determine what structural elements of NSF-D1 promote SNAP-dependent enhancement of nucleotide hydrolysis and facilitate the conformational changes needed for SNAP-SNARE binding and disassembly. 3) To determine the conformational changes that occur in NSF as it progresses through the different nucleotide states of its ATP hydrolysis cycle. For the first two aims structure-based mutagenesis will be combined with a battery of functional assays to assess the importance of specific regions of NSF. For the third aim cryo-electron microscopy and single particle image analysis will be used to generate 3D maps of the NSF hexamer in the different nucleotide-induced conformations (ADP ATP and ADP-Pi). These structures will then be compared to determine what parts of the NSF hexamer change and how they might shift conformations during the ATP hydrolysis cycle. From the knowledge generated by the experiments in these three specific aims it will be possible to better understand the catalytic mechanism of NSF as well as that of a number of other cellular ATPases of the AAA family.

project_terms:
adenosinetriphosphatase;binding sites;conformation;cryoelectron microscopy;hydrolysis;intracellular transport;maleimides;membrane proteins;protein structure function;site directed mutagenesis;structural biology;vesicle /vacuole


application_id: 7088250
project_number: 1R21HL081614-01A1
project_title: The Role of O-GlcNAc in Platelet Activation
administering_ic: NHLBI
award_notice_date: 2006-03-31
opportunity_number: PA-03-015
application_type: 1
activity_code: R21
ic: HL
serial_number: 081614
suffix: A1
program_official: SARKAR, RITA
project_start_date: 2006-04-01
project_end_date: 2008-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): A platelet's role in hemostasis is to respond to lesions in the vasculature. Dysfunction leads to bleeding diatheses or to the pathogenic thrombosis that causes strokes heart attacks and other occlusive events which are major health issues in today's society. To understand hemostasis it is critical to understand platelet activation. This proposal focuses on a recently defined post-translational modification of platelet proteins that seems integral to activation. O-GlcNAcylation is not a standard form of glycosylation. It is the addition of a single N-acetylglucosamine to SER or THR residues. O-GlcNAc residues appear to be reciprocal with phosphorylation on a number of proteins and thus have been tied to key intracellular signaling events in other cell types. In platelets O-GlcNAc is present on as many as 100 proteins and its dynamic turnover is required for platelet function specifically granule release. When cyclical exchange of O-GlcNAc is blocked by a specific inhibitor that prevents its removal platelets fail to respond to thrombin collagen or A23187. The proposed experiments will expand these observations to determine which platelet proteins are modified and thus shed light on how O-GlcNAcylation affects platelet physiology. These studies will provide the initial data to directly address our long term hypothesis that dynamic changes in O-GlcNAcylation of specific platelet proteins are critical for platelet function. One Specific Aim is proposed: To identify platelet proteins which are modified with O-GlcNAc and to determine their site(s) of modification. This Aim will use O-GlcNAc-specific affinity chromatography techniques and mass spectroscopy-based proteomic analysis to identify O-GlcNAcylated proteins in both resting and stimulated platelets. Once completed/the experiments of this two year R21 application will provide the database needed to more fully understand the role of O- GlcNAcylation in platelet function. This information will further elucidate the events essential to the regulation of hemostasis and perhaps lead to a better understanding of how platelet function can be affected by metabolic syndromes such as diabetes.

project_terms:
N acetylglucosamine;affinity chromatography;antibody;biotechnology;glycosylation;hemostasis;immunoprecipitation;laboratory rabbit;mass spectrometry;molecular site;platelet activation;posttranslational modifications;protein structure function;proteomics;western blottings


application_id: 7087950
project_number: 5R01DE015565-03
project_title: REGULATION OF NODAL SIGNALING IN HOLOPROSENCEPHALY
administering_ic: NIDCR
award_notice_date: 2006-06-29
application_type: 5
activity_code: R01
ic: DE
serial_number: 015565
program_official: SMALL, ROCHELLE K
project_start_date: 2004-07-01
project_end_date: 2009-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Holoprosencephaly represents a common birth defect (1:16000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline) which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors Smad2 and 4 and FoxH1 (FAST). Importantly members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto Null allele and recently we generated a Cripto hypomorphic allele Cripto3-loxP by genetic manipulation. Approximately 50 percent of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-( signaling by blocking Smad2 function. Interestingly mutations in human TGIF gene are associated with holoprosencephaly suggesting its function in axial midline formation presumably through regulating Nodal/Smad2 signaling pathway. Based on these results we will pursue the following Specific Aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

project_terms:
biological signal transduction;brain morphology;cleft lip;congenital brain disorder;congenital oral /facial /cranial defect;developmental genetics;developmental neurobiology;embryogenesis;epidermal growth factor;gene targeting;genetic manipulation;genetic models;genetically modified animals;growth factor receptors;homeobox genes;laboratory mouse;mammalian embryology;microarray technology;molecular biology;neurogenesis;phenotype;protein structure function;transforming growth factors


application_id: 7087813
project_number: 5R01AA012600-07
project_title: Development of screens for drugs in alcohol dependence
administering_ic: NIAAA
award_notice_date: 2006-06-26
application_type: 5
activity_code: R01
ic: AA
serial_number: 012600
program_official: EGLI, MARK
project_start_date: 1999-09-23
project_end_date: 2008-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): The absence of accepted simple screens with predictive validity is one of several barriers to the discovery of novel drugs for alcohol dependence. For example modulation of the glutamate - NMDA receptor (NMDAR) is a clear molecular target for drugs that might decrease relapse rates and/or reduce alcohol-associated neurotoxicity but there is no accepted way of preclinically evaluating such drugs for potential value against these therapeutic targets. The original aims of the project were (a) to establish a hierarchy of screens for these therapeutic targets validating the screens with drugs believed or known to be effective and (b) to generate a library of novel active compounds to be evaluated using the screening hierarchy. The screening hierarchy is almost complete with the exception of validation of behavioral screens for alcohol-associated neurotoxicity. Additionally over 600 compounds based on endogenous modulators of the NMDAR have been synthesized and screened for appropriate molecular effects. Two novel and potent structural series have emerged based on tryptamine and agmatine derivatives which are believed to modulate NMDAR function in different ways. Similar naturally occurring compounds have previously been demonstrated to reduce drug-seeking behavior and/or to be neuroprotective. Some of the novel synthetic compounds have now been screened for neuroprotective properties in vitro and anti-seizure properties during withdrawal in vivo. Active compounds will next be evaluated for effects on rat drinking in an "alcohol deprivation effect" paradigm for effects on mouse behavior in a "conditioned pseudowithdrawal" paradigm and in behavioral screens of neuroprotection in rats when these have been validated. The specific aims of this competing renewal are thus to complete the screening hierarchies and to continue to test the two novel compound series in these. Additionally since it may now be possible to identify novel compounds with potential therapeutic value in alcohol dependence further research is necessary to protect the intellectual property in these and to bring them to the stage of toxicity testing prior to clinical evaluation. The overall objective remains to demonstrate the legitimacy of this approach to medications development in alcohol dependence by establishing the reproducibility and predictive validity of the screening hierarchies for evaluation of novel compounds. Even if this objective is not fully achieved the novel compounds and their performance in the different screens will help to elucidate the roles of NMDARs and their modulators in relapse and in alcohol-associated neurotoxicity.

project_terms:
NMDA receptors;alcoholism /alcohol abuse chemotherapy;alcoholism antagonist;calcium flux;central nervous system disorders;chemical structure function;chemical synthesis;chronic disease /disorder;combinatorial chemistry;computer program /software;drug design /synthesis /production;drug screening /evaluation;drug withdrawal;high throughput technology;laboratory mouse;laboratory rat;neural degeneration;neuroprotectants;neurotoxicology;radiotracer;receptor binding;relapse /recurrence;tissue /cell culture;tryptamines


application_id: 7087808
project_number: 5R01AA014371-03
project_title: Mechanisms of Alcohol-Induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2006-06-21
application_type: 5
activity_code: R01
ic: AA
serial_number: 014371
program_official: RADAEVA, SVETLANA
project_start_date: 2004-09-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-F(02)M]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_terms:
S adenosylmethionine;T cell receptor;alcoholism /alcohol abuse;apoptosis;blood tests;cell population study;clinical research;cytogenetics;enzyme activity;enzyme inhibitors;enzyme linked immunosorbent assay;flow cytometry;gel mobility shift assay;gene expression;glutathione;helper T lymphocyte;human subject;immunosuppression;methionine adenosyltransferase;monocyte;polymerase chain reaction;tissue /cell culture;western blottings


application_id: 7087511
project_number: 1U01DP000251-01
project_title: Breast and Prostate Cancer Patterns of Care in Kentucky
administering_ic: NCCDPHP
award_notice_date: 2005-09-15
opportunity_number: RFA-DP-05-071
application_type: 1
activity_code: U01
ic: DP
serial_number: 000251
program_official: COLLEY GILBERT, BRENDA J
project_start_date: 2005-09-30
project_end_date: 2008-09-29
study_section: Special Emphasis Panel[ZDP1 GXC (01)]
contact_pi_person_id: 1860311
contact_pi: FLEMING, STEVEN THOMAS
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 purpose of this research is to conduct "enhanced surveillance and operations research using population-based data" from the Kentucky Cancer Registry (KCR).  KCR has been a part of the Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries (NPCR) since the inception of the initiative and KCR is one of the recent additions to the Surveillance Epidemiology and End Results (SEER) program of the National Cancer Institute.  By focusing on improved "completeness timeliness quality and use of first course of treatment and stage data" we will strengthen the capacity of an already outstanding cancer registry to describe patterns of care for breast and prostate cancer.  We will focus on understanding how tumor patient provider and health system characteristics affect the degree to which patients receive the recognized standard of care.  To this end we propose the following aims:  (1) Describe treatment patterns for stages I through III of female breast cancer in terms of the proportion who receive the recognized standard of care; (2) Describe treatment patterns for all stages of prostate cancer; (3) Determine how tumor patient provider and health system characteristics affect treatment strategies for breast and prostate cancer; (4) Assess the completeness and quality of stage and first course of treatment data and compare the latter to evidence of treatment from Medicare claims data.  We believe that the proposed study will make a significant contribution toward building the capacity to conduct enhanced surveillance at an already outstanding cancer registry in the state of Kentucky.  We also believe that this study will help us to understand the degree to which breast and prostate cancer patients receive the recognized standard of care and the factors that move doctors and patients to deviate from that standard.  Such understanding should help us distinguish those factors that represent legitimate and reasonable causes for such deviation from the factors that may represent unreasonable causes such as barriers to access or discrimination.


application_id: 7086316
project_number: 5K05CA096558-03
project_title: Psychological and Behavioral Impact of Cancer Screening
administering_ic: NCI
award_notice_date: 2006-06-29
opportunity_number: PAR-00-039
application_type: 5
activity_code: K05
ic: CA
serial_number: 096558
program_official: LOHREY, NANCY
project_start_date: 2004-07-01
project_end_date: 2009-06-30
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 1874012
contact_pi: ANDRYKOWSKI, MICHAEL A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  While cancer screening can reduce mortality and morbidity participation in cancer screening can have a negative psychological and behavioral impact even when no malignancy is detected.  Understanding and management of the potential negative impact of cancer screening is the focus of the research and mentoring activities for this award.  The PI has spent over 20 years conducting research in behavioral oncology and mentoring pre- and postdoctoral trainees.  His career has focused on the psychological social and behavioral dimensions of cancer detection diagnosis treatment and recovery.  This award will enable him to continue to develop his research and mentoring activities.  The research builds on the Pl's ongoing study (R01 CA94036) of psychological and behavioral outcomes of transvaginal (TVS) screening for ovarian cancer and the Pl's recent study of psychological and behavioral outcomes of benign breast biopsy (BBB).  Three synergistic studies are proposed: (1) prospective longitudinal study of psychological and behavioral outcomes of an abnormal TVS screening result; (2) development and evaluation of brief psychoeducational interventions for managing the negative psychological and behavioral impact of BBB; and (3) development of brief psychoeducational interventions for managing the negative impact of an abnormal TVS screening result.  The mentoring plan builds on the Principal Investigator's prior experience as PI for three pre-and postdoctoral research training grants.  Mentoring will be provided for 4-6 trainees each year.  All trainees participate in an existing research training program in behavioral oncology.  The training program consists of core elements: (1) coursework; (2) participation in behavioral oncology research; and (3) participation in national professional meetings.  These core elements enable achievement of training objectives: (1) knowledge of the behavioral oncology literature; (2) knowledge of the medical basis of cancer; (3) participation in all phases of research; (4) acquisition of skills critical to both quantitative and qualitative research; (5) familiarity with medical settings in which cancer detection diagnosis and treatment occurs; and (6) professional development.  The overall goal of the training program is to prepare trainees for careers as independent investigators in behavioral oncology.

project_terms:
behavioral /social science research tag;cancer prevention;clinical research;educational resource design /development;health behavior;health care service utilization;human subject;longitudinal human study;mass screening;neoplasm /cancer diagnosis;neoplasm /cancer epidemiology;outcomes research;ovary neoplasms;patient oriented research;role model;training


application_id: 7086183
project_number: 5R03CA112664-02
project_title: Novel strategies to prevent lung cancer
administering_ic: NCI
award_notice_date: 2006-06-29
opportunity_number: PAR-04-147
application_type: 5
activity_code: R03
ic: CA
serial_number: 112664
program_official: STEELE, VERNON E
project_start_date: 2005-07-01
project_end_date: 2008-06-30
study_section: ZCA1-SRRB-U(M1)
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of this project is to translate new knowledge of fundamental mechanisms of mutagenesis into a clinically useful regimen to reduce the incidence of cigarette smoke-induced lung cancer. Mutations in DNA are generally considered to have an etiologic role in the development of cancer. In the case of non-small cell lung cancers multiple mutagenic events in alveolar epithelial cells are thought to be causally involved in carcinogenesis. If so it follows that reducing the frequency of such mutations will reduce the incidence of lung cancer induced by mutagens. Recent data indicates that virtually all mutations induced by the active metabolite of 1 of the principal chemical carcinogens in cigarette smoke benzo[a]pyrene are dependent on a newly-described Y-family DNA polymerase encoded by the REV1 gene. This application proposes to reduce the REV1 mRNA in the lungs of mice by intracellular expression of gene-specific ribozymes that are targeted to specific subcellular compartments. Then the mice will be exposed to an established carcinogen-induced lung cancer protocol. This will be accomplished in 2 Specific Aims: 1) to optimize the aerosolized delivery of a reporter gene to mouse lungs in vivo. 2) to use this method to deliver DNA that expresses ribozymes targeted against REV1 mRNA . The mice and the appropriate controls will be exposed to ongoing protocols that are known to induce lung cancer. The hypothesis predicts that reducing the level of this protein will reduce the mutagenic response of lung epithelial cells to chemical carcinogens in cigarette smoke and will result in a greatly reduced incidence of lung cancer. This pilot study is designed to provide the experimental rationale to expand the approach to larger protocols in which lung tumors are induced in rodents by cigarette smoke. In principle the idea of reducing mutagenesis without altering cytotoxic responses presents a novel and attractive method to reduce the risk of lung cancer in smoke-exposed populations prior to the appearance of disease symptoms.

project_terms:
DNA directed DNA polymerase;benzopyrenes;cancer prevention;carcinogenesis inhibitor;chemical carcinogenesis;gene delivery system;gene therapy;laboratory mouse;lung neoplasms;mutagens;nucleotidyltransferase;reporter genes;respiratory epithelium;ribozymes;tobacco abuse


application_id: 7085725
project_number: 1R01HL084611-01
project_title: Role of the Nuclear Receptor Nor-1 in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2006-03-30
application_type: 1
activity_code: R01
ic: HL
serial_number: 084611
program_official: SRINIVAS, POTHUR R
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
animal breeding;aorta;apolipoprotein E;atherosclerosis;cardiovascular injury;cell proliferation;gene expression;genetic promoter element;genetically modified animals;inflammation;laboratory mouse;laboratory rat;molecular pathology;nuclear receptors;protein structure function;transcription factor;vascular endothelium;vascular smooth muscle


application_id: 7085336
project_number: 5R01GM065459-04
project_title: Novel feedback-regulation of xenobiotic bioactivation
administering_ic: NIGMS
award_notice_date: 2006-07-04
opportunity_number: PA-99-016
application_type: 5
activity_code: R01
ic: GM
serial_number: 065459
program_official: OKITA, RICHARD T
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
contact_pi_person_id: 6807001
contact_pi: LINDER, MARK W
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Background: Xenobiotic metabolism hinges on a delicate balance between phase I (bioactivation) and phase II (detoxification) enzymatic activity.  Suppression of bioactivation has been shown to protect against drug-induced liver injury.  In humans cytochrome P4502E 1 (CYP2E1) is suppressed by IFN-( and other mediators of the inflammatory response.  A mechanism for this decrease in activity and its role in affording host advantage has not yet been proposed.  Preliminary Findings: Based on our preliminary studies of CYP2E1 expression we now propose a novel mechanism of feedback-regulation.  Within the proximal promoter of the human CYP2E1 gene is a nucleotide sequence ((-interferon activation sequence GAS) responsible for y-interferon ((-IFN)-dependent suppression of gene transcription.  A naturally occurring polymorphism G(-71)T within this sequence renders the CYP2E1-promoter insensitive to suppression by (-IFN.  General Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter.  In order to test this hypothesis it is first necessary to demonstrate a viable mechanism.  Thus our Working hypothesis for this proposal is: Interferon-( suppresses CYP2E1 transcription by acting through the GAS element.  This mechanism limits the intracellular pool of CYP2E1 enzyme and decreases the production of reactive metabolic intermediates.  Polymorphism of the GAS structure prohibits IFN-(-dependent regulation of CYP2E1 and therefore increases risk of toxicity due to accumulation of reactive metabolic intermediates Approach: To test this hypothesis we will; i) Characterize the molecular mechanisms of IFN-(-mediated suppression of CYP2E1 in humans; ii) Define the influence of IFN-( on the metabolism and toxicity of substrates bioactivated by CYP2E1; iii) Define the clinical significance of the CYP2E1*7B allele in selected human diseases linked to the bioactivity of CYP2E1; and iv) Demonstrate that control of CYP2E1 expression is linked to inflammation caused by toxic injury in a physiologic model.  Significance: This research will identify a novel and perhaps general mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1.  These findings may lead to an approach for identifying susceptible individuals and provide insight into potential therapeutic or preventive strategies.

project_terms:
acetaminophen;alleles;cell line;clinical research;cytochrome P450;drug metabolism;enzyme activity;enzyme substrate;gel mobility shift assay;genetic polymorphism;genetic transcription;human subject;inflammation;interferon gamma;laboratory mouse;liver disorder;reporter genes


application_id: 7084604
project_number: 5R01DA017186-04
project_title: Neurochem Chip: Methodology to Study Untethered Rats
administering_ic: NIDA
award_notice_date: 2006-06-22
opportunity_number: PAR-03-017
application_type: 5
activity_code: R01
ic: DA
serial_number: 017186
program_official: PILOTTE, NANCY S
project_start_date: 2003-09-30
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-4(03)R]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This Stage II CEBRA application involves the development of Neurochem Chip microelectrodes for neurochemical recordings of neurotransmitter release in rats and mice. The long-term goals of this project are to develop Neurochem Chips for rapid in vivo recordings of glutamate GABA acetylcholine and choline in the CNS of freely moving rats and mice. In developing the technologies we will first implement and improve the technologies of Neurochem Chips in rats and mice. First we plan to optimize the recording approaches in the anesthetized rat and mouse. This will involve microelectrode development in corporation with Thin Film Technologies Hybrid Circuits Inc. and Cleveland Medical Devices Inc. Instrumentation development will occur in cooperation with PCB Assembly Inc. We will carry out extensive in vitro and in vivo recordings of glutamate GABA choline and acetylcholine release and uptake in the prefrontal cortex striatum and hippocampus of anesthetized rats. There are numerous microelectrode instrumentation and recording details that must first be optimized to develop reliable Neurochem Chips. These microelectrodes recordings will be compared with microdialysis measures of glutamate and choline to try and further validate the techniques. As this grant progresses the refined and adapted technologies will be applied to studies in awake behaving rats and mice. Freely moving tethered systems will be developed for 4-channel measures in awake rats and 2-channel recordings in mice. In addition a biotelemetric system will be developed to record from rats with a totally untethered system. This should contribute to 1) increased signal-to-noise of the recordings 2) increased freedom of movement of the rats and 3) the potential for monitoring large numbers of rats. The major goal of these studies is to develop Neurochem Chips that are reliable sensitive and selective for the rapid (second-by-second) determination of neurochemicals in the extracellular space of the brain. This technology could have a major impact on basic science studies of neurotransmitter systems involving drug abuse disease models and behavior. This CEBRA Stage II mechanism is needed due to the number of technical issues that must be addressed before these techniques can be disseminated to other researchers.

project_terms:
acetylcholine;choline;evaluation /testing;extracellular;gamma aminobutyrate;glutamates;laboratory mouse;laboratory rat;microdialysis;microelectrodes;neurochemistry;neurotransmitter transport;technology /technique development;telemetry;wakefulness


application_id: 7084513
project_number: 5R01EY014599-03
project_title: Regulation of the Ocular Immune Response by RPE.
administering_ic: NEI
award_notice_date: 2006-06-19
application_type: 5
activity_code: R01
ic: EY
serial_number: 014599
program_official: SHEN, GRACE L
project_start_date: 2004-08-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-AED(01)Q]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the pathogenesis of uveitis a T cell-mediated autoimmune disease in the eye using experimental autoimmune uveitis (EAU) as an experimental model. Using in vitro co-culture of uveitigeneic T cells derived from rats with uveitis (EAU) and retinal pigment epithelial (RPE) a major parenchymal cell that might be targeted by uveitogeneic T cells we have demonstrated that normal RPE cells are capable of inhibiting uveitogeneic T cell functions including proliferation and cytokine production as evidenced by that T cells are rendered hypo-responsive to their specific antigens presented by APCs when they are pre-exposed to RPE. On the other hand activated RPE  
is capable of promoting T cell responses by expression of MHC molecules and production of cytokines upon confronting uveitogenic T cells. The reciprocal interaction of uveitogeneic T cell and activated RPE elicit significant amounts of inflammatory mediators such as TNF-a IFN-r and NO which may increase target tissue damage.  
The underlying hypothesis of this project is that the outcome of interactions between uveitogenic T cells and the RPE play a critic role in the pathogenesis of the disease. Experiments are designed to determine whether uveitogenic T cells have an increased ability compared to their nonpathogenic counterparts to escape the suppression mediated by RPE or they are more resistant to the apoptotic cell death induced by RPE (Specific Aim 1). We will also test an alternative possibility that uveitogenic T cells are more capable of inducing cascading responses upon interacting with RPEs. Uveitogenic T cells may induce increased expression of MHC class II or co-stimulatory molecules on RPE cells which in turn activate the T cells and result in excessive production of inflammatory cytokines and chemokines (Specific Aim 2). The expertise of this laboratory in generating both autoreactive T cells and RPE cells and the availability of various functional tests assessing interaction between T cells and RPE will provide a competitive advantage in the proposed studies. The results of our studies will provide new insights into the pathogenesis of uveitis.

project_terms:
MHC class II antigen;T lymphocyte;apoptosis;cell cell interaction;cellular immunity;flow cytometry;gene expression;immune response;immunoregulation;interferon gamma;laboratory mouse;laboratory rat;leukocyte activation /transformation;retinal pigment epithelium;retinoid binding proteins;terminal nick end labeling;tissue /cell culture;uveitis;visual photoreceptor


application_id: 7084506
project_number: 5R01EY014366-04
project_title: Characterization of uveitogenic T cells
administering_ic: NEI
award_notice_date: 2006-06-26
application_type: 5
activity_code: R01
ic: EY
serial_number: 014366
program_official: SHEN, GRACE L
project_start_date: 2003-08-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-VISA(01)Q]
contact_pi_person_id: 1959007
contact_pi: SUN, DEMING
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Immunization of Lewis rats with myelin basic protein (MBP) and its peptides induces autoimmune encephalomyelitis (EAE) as well as an anterior uveitis (AU) that closely mimics human anterior uveitis. This reflects the observation in humans that a significant percentage (20%) of multiple sclerosis patients suffer from AU. This proposal stems from the observation that MBP-induced eye disease was more persistent than the disease of the CNS and the uveitogenic activity of MBP-reactive T cells does not always parallel with the encephalitogenic activity of the cell indicating that the mechanism involved in the pathogenesis and tolerance induction of the two diseases differ. These proposed studies will exploit a large volume of data and T cell lines obtained in my laboratory during the previous study of EAE and MBP to characterize uveitogenic T cells and to elucidate the pathogenic mechanism by which MBP-induces different autoimmune diseases in the CNS and in the eye. We propose to determine whether uveitogenic and encephalitogenic T cells are distinct or overlapping subset(s) of MBP-specific T cells and to determine whether uveitogenic T cells have augmented activation in the eye leading to prolonged disease expression. Finally we will determine whether the regulatory T cells elicited by MBP-specific encephalitogenic T subsets are less effective in neutralizing uveitogenic T cell activity and whether non-specific inhibitory cells like NKT cells will be more effective in down-regulating diverse uveitogenic T cells. Our proposal will be greatly promoted by the MBP-specific T cells lines already available in my laboratory and the experience of isolation and characterization of autoimmune regulatory T cells and autoreactive T cells elicited by whole MBP antigen and altered peptides. This project will enhance our ability to understand the mechanisms for the development of autoimmune diseases and also identify targets for the therapeutics in uveitis.

project_terms:
T lymphocyte;cell adhesion molecules;cytokine;disease /therapy duration;experimental allergic encephalomyelitis;immunoregulation;laboratory rat;leukocyte activation /transformation;myelin basic proteins;natural killer cells;pathologic process;surface antigens;uveitis


application_id: 7083562
project_number: 5R01HL070897-04
project_title: Mechanisms of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2006-06-16
application_type: 5
activity_code: R01
ic: HL
serial_number: 070897
program_official: LIANG, ISABELLA Y
project_start_date: 2003-07-01
project_end_date: 2008-06-30
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): We have recently found that HO-1 serves as an obligatory mediator of three different forms of late preconditioning (PC) suggesting a central cardioprotective role of this protein.  Despite this and despite the fact that HO-1 is one of the most frequently induced proteins known to exist the regulation of cardiac HO-1 and the mechanism of its cardioprotective actions are unknown.  The objective of this proposal is to elucidate the molecular mechanisms underlying the newly discovered cardioprotective role of HO-1 and to use this knowledqe to develop novel therapies.  We will test the hypothesis that diverse PC stimuli upregulate HO-1 via eNOS-dependent generation of NO and subsequent activation of a cluster of stress-responsive transcription factors and that the salubrious effects of HO-1 are due to CO-dependent inhibition of apoptosis and modulation of other co-induced proteins (iNOS COX-2).  We propose that CO far from being a toxic waste product plays a fundamental role in protecting the heart against ischemia and apoptosis.  Three different forms of late PC elicited by a pathological (ischemia) physiological (exercise) and pharmacological (NO donor) stimulus will be interrogated in an effort to develop a comprehensive pathophysiologic paradigm.  A broad multidisciplinary approach will be used that will combine diverse techniques (integrative physiology protein chemistry biochemistry pathology confocal microscopy immunohistochemistry molecular biology gene targeting and transgenesis) and will integrate genetic and biochemical information at the molecular level with physiological information at the whole animal level.  A total of 16 genetically engineered mouse lines will be studied.  The effects of late PC and HO-1 on infarct size apoptosis and necrosis will be determined using HO-1-/- and HO-1 transgenic mice in conjunction with state-of-the-art pathology immunohistochemistry and confocal microscopy techniques.  The effects of CO on myocardial ischemia/reperfusion injury and apoptosis will be determined by using a novel class of compounds (CO-releasing molecules) that have potential therapeutic applications.  The role of specific transcription factors (NF-kappaB HIF-1alpha HSF1 STAT1 and STAT3) in HO-1 upregulation will be established by the use of a novel transdominant IkappaBalpha  mutant mouse with cardiac-specific repression of NF-kappaB activity knockouts for HIF-1alpha HSF1 and three specific NF-kappaB subunits (p50 RelB and c-Rel) and a novel conditional STAT3 knockout mouse.  The functional interactions of HO-1 with the other two co-mediators of late PC (iNOS and COX-2) will be deciphered in vivo by cardiac-specific overexpression and targeted disruption of each of these three genes.  This project should produce important new insights into the role of apoptosis vis-a-vis necrosis in late PC and the mechanism of HO-1-dependent cytoprotection.  If the studies of CO donors confirm our preliminary data they may pave the way for the development of novel antiischemic and antiapoptotic therapies predicated upon the supplementation of exogenous CO to patients with coronary artery disease.

project_terms:
JAK kinase;apoptosis;carbon monoxide;confocal scanning microscopy;cytoprotection;exercise;gel mobility shift assay;gene targeting;genetically modified animals;heme oxygenase;hypoxia inducible factor 1;immunocytochemistry;laboratory mouse;myocardial ischemia /hypoxia;nitric oxide;nitric oxide synthase;nuclear factor kappa beta;prostaglandin endoperoxide synthase;transcription factor


application_id: 7082960
project_number: 5U19DA017548-04
project_title: Developmemt of Novel Treatments for Nicotine Addiction
administering_ic: NIDA
award_notice_date: 2006-07-13
opportunity_number: RFA-MH-03-008
application_type: 5
activity_code: U19
ic: DA
serial_number: 017548
program_official: RAPAKA, RAO
project_start_date: 2003-09-30
project_end_date: 2008-06-30
study_section: ZMH1-BRB-S(08)
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Tobacco smoking is the number one health problem accounting for more illnesses and deaths in the US than any other factor. Despite efficacy of some current pharmacotherapies (i.e. nicotine replacement and bupropion) relapse rates continue to be high indicating that novel medications are needed. Research in the current application proposes to develop a new class of subtype-selective nicotinic receptor (nAChR) antagonists as therapeutic agents with efficacy for tobacco use cessation and for treatment of nicotine dependence. As much as tobacco use behavior and nicotine addiction have links to depression these novel drug candidates may also prove to be new treatments for depression. Based on the observations that the bupropion acts as a nAChR antagonist and that the nonselective nAChR antagonist mecamylamine has some efficacy as a tobacco use cessation agent but is limited by its peripherally-mediated side-effect of constipation we predict that the subtype-selective nAChR antagonists which we propose to develop may have therapeutic advantages and efficacy as tobacco use cessation agents in the treatment of nicotine addiction. We hypothesize that quaternizing the pyridine-N atom of the nicotine molecule with a lipophillic N-substituent to afford N-nicotinium analogs and/or by connecting these quaternary ammonium moieties with a lipophillic linker to afford NN'-bis-analogs will result in subtype-selective nAChR antagonists which will inhibit either nicotine-evoked dopamine norepinephrine or serotonin release and thus inhibit nicotine-induced behaviors indicating their potential as nicotine addiction treatments. Brain bioavailability pharmacokinetics and metabolism of the lead candidates will also be evaluated. Comparison of results using native and recombinant nAChRs will provide new insights into the subunit composition of nAChRs mediating these functions. Drug candidates will be assessed for their ability to decrease nicotine self-administration to decrease nicotine-induced reinstatement of nicotine seeking behavior and to precipitate withdrawal in nicotine-dependent animals. Thus an integrative approach (i.e. medicinal chemistry pharmacokinetics metabolism pharmacology psychology and neuroscience) will be used to increase our understanding of the underlying mechanisms of tobacco use and nicotine addiction with focus on pharmacotherapeutic candidate development.

project_terms:
drug abuse chemotherapy;drug addiction antagonist;drug design /synthesis /production;lead;nicotinic receptors;tobacco abuse


application_id: 7082849
project_number: 5K02DE016845-02
project_title: Regulation of Nodal Signaling in Holoprosencephaly
administering_ic: NIDCR
award_notice_date: 2006-05-08
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DE
serial_number: 016845
program_official: HARDWICK, KEVIN S
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
activins;biological signal transduction;brain morphology;congenital brain disorder;developmental neurobiology;embryogenesis;gene expression profiling;gene mutation;gene targeting;growth factor receptors;in situ hybridization;microarray technology;molecular biology;pathologic process;prosencephalon;tissue /cell culture;transforming growth factors


application_id: 7082271
project_number: 1R03AG028162-01
project_title: Myocardial Stiffness in Aging Associated Diastolic Heart Failure
administering_ic: NIA
award_notice_date: 2006-08-30
opportunity_number: PA-03-108
application_type: 1
activity_code: R03
ic: AG
serial_number: 028162
program_official: CARRINGTON-LAWRENCE, STACY
project_start_date: 2006-09-01
project_end_date: 2008-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diastolic dysfunction is the most common cause of congestive heart failure in elderly populations. One year mortality rates for afflicted individuals aged 70 years or older approximate 50%. Therapy options remain empirical. Although very little is known about the etiology of Diastolic Heart Failure (DHF) most studies agree that affected patients exhibit increased ventricular stiffness (reduced chamber compliance). The hypothesis underlying this work is that DHF in elderly populations reflects cross-bridge activity that persists inappropriately during the diastolic (or 'relaxed') phase of the cardiac cycle. These cross-bridges produce an 'active' component of myocardial stiffness that augments the heart's basal (passive) stiffness and impairs ventricular filling by increasing the resistance to inflowing blood. The proposed research will utilize Fischer 344 rats that exhibit aging-associated DHF at 25 months of age. Specific Aim 1 will establish the effects of aging on rat myocardial stiffness. Experiments will test the hypothesis that active stiffness due to inappropriately bound cross-bridges increases to a greater extent with aging than stiffness due to structural components. Intact trabeculae will be isolated from young (5 month) and old (25 month) rats and stretched in the presence and absence of BDM a cross-bridge inhibitor to establish the extent of age-dependent changes in active and passive stiffness. Specific Aim 2 will evaluate the effects of altered metabolite concentrations on active stiffness in young and old hearts. Experiments will utilize chemically permeabilized preparations isolated from 5 month and 25 month rat hearts and active stiffness will be assessed by measuring the tension responses to small stretches imposed under sarcomere length control. It is hypothesized that active stiffness due to persistent cross-bridge activity will be enhanced to a greater extent in the old hearts than in the young hearts when the concentrations of hydrogen ions phosphate ions and ADP are raised to levels mimicking ischemic myocardium. This research is relevant to public health because it investigates the novel hypothesis that aging-related DHF reflects inappropriate contractile activity during the relaxed phase of the cardiac cycle. The experimental results will provide new information about the underlying causes of DHF and should help scientists develop better treatments for diastolic dysfunction in elderly populations.

project_terms:
age difference;aging;animal old age;calcium flux;disease /disorder etiology;heart contraction;heart failure;heart metabolism;hemodynamics;laboratory rat;mature animal;myocardial ischemia /hypoxia;myocardium;myocardium disorder;sarcomeres


application_id: 7082109
project_number: 5R01EY012354-08
project_title: Isolation of congenital stationary night blindness genes
administering_ic: NEI
award_notice_date: 2006-06-21
application_type: 5
activity_code: R01
ic: EY
serial_number: 012354
program_official: MARIANI, ANDREW P
project_start_date: 1999-02-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Under dark-adapted conditions glutamate is released at a maximal rate at the terminals of rod and cone photoreceptors. The net result of light absorption by outer segment photopigments is to hyperpolarize the photoreceptor and to reduce the rate of glutamate release. This reduction is detected by glutamate receptors on the second order neurons of the retina the horizontal and bipolar cells. As ionotropic glutamate receptors are used by horizontal and hyperpolarizing bipolar cells both of these cell types are maintained in a depolarized state in darkness and are hyperpolarized in response to light. In comparison depolarizing bipolar cells (DBCs) incorporate a metabotropic glutamate receptor mGluR6. As a result of an incompletely defined signal transduction cascade DBCs are hyperpolarized in darkness and depolarize in response to light. To date only two key proteins of this process have been identified mGluR6 and Galpha/0 and much of the DBC signal transduction process remains to be elucidated. Nyctalopin is a newly identified protein that appears to play some key role in DBC signal transduction. Mutations in nyctalopin are known to underlie human CSNB 1 and the nob mutant mouse and both disorders are characterized by a lack of DBC function. The overall goal of the present project is to define the functional role of nyctalopin in DBC activity. This question will be addressed in several complementary experiments. There are three specific aims; 1) Determine the cellular and subcellular location of the nyctalopin protein 2) Determine the electrophysiological properties of DBCs from nob mice and 3) Identify proteins that interact with nyctalopin. At the completion of this project we expect to have a thorough understanding of the role that nyctalopin plays in DBC signal transduction and to have identified additional proteins involved in this important process.

project_terms:
antibody specificity;biophysics;cell type;chimeric proteins;congenital eye disorder;electrophysiology;expression cloning;genetically modified animals;glycosylation;immunocytochemistry;immunologic substance development /preparation;immunoprecipitation;laboratory mouse;membrane proteins;night blindness;protein localization;protein protein interaction;protein structure function;proteoglycan;proteomics;retina;retinal bipolar neuron;visual phototransduction;voltage /patch clamp;yeast two hybrid system


application_id: 7082042
project_number: 5R21ES013821-02
project_title: Perinatal Breast Cancer Programming: fat and estrogens
administering_ic: NIEHS
award_notice_date: 2006-05-09
opportunity_number: PAR-04-104
application_type: 5
activity_code: R21
ic: ES
serial_number: 013821
program_official: COLLINS, JENNIFER B
project_start_date: 2005-07-01
project_end_date: 2008-05-31
study_section: Special Emphasis Panel[ZRG1-EMNR-J(50)R]
contact_pi_person_id: 1870694
contact_pi: KNUDSEN, THOMAS B
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this research is to investigate the fetal origins of breast cancer and the role of environmental factors during early development conception-weaning. 2 sources of estrogenic exposure relevant to man will be studied: a phytoestrogen preparation from soy mainly containing genistein and daidzein and the ubiquitous environmental xenoestrogen 4-nonylphenol. Our hypothesis states the maternal estrogenic environment has a strong influence on risk to mammary tumorigenesis in adult life. 2 corollaries are: (a) phytoestrogens (90 ppm genistein/daidzein) in conjunction with an isocaloric 20% fat-diet having high n-3/n-6 polyunsaturated fatty acid balance will significantly lower the risk of mammary tumors; and (b) xenoestrogen exposure (25 ppm 4-nonylphenol) in conjunction with a low dietary n-3/n-6 fatty acid balance will promote the risk. The hypothesis will be tested in a unique mouse model for breast cancer having mammary-specific expression of a conditional mutation in the tumor suppressor Trp53 allele (flox'd p53.R270H/WAP-Cre model). The "humanized" mutant allele is permanently activated in the mammary gland epithelium exclusively in females traversing their first pregnancy-lactation cycle. This expression predisposes females to mammary tumors (-70% incidence) between ages 25-52 weeks. The project has 2 concurrent Specific Aims. (1) To investigate the effects of gestational-neonatal exposure to phyto/xenoestrogens on mammary gland development and tumorigenesis in female offspring heterozygous for the conditional p53.R270H allele reared on diets of low and high n-3/n-6 fatty acid composition. (2) Using the powerful combination of gene expression profiling with laser capture microdissection enumerate the molecular abundance profiles of epithelial end-buds and subtending ducts as foci for pre-malignant changes in the naive (virgin) and initiated (parous) mammary gland of p53.R270H/WAP-Cre females. These studies will provide new biomarker leads based in genetic regulatory networks that correlate (or anti-correlate) with altered fetal programming and pre-malignancy together with the realization of how such networks might relate functionally to the prenatal environmental risk factors in breast cancer.

project_terms:
animal genetic material tag;bioinformatics;breast neoplasms;cancer risk;developmental disease /disorder;dietary lipid;early experience;embryo /fetus;estrogens;gas chromatography mass spectrometry;gene expression profiling;genetically modified animals;hormone regulation /control mechanism;laboratory mouse;laser capture microdissection;longitudinal animal study;mammary epithelium;microarray technology;molecular oncology;mother /embryo /fetus nutrition;nutrition related tag;phytoestrogens;placental transfer;polymerase chain reaction;tumor promoters


application_id: 7082028
project_number: 5R01AG019223-05
project_title: Ceramide and acute phase proteins elevation during aging
administering_ic: NIA
award_notice_date: 2006-07-11
application_type: 5
activity_code: R01
ic: AG
serial_number: 019223
program_official: VELAZQUEZ, JOSE M
project_start_date: 2002-08-01
project_end_date: 2008-06-30
study_section: Medical Biochemistry Study Section[MEDB]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-15
project_abstract:
DESCRIPTION (provided by applicant):  Aging is associated with chronic sub-clinical inflammation that underlies the increased risk of atherosclerosis and cardiovascular disease. It is manifested by chronic low-amplitude increases in the plasma levels of the major acute phase proteins such as C reactive protein (CRP) serum amyloid A (SAA) and alpha1 acid glycoprotein (AGP) in the elderly. The long term objective of the proposed research is to deepen our understanding for the relationship between aging chronic inflammation and regulation of the acute phase proteins. We recently found that ceramide a second messenger molecule that mediates the acute stimulation of CRP AGP and SAA during inflammation is chronically increased in liver from old rats and mice. We hypothesize that increased level of ceramide in aging cause chronic activation of C/EBP transcription factor and increased expression of CRP AGP and SAA. Our objectives are to decipher the role of ceramide increases in aging - associated increase(s) in the expression of APP and to determine to what extent this is similar to the mechanisms that regulate the inflammation-induced changes in APP secretion. We propose the following specific aims: (I) To identify which pathway for ceramide generation leads to induction of acute phase proteins (APP) mRNA increases. Using adenovirus-mediated gene transfer we will overexpress acid and neutral SMases in primary mouse hepatocytes and will test which of the enzymes is sufficient to up-regulate the level of mRNA for three of the major APP in mouse SAP AGP and SAA. To identify the subcellular pool of ceramide involved in signaling subcellular localization of overexpressed ASMase and NSMase will be studied and compared to the localization of the excess ceramide generated during aging and inflammation (2) To test in vitro whether active ASMase or NSMase is required for the induction of APP mRNA by aging and inflammation. In this specific aim we will identify the mechanism for generation of ceramide and induction of APP expression during inflammation and aging. Using hepatocytes from ASMase(-/-) mice and specific inhibitors of NSMase we will identify which of SMases is indispensable for APP up-regulation. (3) To decipher the role of acid and neutral SMase in APP regulation in vivo. Using acid sphingomyelinase knockout mice we will validate the conclusions drawn from Sp. Aim 1 and 2 in a physiological context. 

The results of these studies will elucidate the factors that regulate ceramide level in inflammation and during aging. An understanding of the cellular and molecular mechanisms responsible for this regulation will help to define how ceramide exerts its effects and its role in cardiovascular disease atherosclerosis and perhaps other diseases of the elderly such as stroke and Alzheimer disease.

project_terms:
acute phase protein;aging;alpha 1 acid glycoprotein;amyloid proteins;biological signal transduction;ceramides;inflammation;laboratory mouse;liver cells;protein localization;sphingomyelin phosphodiesterase;tissue /cell culture;transcription factor


application_id: 7081246
project_number: 5R37HL055757-12
project_title: OXYGEN RADICALS AND CARDIAC ADAPTATIONS TO ISCHEMIA
administering_ic: NHLBI
award_notice_date: 2006-07-31
application_type: 5
activity_code: R37
ic: HL
serial_number: 055757
program_official: LIANG, ISABELLA Y
project_start_date: 1995-05-01
project_end_date: 2010-06-30
study_section: NSS-H
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (Adapted from Applicant's Abstract): Based on the hypothesis that                                                                             nitric oxide (NO) is released during exercise the applicant has proposed to        delineate the molecular mechanisms of exercise preconditioning (PC) by              examining the role of NO in signal transduction. The goal of the research will      be achieved by addressing five Specific Aims : (i) by establishing the role of                                                               PKCe in exercise PC; (ii) by establishing the role of the Src family of protein     tyrosine kinase in exercise PC; (iii) by identifying the specific transcription     factors responsible for the transcriptional upregulation of iNOS and the            development of exercise PC; (iv) by establishing the role of PKCe-Src/Lck           signaling pathway in the recruitment of the transcription factors responsible       for exercise PC; and (v) by studying the role of each individual NOS isoform in     triggering and mediating exercise PC and elucidating its post-translational         modulation. The results of this study will shed new light on the mechanisms of      exercise PC.


application_id: 7080434
project_number: 5F30ES013372-03
project_title: Arsenite inhibition of mitotic progression
administering_ic: NIEHS
award_notice_date: 2006-05-31
opportunity_number: PA-01-132
application_type: 5
activity_code: F30
ic: ES
serial_number: 013372
program_official: HUMBLE, MICHAEL C
project_start_date: 2004-06-15
project_end_date: 2009-06-14
study_section: Special Emphasis Panel[ZRG1-F10(20)L]
contact_pi_person_id: 7888753
contact_pi: TAYLOR, BEN F
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This project will determine whether the mechanism by which arsenate induces mitotic effects on the Anaphase Promoting Complex (APC) mediate arrest. We hypothesize that arsenite inhibits the APC and subsequently mitotic progression. The APC orchestrates progress through the cell cycle and mitosis by targeting specific mitotic substrates for proteasomal degradation via ubiquitination. Specific aim 1 will determine whether arsenite treatment inhibits APC substrate degradation necessary for mitotic exit. In Specific aim 2 we will immunoprecipitate (IP) the APC and identify its subunits in order to investigate arsenite binding to APC subunits using radiolabeled Na[73As]O2. Determination of arsenite binding requires resolution of APC subunits using SDS-PAGE examination of protein banding pattern using Sipro-Red and fluorescence imaging and subsequent autoradiography to elucidate bands incorporating radiolabeled arsenite. Western blot analysis of SDS-PAGE resolved APC subunits will be used to identify specific APC subunits. Once arsenite association is determined the proteins will be excised from the gel and identity confirmed by mass spectrometry. Specific aim 3 will determine whether arsenite inhibits APC ubiquitin ligase activity. Isolated APC will be used in an ubiquitin conjugating assay with radiolabeled APC substrates treated with or without arsenite. Reaction products will be resolved on SDS-PAGE and autoradiography will be used to determine the degree of substrate laddering due to ubiquitin conjugation. Identification of the molecular targets of arsenite is important for chemotherapeutic drug development.

project_terms:
SDS polyacrylamide gel electrophoresis;arsenic;autoradiography;cell cycle;cytotoxicity;enzyme activity;immunoprecipitation;ligase;mass spectrometry;molecular genetics;p53 gene /protein;predoctoral investigator;toxicology;ubiquitin;western blottings


application_id: 7080390
project_number: 5R01DK059866-05
project_title: Afri 1: Gene Cloning and its Role in Liver Regulation
administering_ic: NIDDK
award_notice_date: 2006-05-20
application_type: 5
activity_code: R01
ic: DK
serial_number: 059866
program_official: SERRANO, JOSE
project_start_date: 2002-07-15
project_end_date: 2007-04-30
study_section: General Medicine A Subcommittee 2[GMA-2]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT T
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
A fundamental goal of biomedical research is to understand the processes that regulate gene expression during development and disease. The mouse alpha-fetoprotein ATP is particularly well suited for this. AFP is expressed at high levels in the fetal liver but is off in the adult liver. This is due to a 10000 reduction in transcription during the perinatal period. The AFP gene can be reactivated in the adult liver in response to injury and in hepatocellular carcinomas. These aspects of AFP regulation-AFP activation during hepatogenesis repression at birth and reactivation in liver cancer and regeneration-have led to considerable interest in the control of this gene. Postnatal AFP repression is regulated in part by a locus called Alpha-fetoprotein regulator 1 (Afr1). Afr1 was originally identified by differences in AFP levels in different mouse strains. Thus unlike a majority of mammalian factors controlling gene expression that have been identified using biochemical approaches Afr1 was revealed genetically. Of particular interest Afr1 appears to regulate AFP by a mechanism that couples transcription to post-transcription events. While a connection between these events has been established in the literature mechanisms that exist to modulate these connections are only beginning to be uncovered. Using tools of contemporary molecular genetics we propose to identify the Afr1 gene by positional cloning. We can then understand how Afr1 regulates AFP and we are likely to learn more about the transcription/post/transcriptional connections as well as how this may be developmentally regulated to control gene expression.

project_terms:
alpha fetoprotein;artificial chromosomes;developmental genetics;gene expression;genetic mapping;genetic regulatory element;genetic transcription;genetically modified animals;laboratory mouse;laboratory rabbit;liver function;molecular cloning;molecular genetics


application_id: 7077858
project_number: 1P01HL080100-01A1
project_title: Mechanisms of abdominal aortic aneurysm formation
administering_ic: NHLBI
award_notice_date: 2006-04-06
application_type: 1
activity_code: P01
ic: HL
serial_number: 080100
suffix: A1
program_official: WASSEF, MOMTAZ K
project_start_date: 2006-04-08
project_end_date: 2011-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
abdomen;angiotensin II;aorta aneurysm;cardiovascular disorder epidemiology;disease /disorder model;laboratory mouse;pathologic process


application_id: 7077640
project_number: 5R01CA113371-03
project_title: Biochemical basis of WRN and RecQ helicase function
administering_ic: NCI
award_notice_date: 2006-07-14
application_type: 5
activity_code: R01
ic: CA
serial_number: 113371
program_official: PELROY, RICHARD
project_start_date: 2004-08-10
project_end_date: 2008-07-31
study_section: Special Emphasis Panel[ZRG1-CMAD(01)Q]
contact_pi_person_id: 7034221
contact_pi: ORREN, DAVID KEITH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant): RecQ helicases act to maintain genomic stability by an as yet unknown mechanism. When their function is lost levels of illegitimate recombination increase significantly. Not surprisingly the human hereditary RecQ deficiency diseases (Werner Bloom and Rothmund-Thomson syndromes caused by defects in WRN BLM and RECQL4 respectively) demonstrate early onset and increased frequency of cancer. Importantly Werner syndrome also shows accelerated development of many age-related problems. Although these diseases have distinct phenotypes RecQ family members maintain a high degree of homology within and C terminal to the conserved central helicase domain suggesting that they may have a common mechanistic function and/or DNA substrate specificity. We refer to this extended sequence conservation as the RecQ expanded core. Their illegitimate recombination phenotypes suggest that RecQ helicases function in recombination or anti-recombination pathways or possibly in resolution of replication fork blockage. Our laboratory has recently uncovered strand pairing and strand exchange activities in WRN and other RecQ helicases consistent with putative roles in these pathways. We hypothesize that the RecQ expanded core forms a functional unit that encompasses DNA binding and catalytic activities. Further we propose that the function of the RecQ expanded core is to coordinate DNA binding and unwinding to achieve strand exchange reactions in complex recombination or replication intermediates. This hypothesis fits with the putative roles for RecQ members and current biochemical knowledge regarding these proteins. In this proposal WRN is used as a model RecQ helicase for 1) characterizing strand exchange activity reflecting putative coordination between strand pairing and unwinding activities 2) examining DNA binding properties and substrate specificity for replication and recombination intermediates and 3) generating site-directed mutants that pinpoint the DNA binding enzymatic and physiological functions of the RecQ expanded core and its individual domains. Our findings with WRN will be highly relevant to elucidating its DNA metabolic role and specific mechanisms underlying carcinogenesis and certain aging phenotypes. Sequence conservation between RecQ helicases also indicates that our findings will be applicable to the functions of other RecQ helicases (including BLM and RECQL4) and their relationships to human health.

project_terms:
DNA binding protein;DNA repair;DNA replication;DNA replication origin;SDS polyacrylamide gel electrophoresis;Werner&apos;s syndrome;enzyme mechanism;enzyme structure;gene mutation;genetic recombination;helicase;nucleic acid metabolism;site directed mutagenesis


application_id: 7077585
project_number: 5F30NS048770-02
project_title: Postnatal Intermittent Hypoxia and Respiration: Potenti*
administering_ic: NINDS
award_notice_date: 2006-06-19
opportunity_number: PA-04-032
application_type: 5
activity_code: F30
ic: NS
serial_number: 048770
program_official: MITLER, MERRILL
project_start_date: 2005-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-B(21)L]
contact_pi_person_id: 7798502
contact_pi: REEVES, STEPHEN R
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Intermittent hypoxia (IH) is a frequent condition in clinical medicine (e.g. sleep apnea SIDS) which bears substantial morbidity and mortality. Furthermore organismal adaptations to IH suggest the formation of specific forms of neuronal plasticity. While substantial study of the effects of IH has been performed in the mature mammal little if any work has been done during the early phases of post-natal development a unique period of neuronal vulnerability and adaptation. Therefore we hypothesized that post-natal intermittent hypoxia such as occurs in sleep apnea may impose long-term modifications in respiratory control thereby leading to a form of metaplasticity of respiratory patterning. The latter modification of the respiratory network induced by early post-natal IH could impose either a functionally favorable or a maladaptive alteration of the respiratory response system. To examine this issue we will: (i) characterize the effects of post-natal IH on normoxic ventilation and on hypoxic and hypercapnic ventilatory responses in freely behaving rats.; (ii) assess the effects of IH on phrenic motor nerve long-term facilitation (LTF).; (iii) determine the potential role of signaling pathways particularly protein kinase C (PKC) in the long-term modification of ventilation imposed by IH through development. This work will therefore contribute to the understanding of potential mechanisms mediating not only early adaptations to IH but also provide insights to long-lasting changes in ventilation that may develop when a conditioning stimulus is applied during critical phase of maturation.

project_terms:
disease /therapy duration;early experience;enzyme activity;hypoxia;laboratory rat;long term potentiation;phrenic nerve;predoctoral investigator;protein kinase C;pulmonary respiration;respiratory disorder epidemiology;respiratory distress syndrome of newborn;sleep apnea;sudden infant death syndrome


application_id: 7077315
project_number: 3P01ES011860-03S1
project_title: Cardiovascular Toxicity of Emvironmental Aldehydes - Project 5
project_terms: aldehydes;cardiotoxin;cardiovascular disorder;clinical research;environmental exposure
administering_ic: NIEHS
award_notice_date: 2005-12-09
application_type: 3
activity_code: P01
ic: ES
serial_number: 011860
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2002-07-01
project_end_date: 2006-06-30
study_section: Special Emphasis Panel[ZES1 LKB-A (P5)]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant)  
  
This is a proposed supplemental study to the existing Program Project Grant (PPG) investigating the cardiovascular toxicity of environmental aldehydes. Concordant with the overall theme of the PPG to elucidate the role of cardiovascular (CV) oxidative stress in environmentally-induced oxidative injury this project will examine the effects of ambient air particles on insulin resistance.  While multiple studies suggest that diabetes increases susceptibility to PM2.5-induced CV events emerging evidence supports also the existence of the reciprocal relationship i.e. exposure to PM2.5 may increase the risk of developing diabetes.  Developing on the on going PPG studies showing that exposure to acrolein induces dyslipidemia consistent with insulin resistance and drawing from previous epidemiological and experimental studies this project will test the hypothesis that exposure to concentrated ambient PM2.5 (CAP) acutely triggers a state of insulin resistance.  The investigators propose that CAP-induced reduction in insulin sensitivity is mediated in part by oxidative stress increased generation of oxidation-derived aldehydes and mild dyslipidemia.  Accordingly they will measure the effect of CAP on insulin sensitivity in 50 health adults by the frequently sampled intravenous glucose tolerance test in a series of randomized double-blind cross-over exposures to filtered air versus CAP  anti-oxidant pre-treatment. To probe underlying mechanisms they will determine the nature and the extent of oxidative stress using sensitive and unique assays developed by the PPG investigators and will elucidate specific features of oxidative injury associated with changes in vascular function and sympathetic tone.  In addition the investigators will characterize CAP and delineate in particular the contribution of environmental aldehydes to changes in vascular reactivity and insulin resistance.  Collaboration with the PPG will facilitate exchanges of intellectual and material resources by linking laboratory science to clinical research.   The investigators expect that the bioanalytical tools and reagents and the range of animal data will provide continuous support and orientation to the clinical study which in turn will provide input and direction for clinically meaningful evaluation of laboratory end points. This arrangement will enhance the scope and the breath of the on going PPG and help in critically assessing how air pollution causes insulin resistance and thereby contributes to the epidemic of diabetes currently unfolding within the industrialized world.


application_id: 7077104
project_number: 1R01HD052694-01
project_title: Endothelin-2 in Ovarian Follicle Rupture
administering_ic: NICHD
award_notice_date: 2006-05-09
application_type: 1
activity_code: R01
ic: HD
serial_number: 052694
program_official: TAYMANS, SUSAN
project_start_date: 2006-05-15
project_end_date: 2011-02-28
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-15
project_abstract:
DESCRIPTION (provided by applicant): The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in follicle rupture. The program of ovulation is activated by a surge of luteinizing hormone which initiates dramatic changes in molecular biochemical and physical aspects of the ovary eventually leading to rupture of follicles. However the factors involved in and the mechanism governing the process of follicle rupture are yet to be unveiled. Using a gene expression profiling approach we have identified EDN-2 a potent smooth muscle constrictor which is exclusively and transiently expressed in the granulosa cells of periovulatory follicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in the ovarian tissue while tezosentan an endothelin receptor antagonist released the contraction. These novel findings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture of the follicle. Supporting the hypothesis immunohistochemical analysis identified a well-organized smooth muscle layer in the theca externa of each follicle which forms a sponge-like smooth muscle network at the whole ovarian level. Furthermore we found that intraovarian injection of tezosentan prior to ovulation completely blocked follicle rupture. In this study we will elucidate the mechanism of EDN-2 action in follicle rupture. We will determine the target tissues of EDN-2 action the endothelin receptor subtype(s) that mediates EDN-2 action and the ovarian concentration of EDN-2. We will also determine the mechanism of endothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrictive molecules (VIPs PACAPs and prostaglandins). In addition the functional link of progesterone estrogen and prostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposal is in the identification of EDN-2 and the ovarian smooth muscle network as the key components of follicle rupture. The novelty of the proposed experiments is the interdisciplinary approaches (genome-wide gene expression profiling intraovarian injection and isometric tension measurement). The proposed studies are exceptionally important in order to further our understanding of the mechanism of follicle rupture. The proposed experiments will provide clinical direction in identifying the therapeutic target for the cure of annovulatory symptoms one of the leading causes of female infertility.

project_terms:
autoradiography;binding sites;corpus luteum;disease /disorder etiology;endothelin;estrogen receptors;female reproductive system disorder;genetically modified animals;hormone metabolism;hormone receptor;hormone regulation /control mechanism;immature animal;immunocytochemistry;in situ hybridization;laboratory mouse;laboratory rat;mature animal;muscle contraction;ovulation;peptides;progesterone receptors;prostaglandins;protein structure function;radioimmunoassay;receptor expression;smooth muscle


application_id: 7076918
project_number: 5R01DA013677-05
project_title: Neurocognition Nicotine and Polysubstance Abuse
administering_ic: NIDA
award_notice_date: 2006-05-26
opportunity_number: PA-00-045
application_type: 5
activity_code: R01
ic: DA
serial_number: 013677
program_official: GRANT, STEVEN J
project_start_date: 2002-09-30
project_end_date: 2006-10-13
study_section: Biobehavioral and Behavioral Processes 4[BBBP-4]
contact_pi_person_id: 1895286
contact_pi: NIXON, SARA JO
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Current research is providing much needed data regarding the effects of chronic drug use on brain-behavior relations. This literature addressing the neurobehavioral concomitants of long-term substance use disorders (SUDs) however is marked by considerable heterogeneity There are a number of factors which may contribute to this outcome. One likely contributor is the failure to account for the influence of the frequent use/abuse of the stimulant nicotine. This second revision seeks five years of funding to address the role of nicotine in functionally compensating for the long-term neurocognitive effects of chronic substance abusers (SA s). Specifically we propose to test the hypothesis that nicotine's cognitive enhancing properties particularly as evidenced in working memory and attentional processes may serve to counterbalance or functionally overcome the negative effects observed in chronic SAs.  The design entails the direct comparison of male and female abstinent detoxified SA s (n=216) assigned to subgroups on the basis of their primary drug of abuse and current clinical diagnostic information with community controls (smoking and non-smoking; n=144) equated on geographic and demographic variables. In addition to responding to this question the current design will also extend the on-going work regarding differences among drug using subgroups regarding cognitive compromise. Using a double-blind placebo controlled study we propose to study the effect of three levels of nicotine via transdermal administration (0 7 and 21 mg patches) in treatment-seeking SA and community controls (equal numbers of males and females). If the hypotheses are supported existing research may underestimate the effects of chronic drug use on specific cognitive processes. These findings would have considerable clinical and scientific import.  As a secondary aim we plan to investigate associations among relevant and understudied demographic variables including depressive symptoms childhood behavioral disorders and anxiety symptomatology. Furthermore we intend to examine the role of race/ethnicity gender and family history of SUDs. To facilitate this secondary aim we have instituted plans to over-sample American Indians (Al) African American (AA) and female participants.

project_terms:
African American;Native Americans;alcoholism /alcohol abuse;anxiety;child behavior disorders;clinical research;cognition;depression;detoxification;drug addiction antagonist;gender difference;human subject;nicotine replacement;patient oriented research;racial /ethnic difference;short term memory;substance abuse related disorder;transdermal drug delivery


application_id: 7076489
project_number: 2R56AI044254-06
project_title: Analysis of Borrelia Burgdorferi Erp Proteins
administering_ic: NIAID
award_notice_date: 2005-06-26
application_type: 2
activity_code: R56
ic: AI
serial_number: 044254
program_official: BAKER, PHILLIP J
project_start_date: 2000-03-01
project_end_date: 2006-03-14
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
Lyme disease is a significant threat to human health throughout many parts of the USA. The causative agent Borrelia burgdorferi is maintained in nature by infectious cycles involving ticks and many species of vertebrates with humans being incidental hosts.Understanding the mechanisms by which B. burgdorferi infects humans and is transmitted from vector ticks will be important in development of improved methodologies to prevent and treat this disease.During transmission from tick to mammal B. burgdorferi significantly increases expression levels of the Erp family of outer surface proteins. Expression of Erp proteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferi encode multiple Erp lipoproteins a ubiquity that is highly suggestive of important roles for these proteins in B. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulator factor H in vitro raising the possibility that these proteins may function in vivo to protect the bacteria from killing by the host's innate immune system. Based on results of our previous studies we hypothesize that Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processes and that these functions necessitate the bacteria regulate Erp expression. To test this hypothesis we will (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erp mutants for their abilities to bind factor H resist complement-mediated killing and infect mice and ticks; (2) examine mechanisms by which B. burgdorferi controls Erp expression including innovative analyses of transcription throughout mammalian and tick infection; and (3) characterize functions and expression patterns of the novel DNA binding protein we discovered that specifically binds to erp operator DNA. Results of our studies will provide important insight into the mechanisms by which B. burgdorferi infects humans.

project_terms:
Borrelia;DNA binding protein;Ixodes;Lyme disease;bacteria infection mechanism;bacterial proteins;clinical research;complement;disease vectors;emerging infectious disease;gene mutation;genetic transcription;host organism interaction;laboratory mouse;protein biosynthesis;protein structure function


application_id: 7076191
project_number: 5R01AI065545-02
project_title: CHLAMYDIAL INVASION OF NON-PHAGOCYTIC CELLS
administering_ic: NIAID
award_notice_date: 2006-03-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 065545
program_official: HILTKE, THOMAS J
project_start_date: 2005-07-01
project_end_date: 2010-03-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1941640
contact_pi: CARABEO, REYNALDO A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that is the causative agent of a wide spectrum of human diseases including trachoma and the sexually transmitted disease chlamydia. Successful infection of cells by chlamydia involves attachment invasion establishment of a protective vacuole called an inclusion and inhibition of lysosomal fusion. With the advent of the C. trachomatis genome sequence and new cell biological and proteomic tools the mechanisms involved in these processes are just beginning to be revealed advancing our knowledge of chlamydia-host cell interactions. The long term goal is to define the molecular and biochemical mechanisms important for the successful establishment of infection by chlamydia. This proposal will specifically address the process of invasion. It is hypothesized that chlamydia uses multiple pathways of invading non-phagocytic cells. A recently identified molecule termed Tarp has been demonstrated to be translocated from the infecting elementary body across the host plasma membrane and into the cytosol where it is tyrosine phosphorylated by unknown host kinases and recruit actin. As a phosphoprotein Tarp may act as a signaling platform to recruit a number of adapter and effector molecules that mediate actin cytoskeletal remodeling. Specific Aim 1 will address the Rac GTPase dependent pathway and focus on the potential downstream mediators of actin recruitment. Specific Aim 2 will focus on the Tarp protein the tyrosine kinase(s) responsible for its phosphorylation the binding partners their roles in chlamydial invasion and the potential relationship of Tarp with the Rac GTPase. Specific Aim 3 will address the potential mechanism of actin recruitment by the Chlamydophila caviae Tarp homolog which does not contain the multiple repeat sequences present in C. trachomatis serovars L2 and D. These studies would not only reveal important insights into the biology of chlamydia but also the cellular process of signaling to the actin cytoskeleton that chlamydia subverts to facilitate its infection.

project_terms:
Chlamydia trachomatis;HeLa cells;actin binding protein;actins;bacteria infection mechanism;bacterial proteins;chlamydial disease;gene deletion mutation;guanine nucleotide binding protein;host organism interaction;immunoprecipitation;phagocytosis;phosphorylation;protein binding;protein protein interaction;protein structure function;proteomics


application_id: 7076186
project_number: 5R01HL074091-04
project_title: Mechanisms of Long-term Cardiac Ion Channel Regulation
administering_ic: NHLBI
award_notice_date: 2006-06-29
application_type: 5
activity_code: R01
ic: HL
serial_number: 074091
program_official: PRZYWARA, DENNIS
project_start_date: 2003-07-15
project_end_date: 2008-06-30
study_section: Cardiovascular and Pulmonary Research A Study Section[CVA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) and atrial fibrillation (AF) represent two of the most prevalent heart diseases in the U.S. In moderate to severe HF and in AF numerous phenotypic changes occur including a reduction of voltage-gated calcium channel current density. Changes in Ca channel expression may have far-reaching effects on heart function due to their central role in excitation contraction coupling. Also Ca channels have been implicated in excitation-transcription coupling. Thus alterations of Ca channel expression in the heart can also impact on disease progression. The principal voltage-gated Ca channel in the heart (CaV1.2) is extensively studied in the realm of its biophysical characteristics and second messenger modulation. However very sparse information is available regarding longer term regulation of Ca channel expression. In this proposal we introduce a novel mechanistic hypothesis governing the functional expression of cardiac Ca channels in the sarcolemma of cardiac myocytes. In our preliminary data we show evidence for a ras-related monomeric G-protein interaction with the CaV1.2 accessory subunit CaVb2. We propose to test the global hypothesis that G-protein interaction with CaVb subunits reduces Ca channel current density by competing for CaV1.2 binding. Moreover our preliminary data shows strong evidence that this is a dynamic process that is modulated by chronic PKA activity. There are four specific aims that guide our experimental design: Aim 1 will characterize the time course and sub-cellular localization of nascent G-protein and CaVb complexes. Aim 2 will characterize the intracellular second messenger modulation of G-protein-CaVb regulation of Ca channel current expression. Aim 3 will characterize the modulation of Ca channel current and G-protein modulation in native cells. Aim 4 will characterize the function of these G-proteins in heart function. These aims encompass approaches ranging from investigations of a purely molecular nature (protein-protein interactions) to in vitro model systems (heterologous expression of recombinant proteins) to native cell systems (primary isolates and cultures of heart cells) to the impact of a single class of G-proteins on tissue level heart function. This proposal may identify a novel class of therapeutic targets for alleviation of heart dysfunction in HF and AF.

project_terms:
G protein;atrial fibrillation;biological signal transduction;calcium channel;calcium ion;cardiac myocytes;cell membrane;confocal scanning microscopy;electrophysiology;heart failure;heart function;laboratory mouse;laboratory rat;polymerase chain reaction;protein binding;protein kinase A;protein protein interaction;recombinant proteins;sarcolemma;second messengers;telemetry;voltage gated channel;western blottings


application_id: 7074809
project_number: 5R01HL071071-04
project_title: Sphingolipid Signaling in Endothelial Function
administering_ic: NHLBI
award_notice_date: 2006-06-09
application_type: 5
activity_code: R01
ic: HL
serial_number: 071071
program_official: GOLDMAN, STEPHEN
project_start_date: 2003-07-01
project_end_date: 2007-12-31
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 6981385
contact_pi: LEE, MENQ-JER
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Sphingosine-1-phosphate (S1P) a bioactive sphingolipid regulates a variety of cellular functions such as proliferation survival chemotaxis etc. Recently it has been shown that S1P is the high affinity ligand for the G-protein coupled receptor EDG-1 (Endothelial Differentiation Gene-1). Importantly a novel function of S1P/EDG-1 in blood vessel development and maturation has been proposed recently. For example S1P promotes morphogenesis of endothelial cells in vitro and potentiates VEGF and FGF-induced angiogenesis in vivo. Furthermore deletion of EDG-1 resulted in embryonic lethality due to the formation of immature vasculature. However the molecular mechanisms underlying S1P/EDG-1 regulated angiogenesis remain elusive. Thus our long-term goal is to understand the signaling and roles of this sphingolipid in endothelial functions. In this proposal we will characterize signaling pathways regulated by the EDG-1 receptor. Initially by utilizing the affinity purification procedure a panel of cellular polypeptides was found to specifically associate with the third intracellular loop (i3 domain) of EDG-1 receptor. Among them two protein kinases with apparent molecular masses of 120- and 56-kDa and a 21-kDa phosphoprotein were identified. We hypothesize that these EDG-1 associated kinases/polypeptides are critical for the S1 P/EDG-1 signaling in particular in regulating the function of endothelial cells. Preliminary data suggest that pp120 kinase may be functionally important in EDG-1 signaling. Thus we propose to prioritize and focus on determining the identity and functions of pp120 kinase in EDG-1 signaling in the context of vascular biology. The research aims are I) purify and clone the pp120EDG-1 associated kinase II) characterize the relevance of pp120 kinase in S1 P/EDG-1 signaling III) study the functions of pp120 kinase in endothelial cells activation and IV) determine the structure-function relationship of EDG-I-i3. The completion of these studies is anticipated to better our knowledge of molecular mechanisms underlying angiogenesis which ultimately may lead to future therapeutic development.

project_terms:
affinity chromatography;angiogenesis;athymic mouse;binding sites;biological signal transduction;cell surface receptors;enzyme activity;enzyme structure;laboratory rabbit;liquid chromatography mass spectrometry;molecular cloning;phosphoproteins;posttranslational modifications;protein kinase;protein purification;protein structure function;site directed mutagenesis;sphingolipids;vascular endothelium


application_id: 7073448
project_number: 5R01HL073085-04
project_title: Angiotensin: A Link Between Obesity and Hypertension
administering_ic: NHLBI
award_notice_date: 2006-05-30
opportunity_number: RFA-HL-02-016
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: BAROUCH, WINIFRED
project_start_date: 2003-06-03
project_end_date: 2008-05-31
study_section: ZHL1-CSR-S(F1)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The proposed studies are in response to RFA-HL-02-016 and will address the working hypothesis that a moderately high fat diet (MHF) stimulates the adipose renin-angiotensin system contributing to obesity-related elevations in blood pressure.  Preliminary data demonstrates that rats fed a MHF diet segregate into obesity prone (OP) versus obesity-resistant (OR) populations.  In OP rats blood pressure was increased coincident with activation of the systemic and adipose renin-angiotensin system.  The first hypothesis is that a MHF diet activates the adipose renin-angiotensin system resulting in an increase in circulating angiotensin peptides and blood pressure.  Time-dependent regulation of adipose versus non-adipose components of the renin-angiotensin system will be examined in control OR and OP rats and compared to the time course for elevations in blood pressure.  The contribution of various circulating angiotensin peptides to blood pressure elevations in control OR and OP rats will be determined.  The second hypothesis is that adipocytes from OP rats exhibit a redistribution of free cholesterol from the plasma membrane to intracellular triglyceride pools thereby increasing the activity of sterol regulatory binding protein-2 and stimulating angiotensinogen (Ao) mRNA expression.  This would provide an adipocyte-specific mechanism for regulation of Ao gene expression in response to the MHF diet.  The intracellular localization of free cholesterol in adipocytes prepared from control OR and OP rats will be determined and compared to the level of Ao mRNA expression.  The effect of depletion of intracellular free cholesterol pools on adipocyte Ao mRNA expression will be determined.  The third hypothesis is that elevations in circulating angiotensin peptides increase blood pressure in OP rats by stimulating sympathetic drive.  The responsiveness of the baroreceptor reflex and the blood pressure response to ganglionic blockade will be determined in control OR and OP rats.  A second approach will determine the effect of neonatal sympathectomy on blood pressure elevations in diet-induced obesity. In hypothesis 4 a novel animal model will be developed to determine the effect of targeted deficiency of Ao in adipose tissue on blood pressure regulation in diet-induced obesity.  The goals of this research are to definitively determine the role of adipose-derived angiotensins and the systemic renin-angiotensin system in blood pressure elevations in diet-induced obesity.

project_terms:
adipocytes;angiotensin /renin /aldosterone hypertension;angiotensin II;autoradiography;blood pressure;dietary lipid;high performance liquid chromatography;hypertension;laboratory mouse;laboratory rat;messenger RNA;obesity;polymerase chain reaction;renin angiotensin system


application_id: 7073421
project_number: 5F31AR050951-03
project_title: Use of Cellular Energy Delivery System in Wound Healing
administering_ic: NIAMS
award_notice_date: 2006-05-12
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: AR
serial_number: 050951
program_official: BAKER, CARL
project_start_date: 2005-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-DIG-B(29)L]
contact_pi_person_id: 7141987
contact_pi: THOMAS, CANDICE M
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goals of Ms. Thomas' project are to understand how topically applied VitaSol (ATP encapsulated in fusogenic lipid vesicles) can accelerate the rates of wound closure and how VitaSol affect scar formation. A wound to the integument is an area of ischemia and a number of reviews have suggested that the major inhibition to wound healing is the lack of oxygen and nutrients to the wound border cells. vltaSol overcomes the problem of ischemia because ATP is delivered directly to the cells and thus the need for oxygen and nutrients to produce ATP is significantly reduced. Preliminary data in the PI's lab has shown a superior effect of VitaSol on wound closure rates (>70% increase in wound closure time). The specific aims the project are: 1) Identify the ATP consumption rate of epidermal and dermal skin in swine 2) Adjust the formulation of VitaSol in order to deliver ATP to the epidermal and dermal wound broader cells at rates that match or exceed the ATP consumption rate of the skin cells 3) Apply VitaSol to full-thickness and partial thickness wounds and measure the rates of wound closure and scare formation and 4) Determine the toxicity and morbidity of topically applied VitaSol to the skin and to the whole animal.

project_terms:
adenosine triphosphate;bioenergetics;biopsy;drug design /synthesis /production;histology;hydrolysis;lipids;oxygen consumption;predoctoral investigator;scars;skin;swine;vesicle /vacuole;wound healing


application_id: 7073332
project_number: 5R41DK074331-02
project_title: Induction of Donor Tolerance in Renal Transplants
administering_ic: NIDDK
award_notice_date: 2006-05-29
application_type: 5
activity_code: R41
ic: DK
serial_number: 074331
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2005-06-03
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-HEME-E(10)B]
contact_pi_person_id: 1871961
contact_pi: TOLLERUD, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140644969
duns_number: 140644969
fips: US
organization_id: 10001459
organization_name: REGENEREX, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
budget_end_date: 2007-11-30
assistance_listing_number: 93.849
project_abstract:
DESCRIPTION (provided by applicant): Bone marrow transplantation (BMT) can treat sickle cell anemia type 1 diabetes multiple sclerosis and other autoimmune disorders and induces immune tolerance in solid organ and cell transplant recipients. However the toxicity and complications associated with BMT primarily graft versus host disease (GvHD) limit the therapeutic application of BMT to treatment of life threatening disorders such as leukemia. Our goal is to market a well-defined bone marrow cell processing procedure called FCRx that will support durable bone marrow transplant engraftment following minimal patient conditioning without GvHD in mismatched recipients. We have identified and others have confirmed a bone marrow cell population of graft facilitating cells (FC) that facilitates engraftment of marrow in mismatched recipients without causing GvHD. The discovery of FC is an important finding as it opens the door to employing BMT as a standard therapy for nonmalignant conditions. The process proposed for commercialization FCRx. will produce a bioengineered bone marrow graft that includes hematopoietic stem cells (HSC) and facilitating cells (FC) but excludes harmful T cells.  We propose the following specific aims for proof-of-concept in Phase I. The FCRx-produced graft will be tested in an FDA-approved clinical trial involving combined kidney and BMT whose ultimate goal is the induction of immune tolerance and the consequent elimination of or reduction in the need for expensive and harmful imrnunosuppressive drugs. In Aim I we will demonstrate that the proprietary procedure can routinely produce a graft with defined specifications for stem cells facilitating cells and aa3TCR+ cells. The reproducibility and quality assurance of graft production through the FCRx process will lead to its successful commercial launch. In Aim II we will test the hypothesis that this process will produce a BMT graft that will achieve engraftment of highly HLA mismatched donor stem cells in transplant recipients without causing significant GVHD. Regenerex LLC is a woman-owned business located in Kentucky an EPSCoR state.

project_terms:
bioengineering /biomedical engineering;biotechnology;bone marrow transplantation;clinical research;clinical trials;graft versus host disease;hematopoiesis;hematopoietic stem cells;homologous transplantation;human subject;human therapy evaluation;immune tolerance /unresponsiveness;kidney transplantation;leukocyte depletion therapy;stem cell transplantation;tissue engineering;transplantation immunology


application_id: 7073287
project_number: 5R01HL062892-08
project_title: Antioxidant transgene in diabetic cardiomyopathy
administering_ic: NHLBI
award_notice_date: 2006-05-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 062892
program_official: LIANG, ISABELLA Y
project_start_date: 1999-08-01
project_end_date: 2007-12-30
study_section: Metabolism Study Section[MET]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N.
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Many diabetics suffer from severe cardiomyopathy even in the absence of vascular disease. Evidence from animal models and clinical samples implicate reactive oxygen species (ROS) in the development of diabetic cardiomyopathy. Our results confirm the importance of ROS. In the OVE26 model of Type I diabetes we find increased cardiac oxidative damage increased production of ROS by diabetic cardiomyocytes and protection by antioxidant transgenes. Two different antioxidant proteins targeted to the cardiomyocyte metallothionein (MT) and catalase prevented most of the primary characteristics of diabetic cardiomyopathy including reduced contractility impaired calcium homeostasis and disrupted morphology. Our most recent data implicate mitochondrial electron transport and the enzyme NADPH oxidase in the production of oxidative damage in diabetic cardiomyocytes. This project will identify the cellular source of increased ROS production in diabetic hearts determine which proteins are the targets of ROS modification and test whether the importance of ROS in Type I diabetes also applies to cardiomyopathy in Type II diabetes. Sources of ROS will be tested by measuring ROS production in diabetic cardiomyocytes as a function of genetic knockout or drug inhibition of potential sources. Breeding diabetic mice to knockout mice for NADPH oxidase will determine if this enzyme is required for the development of diabetic cardiomyopathy. Protein targets of ROS modification in whole heart mitochondria and sarcoplasmic reticulum will be identified by using proteomic analysis combined with antibodies against oxidatively modified amino acids. To analyze the role of ROS in Type II diabetic cardiomyopathy we will characterize cardiac morphology ROS production cardiac function and oxidative damage in the agouti model of Type II diabetes. Agouti mice will be bred to mice protected by cardiac specific antioxidant transgenes to determine if oxidative damage is a requirement for cardiomyopathy in this model.

project_terms:
NAD(P)H dehydrogenase;antioxidants;catalase;confocal scanning microscopy;diabetes mellitus;diabetic cardiomyopathy;disease /disorder model;electrospray ionization mass spectrometry;free radical oxygen;free radical scavengers;gene expression;genetically modified animals;heart contraction;laboratory mouse;matrix assisted laser desorption ionization;metallothionein;myocardial infarction;western blottings


application_id: 7073252
project_number: 7R03EY014578-04
project_title: AUTOIMMUNITY ASSOCIATED WITH PIGMENT DISPERSION GLAUCOMA
administering_ic: NEI
award_notice_date: 2005-11-04
application_type: 7
activity_code: R03
ic: EY
serial_number: 014578
program_official: SHEN, GRACE L
project_start_date: 2005-05-01
project_end_date: 2008-02-28
study_section: ZEY1-VSN(01)
contact_pi_person_id: 8239924
contact_pi: MO, JUN SONG
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION (provided by applicant): Pigment dispersion syndrome is an important cause of secondary glaucoma in humans its pathogenesis is obscure and therapeutic measures are satisfactory at best. A new mouse model that bears a distant but interesting resemblance to the human disease has been described in DBA/2J mice. In this model as pigment dispersion escalates leaving iris atrophy in its wake elevated intraocular pressure ensues leading to optic nerve atrophy and vision impairment.  One of the two mutant genes that give rise to the disease is expressed surprisingly in dendritic cells of bone marrow origin implying a possible role for inflammation/immunity in the pathogenesis.  The phenotype resulting from mutation of this gene involves pigment dispersion slit-like radial trans-illumination defects and deterioration of the iris pigment epithelium. Recent experiments have determined that aqueous humor from eyes of affected DBA/2 J mice lacks the capacity to suppress T cell activation an abnormality that actually precedes the onset of clinical evidence of pigment dispersion and evidence of inflammation is already present at 4 months of age implying a pathogenic role for inflammation in the disease.  Moreover DBA/2J eyes destined to develop glaucoma lack the capacity to promote anterior chamber associated immune deviation and they display impaired ocular immune privilege.  Based on these findings and the knowledge that degeneration of pigment epithelial cells of iris and ciliary body is an important manifestation of the disease we have developed an experimental plan that links abnormalities in the ability of the DBA/2J eye to regulate inflammation and immune responses to the pathogenesis of pigment dispersion and iris atrophy.  We hypothesize that ocular immune abnormalities in DBA/2J mice predispose to the development of autoimmunity directed at melanin-associated antigens and that this autoimmunity initiates and/or amplifies the degeneration of iris pigment epithelium and stromal atrophy. As a consequence secondary structural changes in the anterior chamber especially at the angle and trabecular meshwork lead to increased intraocular pressure and eventual optic neuropathy.

project_terms:
antigen presentation;autoimmunity;confocal scanning microscopy;corneal stroma;enzyme linked immunosorbent assay;flow cytometry;fluorescence microscopy;gene mutation;glaucoma;immunocytochemistry;immunoregulation;inflammation;iris;laboratory mouse;leukocyte activation /transformation;optic nerve disorder;pathologic process;pigments;uvea ciliary body;western blottings


application_id: 7072798
project_number: 5R01AG020972-04
project_title: Macrophage Dysfunction in Immunosenescence
administering_ic: NIA
award_notice_date: 2006-04-25
application_type: 5
activity_code: R01
ic: AG
serial_number: 020972
program_official: FLORES, ROBERTO L
project_start_date: 2003-06-01
project_end_date: 2008-04-30
study_section: Geriatrics and Rehabilitation Medicine[GRM]
contact_pi_person_id: 1969952
contact_pi: STOUT, ROBERT D
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Macrophages resident in the bone marrow spleen lung and peritoneal cavity of elderly humans or aged animals display dysregulated functions including decreased antigen presenting capability decreased ability to mobilize in response to tissue injury and decreased inflammatory function in response to specific stimuli such as CD40-ligation or CD 14-ligation. Evidence is accumulating that environmental influences such as stromal function and imbalances in cytokines and growth factors may be responsible for much of the dysfunction associated with immunosenescence. It is also known that treatment of macrophages with either type 1 (e.g. IFNgamma) or type 2 (e.g. IL-4 IL-10 TGFbeta) cytokines alters their functional responsiveness to subsequent activating stimuli. Whereas type 1 cytokines promote cytocidal and pro-inflammatory activities upon receipt of an activating signal (LPS or CD40 ligation) type 2 cytokines promote anti-inflammatory and tissue restructuring activities upon receipt of an activating signal. This proposal examines the hypotheses (1) that the macrophage dysfunction observed in aged animals and humans may be a polarization of the macrophages to type 2-cytokine promoted functions as opposed to the classical type 1 cytokine promoted functions (2) that the apparent macrophage dysfunction or polarization is the reversible result of cytokine imbalance in the microenvironment rather than due to inherent irreversible defects in the myeloid lineage and (3) that correction of the cytokine imbalance may improve macrophage function. The phenotype and pattern of inducible activities of resident macrophages will be assessed to determine if the macrophages from aged animals are generally hyporesponsive to stimuli or are polarized in the pattern of their functional response to stimuli. The influence of the aged environment on these macrophages will be assessed by removing the macrophages from the aged animals to determine if the functional response pattern observed in young mice is partially or completely restored. Finally the efficacy of treatment of mice with type 1 cytokine agonists and type 2 cytokine antagonists in restoring type 1 macrophage functions will be assessed. Overall these studies will increase our understanding of age-related dysregulation of macrophage function and provide possible avenues of therapeutic intervention which may enhance macrophage function in the elderly thus improving their ability to resist infectious disease.

project_terms:
CD40 molecule;RNase protection assay;aging;animal old age;biological signal transduction;cell biology;cell transplantation;cytokine;flow cytometry;genetically modified animals;immunologic assay /test;immunopharmacology;immunosenescence;inhibitor /antagonist;interferons;interleukin 10;interleukin 4;laboratory mouse;leukocyte activation /transformation;lipopolysaccharides;macrophage;mature animal;stimulant /agonist;tissue /cell culture;tissue /cell preparation;transforming growth factors;tumor necrosis factor alpha


application_id: 7071854
project_number: 5K01DA018772-02
project_title: A Pharmacological Analysis of Delta 9-THC in Humans
administering_ic: NIDA
award_notice_date: 2006-05-31
opportunity_number: PA-95-049
application_type: 5
activity_code: K01
ic: DA
serial_number: 018772
program_official: AIGNER, THOMAS G
project_start_date: 2005-06-01
project_end_date: 2010-05-31
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
GABA receptor;behavior disorders;behavior test;behavioral /social science research tag;cannabinoid receptor;cannabinoids;clinical research;cognition disorders;data collection methodology /evaluation;dopamine agonists;dopamine receptor;human subject;impulsive behavior;longitudinal human study;neurotoxicology;neurotransmitter agonist;neurotransmitter antagonist;opiate alkaloid;pharmacokinetics;psychomotor function


application_id: 7071154
project_number: 5R21HL080108-02
project_title: Engineering Bone Marrow Cells for Immunotherapy
administering_ic: NHLBI
award_notice_date: 2006-05-22
opportunity_number: PA-03-058
application_type: 5
activity_code: R21
ic: HL
serial_number: 080108
program_official: MASSICOT-FISHER, JUDITH
project_start_date: 2005-06-01
project_end_date: 2008-05-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 8029708
contact_pi: YOLCU, ESMA S
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The main objective of this proposal is to use a novel and practical approach to engineer bone marrow cells to display on their surface a modified form of FasL protein with potent apoptotic activity as an immunomodulatory agent and test the capacity of the engineered cells to engraft in allogeneic recipients without complications of graft-versus-host (GVH) or host-versus-graft (HVG) reactions.  
Allogeneic bone marrow transplantation (BMT) has the potential to cure a series of inherited and acquired hematological disorders and malignancies. BMT can also be used as a cell-based immunomodulatory approach to induce tolerance to foreign and auto-antigens for the prevention and/or treatment of foreign graft rejection and autoimmune disorders. The routine application of BMT as a therapeutic intervention in the clinic however is complicated by two different types of immunological reactions; HVG and GVH. HVG reaction is responsible for rejection of allogeneic BM transplants whereas GVH reaction is the major cause of graft versus- host disease (GVHD) which is a life-threatening complication of BMT without effective treatment modalities. T cells specific for alloantigens are the primary culprit in GVH and HVG reactions. Elimination of T cells from the donor BM inoculum or the graft recipient can curtail both types of reactions lack of engraftment and immunoincompetence are the observed complications. Thus strategies targeting specific and effective elimination of only the pathogenic T cells may have important implications for routine application of BMT to the clinic for the treatment of a variety of diseases. A novel technique designated as ProtEx(tm) has recently been developed in our laboratory that allows for rapid (~ 2 hr) and efficient (100% of the targetted cells) display of exogenous proteins of interest on any cell without compromising the function of the cell or the proteins. In this application ProtEx(tm) will be used to display a modified form of FasL protein with potent apoptotic activity on BM cells and the engineered cells will then be used for transplantation into allogeneic lethally irradiated mice to prevent GVHD and into minimally conditioned hosts to establish mixed chimerism and donor specific tolerance. The use of FasL as an immunomodulatory agent is based on the critical role this molecule plays in immune homeostasis and establishment of self tolerance. We hypothesize that mature T cells in the BM inoculum displaying FasL will respond to the host antigens upregulate the death receptor Fas and undergo apoptosis following the engagement of FasL with Fas on the same or a different cell resulting in the prevention of GVHD. Similarly recipient T cells reacting to the donor BM cells displaying FasL are expected to undergo apoptosis leading to engraftment and establishment of mixed chimerism. Rapamycin an apoptosis-inducing agent and bisulfan an alkylating agent that preferentially depletes early hematopoietic stem cells will be used as adjuvant therapies to i) accentuate FasL-mediated apoptosis ii) create "space" for donor stem cell engraftment and iii) establish a clinically applicable protocol. Specific elimination of pathogenic T cells in lethally irradiated or minimally conditioned hosts is expected to results in allogeneic BM engraftment without complications of GVHD and immunoincompetence with strong therapeutic implications.

project_terms:
T lymphocyte;apoptosis;bioengineering /biomedical engineering;biological models;biotechnology;bone marrow;bone marrow transplantation;busulfan;genetic manipulation;histocompatibility;homologous transplantation;immune tolerance /unresponsiveness;immunomodulators;immunosuppressive;immunotherapy;isoantigen;laboratory mouse;leukocyte activation /transformation;sirolimus;surface antigens;therapy design /development;tissue mosaicism;transplantation immunology


application_id: 7071139
project_number: 5R01NS040334-05
project_title: TRANSGENETIC STUDIES OF PRION DISEASE IN CERVIDS
administering_ic: NINDS
award_notice_date: 2006-06-30
application_type: 5
activity_code: R01
ic: NS
serial_number: 040334
program_official: NUNN, MICHAEL
project_start_date: 2000-08-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1-CNBT(01)]
contact_pi_person_id: 7875112
contact_pi: TELLING, GLENN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_terms:
Ungulate;bioassay;genetic polymorphism;genetic susceptibility;genetically modified animals;laboratory mouse;prions;spongiform encephalopathy;technology /technique development


application_id: 7071036
project_number: 5R01NS047341-03
project_title: Survival signaling in CNS neurons exposed to DNA damage
administering_ic: NINDS
award_notice_date: 2006-06-07
application_type: 5
activity_code: R01
ic: NS
serial_number: 047341
program_official: GOLANOV, EUGENE V
project_start_date: 2004-08-15
project_end_date: 2009-05-31
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): Neurons are targets for damaging stimuli which may trigger cell death and in consequence serious neurological diseases. Interestingly most neurons survive minor damages which they are challenged with during the life span. Therefore one can propose existence of a mechanism that helps neurons to survive the initial injury and resume proper functions after an insult. Identification of this mechanism may result in development of treatments that would harness the intrinsic neuronal defense machinery to combat against neurological diseases. An important damaging stimulus in the CNS is oxidative stress. It exerts its toxic effects at least in part through injury of DNA whose integrity is critical for proper neuronal survival. Indeed neurons are very sensitive to DNA damage. Interestingly DNA damaging agents that are used in cancer therapy frequently produce neurological side effects. Our recently published results indicate that Extracellular Signal Regulated Kinase 1/2 (ERK1/2) is activated in rat cortical neurons by a neurotoxic DNA-damaging drug cisplatin (CPDD) (J Biol Chem 278:43663-43671). Furthermore we have found that inhibition of ERK1/2 pathway enhances toxic response to CPDD. Consequently the general aim of our proposal is testing a hypothesis that neuronal DNA damage activates ERK1/2 to suppress neuronal death and to enhance repair of the cellular damage. We will approach this goal by (i) identification of the mechanism behind ERK1/2 mediated protection against DNA damage (ii) dissection of the pathway linking DNA damage and survival signaling by ERK1/2 (iii) identification of factors which could enhance defensive signaling by ERK1/2 in neurons and finally by (iv) evaluation of ERK1/2 activation as a general compensatory response to diverse forms of DNA injury. To realize the proposal we will use cultured rat primary neurons. The proposed research may result in identification of new drug targets for treatment of neurological diseases and/or deleterious neurological side effects of cancer therapy.

project_terms:
DNA damage;NMDA receptors;SDS polyacrylamide gel electrophoresis;apoptosis;biological signal transduction;central nervous system;cerebellum;cisplatin;hippocampus;immunocytochemistry;laboratory rat;mitogen activated protein kinase;neurons;neurotoxicology;neurotoxins;oxidative stress;polymerase chain reaction;spinal ganglion;tissue /cell culture


application_id: 7070531
project_number: 5R01EY015422-03
project_title: Novel Mouse Models of Age-Related Macular Degeneration
administering_ic: NEI
award_notice_date: 2006-05-22
opportunity_number: PA-00-009
application_type: 5
activity_code: R01
ic: EY
serial_number: 015422
program_official: SHEN, GRACE L
project_start_date: 2004-06-01
project_end_date: 2008-05-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Introduction: Age-related macular degeneration (AMD) is the leading cause of elderly blindness in the U.S. Absence of good animal models has limited mechanistic understanding and thwarted development of therapies. We observed that mice genetically deficient either in the macrophage chemokine CCL2 or its cognate receptor CCR2 develop the pathological hallmarks of AMD in an age-dependent fashion.    Preliminary Data: (1) CCL2-/- and CCR2-/- mice develop lipofuscin drusen geographic atrophy and choroidal neovascularization (CNV) as they age. (2) Complement C5 and IgG are deposited in the retinal pigmented epithelium (RPE) and choroid of both knockout strains as they age as in patients with AMD. (3) These findings are not present in age-matched wild-type mice. (4) Macrophages infiltrate into the choroid of aged wild-type mice but not knockouts in large numbers. (5) C5a and IgG upregulate RPE secretion of CCL2. (6) C5a and IgG upregulate RPE and choroidal endothelial cell secretion of vascular endothelial growth factor (VEGF) consistent with CNV development. (7) Macrophages are immobilized by and adhere to C5a & IgG.    Hypotheses: (1) The accumulation of drusen and lipofuscin associated with senescence in CCL2-/- or CCR2- /- mice is due to impaired clearance by scavenger macrophages whose recruitment is impaired in the absence of CCL2 or its receptor CCR2 and ultimately leads to geographic atrophy and CNV. (2) Rescue of CCL2 or CCR2 function can prevent or regress AMD-like pathology in knockout mice.    Specific Aims: (1) To quantify the development of AMD-like features in CCL2-/- or CCR2-/- mice by ophthalmoscopy angiography and histopathology compared to age-matched wild-type mice. (2) To demonstrate that protein deposits found in the RPE and choroid of senescent CCL2-/- or CCR2-/- mice stimulate CCL2 and VEGF production and that macrophages adhere to and degrade these protein deposits. (3) To demonstrate that rescue of CCL2 or CCR2 function inhibits or regresses AMD-like pathology in elderly CCL2-/- or CCR2-/- mice.    Significance: These studies will provide mechanistic insights into and more effective treatments for AMD.

project_terms:
amyloid proteins;angiography;cell adhesion;chemokine receptor;clinical research;disease /disorder model;enzyme linked immunosorbent assay;genetically modified animals;histopathology;human tissue;immunocytochemistry;immunoglobulin G;laboratory mouse;lipofuscin;macrophage;macular degeneration;macular drusen;monocyte chemoattractant protein 1;optic nerve disorder;protein degradation;retinal pigment epithelium;scavenger receptor;uvea disorder;vascular endothelial growth factors;vitronectin;western blottings


application_id: 7070133
project_number: 5T32CA009509-20
project_title: Tumor Immunology and Cancer Cell/Molecular Biology
administering_ic: NCI
award_notice_date: 2006-05-31
application_type: 5
activity_code: T32
ic: CA
serial_number: 009509
program_official: ECKSTEIN, DAVID J
project_start_date: 1985-07-01
project_end_date: 2007-04-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1880202
contact_pi: KAPLAN, ALAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-31
project_abstract:
DESCRIPTION  (provided  by  applicant):   The continuing goal of this training      grant  for  seven predoctoral and two postdoctoral fellows in Tumor Immunology      and  Cancer  Cell/Molecular  Biology  is  to  educate and train scientists for      research  and  education  in  academia government and industry.  The training      grant  program  is housed in the Department of Microbiology and Immunology but      also   includes  faculty  from  the  Departments  of  Biochemistry  Medicine      Pathology Pharmacology and Radiation Medicine.  The program of study is based      on  a  new  Integrated  Biomedical Sciences Curriculum which provides a strong      didactic  base  in  Biochemistry  Cell  Biology  and Signaling Genetics and      Molecular  Biology  during  the  first  year  along  with  the availability of      exciting well-funded research programs administered by faculty with experience      in  training  both  predoctoral and postdoctoral fellows.  A major strength of      this  program is the strong interactive training environment which exists with      regard  to  both teaching and research.  This has resulted in a high degree of      collaborative  research  among  the  program  faculty  and  trainees  and with      scientists  outside  the  institution.    Research  training  in  which the 24      participating  faculty  are  currently involved encompasses the areas of tumor      immunology oncogenes tumor stem cells gene regulation molecular immunology      and  tumor  metastasis.    The  program  emphasizes multidisciplinary research      training  based  on  a foundation of formal instruction supported by guest and      student   seminar  programs  journal  clubs  laboratory  research  meetings      minisymposia  and  attendance  at regional and national meetings.  The Cancer      Center  has recently recruited a new Cancer Center Director Dr.  Alfred Cohen      from  Memorial  Sloan-Kettering  Institute  who  has  been given a substantial      commitment  to  expand  the  faculty  in  cancer research which should benefit      future training opportunities.  In summary this has been a successful program      that  has  emphasized multidisciplinary training and has since 1985 trained 35      predoctoral  and  16  postdoctoral  fellows whose careers have developed in an      exemplary manner.


application_id: 7069566
project_number: 5R03NS050289-02
project_title: Modeling Brain Hypoxia to Predict Clinical Outcomes
administering_ic: NINDS
award_notice_date: 2006-06-07
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: NS
serial_number: 050289
program_official: GOLANOV, EUGENE V
project_start_date: 2005-05-24
project_end_date: 2009-04-30
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 1918429
contact_pi: BRUCE, EUGENE N
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Impaired O2 delivery to the brain is thought to be a major etiologic factor in the neurocognitive dysfunction experienced by patients after certain surgical procedures and after exposure to carbon monoxide (CO). Knowledge of the extent to which these events impair oxygen (O2) delivery to specific regions of the brain is key to understanding the extent of neurologic damage and to assessing the efficacy of treatment strategies designed to prevent neurologic sequelae in these patients. For CO-poisoned patients for example there is neither an accepted clinical measure that predicts neurological outcome nor agreement regarding the efficacy of normobaric (NBO) vs. hyperbaric (HBO) hyperoxia treatments that are presumed to increase partial pressure of oxygen (PO2) in brain tissue and minimize injury. MR imaging studies of CO-poisoned patients however are in general agreement regarding the specific regions of the brain in which gross changes occur (e. g. frontal cortex and white matter basal ganglia hippocampus). We propose to develop a mathematical model of tissue PO2 distributions in specific brain regions and test the hypothesis that model-based estimates of regional brain tissue hypoxia will correlate with neurological outcome in CO-poisoned patients. Our model will represent six specific regions of the brain: frontal cortex frontal white matter basal ganglia hippocampus generic gray matter and generic white matter. In this R03 (Small Research Grant) proposal we will first expand our existing model of O2 delivery to one brain region so that it represents the 6 specified brain regions. Next we will use our model to estimate by retrospective analyses of a large (existing) clinical database the duration and degree of regional brain hypoxia in individual CO-poisoned patients during both CO exposure and therapy. Finally we will correlate the clinical outcomes (MRI findings neurologic sequelae) from CO-poisoned patients with model-derived indices of the degree duration and spatial extent of local hypoxia in specific regions of the brain. We anticipate that this modeling approach will help to explain outcome and enhance the understanding of the efficacy of HBO vs. NBO in individual cases of CO poisoning. Furthermore with appropriate modifications this simulation modeling approach can be applied to other clinical and experimental situations involving impaired O2 delivery to the brain such as stroke and cardiac surgery.

project_terms:
bioimaging /biomedical imaging;brain imaging /visualization /scanning;brain mapping;carbon monoxide poisoning;cerebral ischemia /hypoxia;cognition disorders;computer simulation;human data;human therapy evaluation;hyperbaric oxygen therapy;magnetic resonance imaging;mathematical model;model design /development;nervous system disorder therapy;neuropathology;outcomes research;oxygen therapy;prognosis


application_id: 7069024
project_number: 5R01NS052290-02
project_title: PKC inhibition-mediated spinal cord regeneration
administering_ic: NINDS
award_notice_date: 2006-05-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 052290
program_official: KLEITMAN, NAOMI
project_start_date: 2005-07-01
project_end_date: 2010-04-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7378367
contact_pi: XU, XIAO-MING
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): Inability of lesioned axons in the adult mammalian central nervous system (CMS) to regenerate has been hypothesized to result from both a decrease in intrinsic regenerative capacity of mature neurons and a local inhibitory environment at the site of injury. It appears that the majority of inhibitory activities in the adult CNS are derived from two CNS-specific glial cell types the oligodendrocyte and astrocyte. While chondroitin sulfate proteoglycans (CSPGs) have been implicated as a major class of inhibitors in astrocyte-derived glial scar several myelin-associated molecules account for the major inhibitory activities of the oligodendrocytes. Our recent data demonstrated that conventional isoforms of protein kinase C (PKC) are key signaling components in the pathways that mediate the inhibitory activities of both myelin components and CSPGs. Strikingly intrathecal infusion of a PKC inhibitor Go6976 into the site of C3 dorsal hemisection made by a unique VibraknifeTM device promoted robust axonal regeneration of the ascending dorsal column (DC) across and beyond the lesion site which led to functional reinnervation. Our data also indicates that PKC inhibition may have an effect on regeneration of the rubrospinal tract (RST). It remains unclear however whether these regenerating axons are able to reach their original targets and form synaptic connections. Unexpectedly the same PKC inhibitor did not promote the regeneration of the corticospinal tract (CST) in this model. These results provide us with a unique opportunity to investigate whether different CNS pathways differ in their requirements for regeneration and how regenerating axons behave in the injured adult CNS. In this application we will explore the role and mechanism of PKC inhibition-mediated axonal regeneration and functional recovery after the C3 dorsal hemisection with the following three (3) Specific Aims: Aim 1 will determine anatomical regeneration reinnervation somatotopic organization and function following DC axonal regeneration elicited by PKC inhibition. Aim 2 will determine whether PKC inhibition also induces regeneration of another descending pathway the RST in the same lesion model to test whether it has a broad effect on axonal regeneration. Aim 3 will explore combinatorial strategies to maximize regeneration and functional recovery after C3 dorsal hemisection. Specifically we will combine the PKC inhibition with three promising strategies to: 1) enhance injured neuron's intrinsic regenerative capacity 2) provide chemotropism for regenerating axons with neurotrophins and 3) remove CSPGs deposited within the glial scar. We will examine whether the combination strategies will result in stronger neurite outgrowth on inhibitory substrates in vitro and greater axonal regeneration and functional recovery in vivo. Collectively these studies may allow us to understand mechanisms underlying PKC-mediated axonal inhibition of different CNS pathways and provide new insights into designing effective therapeutic strategies to encourage axonal regeneration of different types of axons in the injured adult spinal cord.

project_terms:
axon;biological signal transduction;chondroitin sulfates;dendrites;dorsal column;enzyme inhibitors;immunocytochemistry;laboratory rat;nervous system regeneration;neuronal transport;neurotrophic factors;protein kinase C;proteoglycan;pyramidal tracts;spinal cord injury


application_id: 7069013
project_number: 5R01CA067978-10
project_title: Molecular Dissection of Yeast Nucleotide Excision Repair
administering_ic: NCI
award_notice_date: 2006-05-22
application_type: 5
activity_code: R01
ic: CA
serial_number: 067978
program_official: OKANO, PAUL
project_start_date: 1995-09-30
project_end_date: 2007-06-30
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 1866940
contact_pi: WANG, ZHIGANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
Our long-term objective is to understand the molecular mechanism of nucleotide excision repair (NER) in eukaryotes.  DNA damage can be induced by radiation and many chemical carcinogens and is potentially mutagenic and carcinogenic.  NER is an important repair mechanism for removing a wide spectrum of different damage.  Compromising NER activity would lead to a high risk of human carcinogenesis such is the case of the cancer- prone human disease xeroderma pigmentosum (XP).  We have been studying the NER mechanism by using the yeast Saccharomyces cerevisiae as a eukaryotic model organism.  Yeast NER involves at least the following proteins and protein factors: Rad1 Rad2 Rad4 Rad7 Rad10 Rad14 Rad16 Rad23 Mms19 TFIIH RPA PCNA RFC DNA polymerases delta and epsilon and DNA ligase I.  NER pathway can be divided into five steps: damage recognition incision excision repair synthesis and DNA ligation.  The roles of many proteins in NER and several steps of this repair pathway have been elucidated in eukaryotes.  In contrast the damage recognition step and roles of Rad23 and Mms19 proteins in NER have not been clearly defined.  These important aspects of NER will be studied in this proposal.  Our specific aims are (1) to delineate the damage recognition step of NER; (2) to elucidate the function of Rad23 protein in NER; and (3) to determine the role of MMS19 gene product in NER.  The damage recognition step of NER will be analyzed with respect to protein binding to damaged DNA correlation between damage binding and repair efficiency and the ability of the damage binding factor to subsequently recruit other repair proteins for further assembly of the NER machinery.  In vitro biochemical experiments and in vivo genetic experiments will be used to test several hypotheses regarding functions of Rad23 and Mms19 proteins in NER.  These studies should lead to a better understanding of the NER pathway in eukaryotes which in turn should advance our understanding on the interaction between human health and many genotoxic agents in our environment.

project_terms:
DNA binding protein;DNA damage;DNA repair;DNA replication;Saccharomyces cerevisiae;enzyme activity;eukaryote;fungal genetics;gel electrophoresis;gel mobility shift assay;high performance liquid chromatography;mass spectrometry;molecular cloning;molecular genetics;nucleotides;phosphoester ligase;protein binding;protein protein interaction;protein structure function;transcription factor


application_id: 7068618
project_number: 5R01NS045103-04
project_title: Regulation of Neuronal Survival by Ras-like GTPase
administering_ic: NINDS
award_notice_date: 2006-04-26
application_type: 5
activity_code: R01
ic: NS
serial_number: 045103
program_official: MAMOUNAS, LAURA
project_start_date: 2003-07-01
project_end_date: 2008-04-30
study_section: Molecular, Cellular and Developmental Neurosciences 2[MDCN-2]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): Aberrant apoptosis contributes to various neurodegenerative disorders. Elaborating the signal transduction mechanisms that regulate neuronal survival is thus important for understanding both basic biology and for therapeutic intervention. Neurotrophins potently stimulate neuronal survival in part by activating the small GTP-binding protein Ras which functions by translating and directing neurotrophin-initiated signals into multiple signaling pathways. Recent data indicate that the Ras-dependent signaling pathways PI-3 kinase/Akt and MEK/ERK and the Ras-independent MEK5/ERK5 signaling cascade are the primary mediators of neurotrophin-dependent survival. We have discovered a novel evolutionarily conserved group of Ras-related proteins. There are at least two highly related human genes (Rit and Rin) while Drosophila express only one family member (Ric). These proteins represent a gene family that functions to regulate signaling networks that have been conserved from flies to man. Overexpression of a constitutively active mutant of Rit in pheochromocytoma cells induces neurite outgrowth and survival by activating a MEK-dependent but PI-3 kinase/Akt-independent signaling pathway. In addition activated Rit expression in primary neurons inhibits trophic factor-withdrawal induced apoptosis and promotes axonal outgrowth. Thus Rit controls survival pathway(s) in a manner distinct from that of Ras likely functioning to control MEK5/ERK5 signaling or regulating a novel signaling pathway which activates ERK kinases. We hypothesize that Rit functions to translate and direct neurotrophin-initiated signals to pro-survival signaling cascades in a manner distinct from Ras. Three specific aims are described to evaluate this hypothesis. Specific Aim 1 will determine if activation of Rit signaling pathways promotes the survival of primary cultured neurons and if Rit function is essential for neuronal cell survival. Specific Aim 2 will examine the extracellular stimuli that regulate Rit function via neurotrophin-associated or neurotrophin-independent pathways. Specific Aim 3 will examine the mechanism of Rit-mediated ERK activation and determine if established ERK-dependent pro-survival signaling pathways are important for Rit-mediated neuronal survival. Preliminary studies have demonstrated that Drosophila is sensitive to altered Ric activity resulting in developmental defects in the wing and eye. We will undertake a genetic screening approach to identify genes that interact with Ric and vertebrate homologues will be analyzed for their ability to contribute to Rit function in neuronal cells. Through the combined use of biochemistry molecular biology and genetics these studies will form the foundation for understanding the function of this unique regulator of neuronal survival.

project_terms:
DNA damage;Drosophilidae;apoptosis;biological signal transduction;developmental genetics;enzyme activity;genetic screening;guanine nucleotide binding protein;guanine nucleotide exchange factors;guanosinetriphosphatases;laboratory rat;mitogen activated protein kinase;neurons;neuroprotectants;neuroregulation;neurotrophic factors;newborn animals;oxidative stress;phosphatidylinositol 3 kinase;tissue /cell culture;transcription factor;transfection


application_id: 7068491
project_number: 5R01CA093712-05
project_title: Molecular Dissection of Hepatitis C Virus Replicase
administering_ic: NCI
award_notice_date: 2006-06-13
application_type: 5
activity_code: R01
ic: CA
serial_number: 093712
program_official: READ-CONNOLE, ELIZABETH LEE
project_start_date: 2002-07-05
project_end_date: 2008-06-30
study_section: Virology Study Section[VR]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the major etiologic agent of non-A non-B (NANB) viral hepatitis infecting approximately 4 million people in the U.S. HCV is an enveloped RNA virus containing a single positive-stranded RNA genome. The viral protein NS5B is an RNA-dependent RNA polymerase (RdRp) essential for HCV RNA replication and represents a unique target for antiviral intervention. Although NS5B has been studied in vitro and its crystal structure determined its molecular mechanism in HCV RNA replication in vivo is poorly understood. The recent development of a reverse genetics system for HCV provides the opportunity to perform genetic analysis of NS5B and other nonstructural viral proteins in HCV RNA replication. The overall goal of this research proposal is to determine the molecular basis underlying HCV RNA replication using biochemical and reverse genetic approaches. We have recently demonstrated that NS5B is able to initiate de novo RNA synthesis with purine but not pyrimidine nucleotides. In this study we will determine the ribonucleoside triphosphate (NTP) binding site(s) of NS5B using chemical cross-linking and peptide sequence analysis. The biological roles of the NTP binding site(s) of NS5B will then be defined through mutagenesis analysis in conjunction with cross-linking analysis and in vitro RdRp assays for initiation and elongation of RNA synthesis. We have developed efficient cell culture systems for HCV replicon replication. The replicon replication systems will be used to determine the effects of mutations in the NTP binding sites on HCV RNA replication in the cell. As purified recombinant NS5B lacks template specificity in vitro other nonstructural viral and cellular proteins may be required for specificity of HCV RNA replication in vivo. We will dissect the roles of NS5B and other nonstructural viral proteins in the control of HCV RNA replication by mutagenesis analysis coupled with reverse genetics approaches. These initial studies will lead to our long-term goal to understand the roles of the conserved genomic RNA sequences/structures and viral proteins in HCV RNA replication virion assembly and molecular pathogenesis. Information gained from these studies will provide not only meaningful insight to the molecular mechanisms of HCV RNA replication but also novel antiviral targets for development of specific replicase inhibitors to treat HCV infection.

project_terms:
RNA biosynthesis;binding sites;crosslink;gene mutation;hepatitis C virus;nucleoside triphosphate;protein sequence;replicase;replicon;ribonucleosides;tissue /cell culture;virus RNA;virus genetics;virus replication


application_id: 7068478
project_number: 5R01EY012998-06
project_title: Determinants of extraocular muscle function
administering_ic: NEI
award_notice_date: 2006-02-22
opportunity_number: RFA-EY-03-001
application_type: 5
activity_code: R01
ic: EY
serial_number: 012998
program_official: HUNTER, CHYREN
project_start_date: 2000-04-01
project_end_date: 2008-02-29
study_section: ZEY1-VSN(04)
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Congenital strabismus or eye misalignment affects about 4% of children.  However available therapies are not yet optimal with significance incidence of recurrence or unsatisfactory functional results.  The extraocular muscles the final effector arm of the oculomotor system are the target of surgical and pharmacological treatments for strabismus.  This is despite the fact that our understanding of extraocular muscle biology and function remains incomplete. Although the extraocular muscles are included in the skeletal muscle class there is emerging evidence that basic metabolic and functional characteristics of these small muscles are significantly different from those seen in typical skeletal muscles.  First mitochondria serve as novel fast calcium sinks in extraocular muscles and this mechanism is an important determinant of the functional characteristics of these muscles.  Second abnormal visual experience during a postnatal critical period significantly alters the extraocular muscles and renders them weaker slower and more fatigable.  Third the gene expression profile of the extraocular muscles is greatly different from that of other skeletal muscles. These data suggest that the divergent functional properties of the extraocular muscles must be met by alternative strategies for energy supply.  In consequence the objective of this project is to understand how metabolic pathways have adapted in the extraocular muscles to cope with their extreme functional requirements.  Using well-established functional molecular biological and biochemical assays this project will determine (1) the role of alternative energy supply pathways in rat extraocular muscles; (2) the extent to which rat extraocular muscle mitochondria are different; and (3) the role of normal visual experience in establishing these metabolic properties in rat extraocular muscles.  It is expected that these experiments will obtain significant new information the overall metabolic characteristics of the extraocular muscles and provide an integrative view of functional and metabolic properties of these muscles.  By understanding what sets the extraocular muscles apart from other skeletal muscles interventions that directly target these muscles can be envisioned.

project_terms:
adenylate kinase;bioenergetics;calcium ion;calcium metabolism;extraocular muscle;eye movement disorders;laboratory rat;lactates;mitochondria;muscle function;polymerase chain reaction


application_id: 7067549
project_number: 5R01HL068007-06
project_title: Network mechanisms for respiratory rhythm generation
administering_ic: NHLBI
award_notice_date: 2006-06-09
application_type: 5
activity_code: R01
ic: HL
serial_number: 068007
program_official: GOLDEN, AL
project_start_date: 2001-07-01
project_end_date: 2009-05-31
study_section: Special Emphasis Panel[ZRG1-RES-D(03)S]
contact_pi_person_id: 1896681
contact_pi: MELLEN, NICHOLAS M
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): New evidence indicates that two mechanistically distinct spatially separate networks can independently generate respiratory rhythm. We propose that the two networks in concert meet the conflicting demands of adaptive-ness and robustness required for the maintenance of blood-gas homeostasis. This new finding puts emphasis on the role of network interactions in rhythm generation. Because preparations currently available allow easy access to neurons but are too reduced (transverse slice preparation) or retain the networks of interest but do not allow easy access to them (en bloc preparation) we have developed a tilted saggital slice preparation that retains the networks present en bloc but affords good access to the networks of interest. We used optical recordings using a membrane permeable Ca++ indicator to determine the best parameters for cutting the slice and use optical recording techniques routinely to monitor local network activity along the column of respiration modulated neurons in ventrolateral medulla that are exposed at the surface of the saggital slice. We will use optical signals to identify 2 classes of endogenously bursting respiratory neurons for detailed investigation using intracellular recording techniques. These endogenous bursters differ in that one population changes its bursting frequency as a function of membrane potential (voltage-dependent endogenous burster; VDEB) while the other does not (voltage-independent endogenous burster; VIEB). Due to this difference VDEB cycle period can be altered by transient de- or hyperpolarizing impulses; while VIEBs will be less sensitive to such inputs. This provides a mechanism for our hypothesis; we propose that VDEBs mediate cycle-to-cycle adaptiveness to respiratory rhythm-generating networks while VIEBs maintain network stability by rapidly restoring baseline rhythm. We propose to test this hypothesis at the network level by selectively modulating VIEB and VDEB networks and at the single neuron level by characterizing perturbation responses in synaptically isolated VIEBs and VDEBs.

project_terms:
biological clocks;brain electrical activity;brain stem;intracellular;laboratory rat;mechanoreceptors;neurons;newborn animals;pulmonary respiration;respiratory reflex;spinal cord;vagus nerve


application_id: 7066591
project_number: 5R01NS045601-04
project_title: Estrogen NADPH Oxidase and Neurotrauma
administering_ic: NINDS
award_notice_date: 2006-06-19
application_type: 5
activity_code: R01
ic: NS
serial_number: 045601
program_official: HICKS, RAMONA R
project_start_date: 2003-09-30
project_end_date: 2008-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-3(01)Q]
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts almost 500000 Americans a year but unfortunately existing treatments have only minimal ability to prevent secondary brain damage accompanying traumatic brain injury.  Epidemiological data that suggests that women fare better then men following TBI but the basis for this difference is not understood. It is likely that action of female sex hormones particularly estrogen may have significant effects on the progression of brain injury and recent data from our laboratory suggests that estrogen has potent anti-inflammatory properties that could account for its ability to attenuate traumatic brain injury.  In particular data indicates that estrogen is able to decrease oxidative burst activity and subsequent redox-based inflammatory signaling in glial cells thereby attenuating neurotoxic brain inflammation. Therefore it is proposed that estrogen acts to preserve brain function following TBI by decreasing both blood-brain barrier (BBB) breech and neuronal injury and that these distinct endpoints are mediated by a single mechanism: modulation of the glial oxidative burst. Specific Aim 1 will test the hypothesis that estrogen is able to significantly attenuate oxidative burst activity in astrocytes microglial cells and endothelial cells both in vitro and in vivo and will determine the role of estrogen receptors in this process through use of estrogen receptor knockout mice. Specific Aim 2 will test the hypothesis that by directly interfering with oxidative burst activity estrogen blocks the release of matrix metalloproteinases and thus preserves blood-brain barrier integrity in mice following traumatic brain injury.  Specific Aim 3 will build upon these studies by testing the hypothesis that by decreasing oxidative burst activity and redox signaling estrogen blocks the formation of neurotoxic inflammatory mediators (excitotoxins and cytokines) culminating in decreased injury and increased recovery following traumatic brain injury.  Completion of these studies will result in a thorough understanding of the mechanisms of estrogen-mediated neuroprotection in TBI and could highlight a novel target for therapeutic intervention following brain trauma in both women and men.

project_terms:
NAD(P)H dehydrogenase;antiinflammatory agents;astrocytes;blood brain barrier;brain injury;cellular pathology;cytokine;enzyme activity;enzyme inhibitors;estrogen receptors;estrogens;genetically modified animals;glia;hormone regulation /control mechanism;hormone therapy;immunocytochemistry;laboratory mouse;neurons;neuroprotectants;neurotoxins;northern blottings;polymerase chain reaction;receptor expression;western blottings


application_id: 7066067
project_number: 5R01HL075080-04
project_title: Altered glucose homeostasis by sleep impairment
administering_ic: NHLBI
award_notice_date: 2006-04-12
opportunity_number: RFA-HL-03-008
application_type: 5
activity_code: R01
ic: HL
serial_number: 075080
program_official: TWERY, MICHAEL
project_start_date: 2003-09-30
project_end_date: 2007-10-30
study_section: ZHL1-CSR-P(S1)
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N.
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Obstructive sleep apnea (OSAs) a condition characterized by repeated episodes of upper airway obstruction during sleep affects 2-5 % of the general population. Extensive clinical data has clearly established an association between (OSAS) obesity and impaired glucose tolerance. If this association between OSAS and impaired glucose tolerance is causal than sleep apnea may be one of the more important risk factors for development of Type II diabetes. We will use two primary characteristics of sleep apnea intermittent hypoxia and sleep fragmentation in mouse models of OSAS to determine if components of sleep apnea are capable of causing disruption of glucose homeostasis. Most studies of sleep disorders and glucose regulation have focused on the development of insulin resistance. However Type II diabetes cannot develop unless there is also at least partial failure of insulin secretion by pancreatic beta cells. Sleep apnea and intermittent hypoxia produce oxidative stress and beta cells are exquisitely sensitive to oxidative stress. To determine whether sleep apnea stresses or damages the beta cell we will measure insulin synthesis and secretion and test if beta cells exhibit signs of stress particularly oxidative stress. To establish whether oxidative stress plays a critical role in apnea induced damage to glucose regulation we will test whether overexpression of antioxidant transgenes provide protection from intermittent hypoxia or sleep fragmentation. Our preliminary results indicate that obese mice are much more sensitive to the detrimental effects of sleep disruption on glucose tolerance and insulin secretion than are lean mice. Since obesity and sleep apnea are common and associated many patients exhibit both pathologies. This may produce synergistic damage to glucose homeostasis. We will test the effect of OSAS on congenic strains of obese and lean mice.

project_terms:
antioxidants;biosynthesis;catalase;diabetes risk;disease /disorder model;genetically modified animals;glucose tolerance;hypoxia;immunocytochemistry;insulin;insulin sensitivity /resistance;laboratory mouse;nuclear factor kappa beta;obesity;oxidative stress;pancreatic islet function;pancreatic islets;perfusion;radioimmunoassay;sleep apnea;sleep disorders;superoxide dismutase;tissue /cell culture


application_id: 7066010
project_number: 5R01NS046267-03
project_title: Tat NADPH oxidase and HIV-dementia
administering_ic: NINDS
award_notice_date: 2006-05-27
application_type: 5
activity_code: R01
ic: NS
serial_number: 046267
program_official: NUNN, MICHAEL
project_start_date: 2004-07-15
project_end_date: 2009-04-30
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): HIV dementia (HIVD) is a central nervous system complication of HIV viral infection that appears in as much as one fourth of AIDS patients. As HIV infection in the brain is relatively restricted an unresolved issue in HIV research is how the low viral load in the brain causes such pronounced neuronal dysfunction. An intriguing possibility is that the deleterious effects of HIV infection in the brain are mediated by viral proteins and a viral protein that has been repeatedly implicated in the pathogenesis of HIVD is the regulatory protein Tat. While it is not yet clear how Tat could cause the many manifestations of HIVD recent data from our laboratory show that Tat is able to specifically increase NADPH oxidase-associated superoxide release and subsequent redox-based  inflammatory signaling in glial cells thereby driving toxic brain inflammation. Based on this data we propose that Tat perturbs brain function by increasing both blood brain barrier breech and neuronal injury and that these distinct pathways are mediated by a single mechanism: Tat-mediated induction of NADPH oxidase. To test this hypothesis we have designed in vitro and in vivo studies making use of 2 novel mouse models of Tat-neurotoxicity to model HIVD. Specific aim 1 will test the hypothesis that Tat is able to significantly induce oxidative burst activity and  redox-based signaling in astrocytes and microglial cells both in vitro and in vivo. Specific aim 2 will test the hypothesis that by directly triggering oxidative burst activity Tat causes the release of  matrix metalloproteinases and thus disrupts blood brain barrier integrity in mouse models of HIVD.  Specific aim 3 will build upon these studies by testing the hypothesis that by increasing oxidative burst activity and redox signaling Tat causes the release of neurotoxic inflammatory mediators (free radicals excitotoxins and cytokines) culminating in neuronal injury and behavioral abnormalities in  mice. Completion of these studies will result in a thorough understanding of the mechanisms of Tat-mediated neurotoxicity and could highlight a novel target for therapeutic intervention in HIVD.

project_terms:
AIDS dementia complex;JUN kinase;NAD(P)H dehydrogenase;astrocytes;behavior test;biological signal transduction;blood brain barrier;cellular pathology;collagenase;enzyme activity;enzyme induction /repression;genetically modified animals;glutamates;inflammation;laboratory mouse;microglia;mitogen activated protein kinase;neuropathology;neurotoxins;nuclear factor kappa beta;oxidative stress;superoxides;tissue /cell culture;transcription factor;tumor necrosis factor alpha;vascular endothelium permeability;virus protein


application_id: 7065714
project_number: 5R01HL058727-08
project_title: Role of vagal nerves in hyperpnea
administering_ic: NHLBI
award_notice_date: 2006-05-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 058727
program_official: GOLDEN, AL
project_start_date: 1998-07-10
project_end_date: 2009-05-31
study_section: Special Emphasis Panel[ZRG1-SSS-3(03)M]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant):  The long-term objective of this application is to elucidate the roles of pulmonary afferents in cardiopulmonary diseases. Hyperpnea tachypnea and dyspnea are common symptoms and signs of cardiopulmonary patients. Those patients often hyperventilate which is detrimental to their existing disease. There are several types of nerve endings in the lung which provide the respiratory center with information about mechanical and chemical changes. However what roles these nerve endings play are still not fully understood. Recently a vagally mediated 'excitatory lung reflex' is described. Initiation of the reflex may be a key step for the hyperpnea tachypnea as well as dyspnea during cardiopulmonary diseases. Our preliminary data indicate that the receptor endings for the reflex are located in the small airways. The specific aims of this project are to identify the structure mechanical and chemical properties of the responsible endings and to identify their afferent pathways. Phrenic nerve activity and intraluminal pressure in the trachea will be recorded for assessing respiration. The activity in the sensory endings will be recorded to quantify the afferent response. Using neurological and pharmacological methodology to stimulate or block nerve traffic the reflex effects will be assessed the reflex pathway will be established and the mechanisms for activation of the receptors will be explored. These physiological results will be confirmed by morphological studies with the techniques such as neural tracing and histochemistry. The information gained will improve our understanding of neural control of breathing leading to better clinical management of pulmonary problems.

project_terms:
cardiovascular function;chemoreceptors;electromyography;histamine;hyperpnea;immunocytochemistry;laboratory rabbit;muscle tone;neuropharmacology;neuroregulation;ouabain;phrenic nerve;prostacyclins;pulmonary circulation;respiratory airflow measurement;respiratory function;respiratory muscles;respiratory pharmacology;respiratory reflex;smooth muscle;stimulant /agonist;trachea;vagus nerve


application_id: 7065691
project_number: 5R01HL065270-08
project_title: Neurocognitive Function in Snoring Children
administering_ic: NHLBI
award_notice_date: 2006-07-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 065270
program_official: TWERY, MICHAEL
project_start_date: 1999-09-30
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-SSS-3(03)M]
contact_pi_person_id: 1896463
contact_pi: GOZAL, DAVID
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): Sleep-disordered breathing (SDB) a condition affecting at least 2-3% of children ages 2-10 years is associated with delayed diagnosis and treatment and substantial neurocognitive and learning deficits. However only a proportion of children with SDB will develop such deficits while the remainder will retain normal or near-normal neurocognitive function. The mechanisms underlying such discrepancy in SDB-associated morbidity are unknown. Based on exciting preliminary findings we now propose that SDB will induce systemic inflammatory responses and that the magnitude of such inflammatory response will be the major determinant of the severity of neurocognitive dysfunction associated with SDB. We therefore will (i) determine whether SDB is associated with increases in inflammatory markers in the serum and urine of 6-8 year-old children. Specifically we will examine gene expression and serum levels of IL-1beta IL-8 IL-6 TNFalpha and ApoE polymorphisms as well as serum levels of ICAM-1 VCAM E-selectin and high sensitivity CRP and urine levels of 15f2t-lsoprostane in snoring children with varying severity levels of SDB and controls; (ii) in these same children we will assess whether the magnitude of neurocognitive dysfunction assessed with multiple well validated batteries is positively correlated with particular individual inflammatory markers and whether a sub-group of such markers exhibits reliable predictive value for SDB-associated neurocognitive dysfunction; (iii) finally we will establish whether the improvement in neurocognitive function associated with treatment of SDB is paralleled by similar ameliorations in the serum and/or urine levels of the selected inflammatory correlates. These studies will identify highly predictive biological correlates of cognitive morbidity in a large population of children with varying degrees of SDB. Furthermore they may allow for future development of treatment-based clinical algorithms for snoring children that employ validated combinations of symptoms physical findings and biological markers. Such approaches may lead to timely recognition of SDB and prevention of its associated morbidities.

project_terms:
adenoidectomy;apolipoprotein E;biomarker;cell adhesion molecules;child behavior;clinical research;cytokine;cytoskeletal proteins;gene induction /repression;human subject;lipid peroxides;lymphatic tissue surgery;middle childhood (6-11);neuropsychological tests;neuropsychology;otorhinolaryngologic surgery;patient oriented research;polysomnography;questionnaires;respiratory airflow disorder;sleep apnea;sleep disorders;statistics /biometry;tumor necrosis factor alpha;urinalysis;vascular cell adhesion molecule


application_id: 7064906
project_number: 5R01DE010729-11
project_title: Control of A actinomycetemcomitans Leukotoxin Expression
administering_ic: NIDCR
award_notice_date: 2006-04-10
application_type: 5
activity_code: R01
ic: DE
serial_number: 010729
program_official: LUNSFORD, DWAYNE
project_start_date: 1994-04-01
project_end_date: 2008-04-30
study_section: Oral Biology and Medicine Subcommittee 1[OBM-1]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION: A. actinomycetemcomitans is associated with human periodontal disease and expresses a leukotoxin (ItX) that kills human cells that are required for the immune response against infection. Most A. actinomycetemcomitans strains express low levels of this toxin but some strains contain alterations in the ltx promoter and exhibit a hyper-leukotoxic phenotype. These strains exhibit altered regulation of the Itx genes and are associated with localized juvenile periodontitis. We will determine how the ltx genes are regulated in minimally leukotoxic organisms and how the regulatory processes are altered in hyper-leukotoxic organisms. We have identified a c/s-acting negative regulator of toxin expression that interacts with a trans-acting protein. This protein will be isolated and we will determine how this interaction reduces ltx expression. We will also determine if the acquisition of an insertion element (IS) leads to increased toxin expression by displacing this c/s-acting negative regulator upstream from the ltx genes. We will also determine if IS introduces an outwardly directed promoter that transcribes the ltx genes. We have also shown that ltx expression is induced during anaerobic growth. A c/s-acting sequence and a trans-acting polypeptide that may play a role in anaerobic regulation have been identified. We will determine if this sequence functions as an UP element that interacts with the ltx-subunit of RNA polymerase. Finally the ltx operon possesses a fifth gene orphan that resides upstream from IXC. Frame shift mutations in orfA reduce ltx expression. Therefore we will determine if the OrfA polypeptide is involved in the regulation of It expression and whether a naturally occurring deletion in orfA leads to the hyper-leukotoxic phenotype. It is clear that the leukotoxin is an important virulence determinant of A. actinomycetermcornitans and thus it is important to understand the mechanisms that lead to the hyper-leukotoxic phenotype. These studies will determine how/Ix expression is regulated in A. actinomycetemcomitans and will identify mechanisms that contribute to hyper-expression of the toxin. The cis- and/or transacting components that are found to differ in ltx hyper-expressing strains may represent new diagnostic targets to detect hyper-virulent A. Actinomycetemcomitans. It is also possible that the regulatory processes themselves may represent targets that can be exploited for the development of local or systemic therapies Aimed at affecting leukotoxin expression in vivo.

project_terms:
Actinobacillus actinomycetemcomitans;affinity chromatography;bacterial cytopathogenic effect;bacterial genetics;bacterial toxins;gene deletion mutation;gene expression;gene induction /repression;genetic regulation;genetic regulatory element;genetic transcription;oral bacteria;phenotype;polymerase chain reaction;protein protein interaction;site directed mutagenesis;virulence


application_id: 7064846
project_number: 5R01DC005989-03
project_title: Functional Analysis of Inner Ear Gap Junctions
administering_ic: NIDCD
award_notice_date: 2006-05-15
application_type: 5
activity_code: R01
ic: DC
serial_number: 005989
program_official: WATSON, BRACIE
project_start_date: 2004-07-15
project_end_date: 2009-06-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-07-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to investigate functions of gap junctional coupling in the inner ear. A gap junctional channel is an intercellular cytoplasmic conduit and is encoded by the connexin gene family in mammals. Six connexin isoforms assemble to form a hexadal connexon (hemichannel) and dock with another connexon in the opposite cell membrane to form an intercellular gap junctional channel through which molecules up to 1 kDa can pass. Cx26 and 30 are the predominant isoforms in cochlear supporting cells. Each connexin mutation can induce hearing loss. It has been found that gap junctions between supporting cells have various asymmetrical voltage gates indicative of the occurrence of heterotypic and heteromeric hybrid channel configurations in the cochlea. The working hypothesis of this project is that Cx26 and 30 may dock to form heterotypic and heteromeric channels with specific permeability to selectively transfer ions and molecules in the cochlea; asymmetric heterotypic channels may also induce directional intercellular transfer in this multicellular system. Specific aim (SA) 1 is to define connexin-specific functions in the cochlea. We will use immunofluorescent staining to identify connexin expression and distributions patch clamp recording to measure channel conductance and gating to identify channel types and configurations and fluorescent probes to assess connexin channel permeability. Charge and size selectivity in gap junctional permeability will be assessed by use of multiple florescent probes with patch clamp recording. Fluorescence recovery after photo bleaching (FRAP) with confocal microscopy will also be employed to quantitatively define gap junctional permeability. The asymmetry of transjunctional diffusion between cochlear supporting cells and directional passage in the cochlear sensory epithelium will be defined by FRAP measurement and time-lapse fluorescent microscopy (SA2). SA3 is to define the activity and permeability of connexin hemi channels in native cochlear supporting cells to further elucidate structure-function relationship of gap junctional coupling in the cochlea. SA 4 is to test the K+-recycling hypothesis that has long been proposed but has yet to be tested. We will use patch clamp technique to directly record K+ passage between cochlear supporting cells. SA5 is to explore the effect of supporting cell's junctional coupling on outer hair cell electro motility. Undoubtedly completion of these studies will contribute signaificantly towards understanding the mechanisms of gap junctional coupling in the inner ear and in turn develop therapeutic and protective interventions for this common hereditary deafness.

project_terms:
adenosine triphosphate;auditory nuclei;calcium ion;cell cell interaction;cell population study;confocal scanning microscopy;diffusion;fluorescence microscopy;fluorescence recovery after photobleaching;gap junctions;guinea pigs;hearing;intracellular transport;ion channel blocker;ion transport;labyrinth;membrane activity;membrane channels;membrane permeability;membrane potentials;potassium channel;potassium ion;protein structure function;voltage /patch clamp;voltage gated channel


application_id: 7064772
project_number: 5R01AR049010-03
project_title: Prostaglandin E synthase in rheumatoid arthritis
administering_ic: NIAMS
award_notice_date: 2006-01-12
application_type: 5
activity_code: R01
ic: AR
serial_number: 049010
program_official: MANCINI, MARIE
project_start_date: 2004-12-01
project_end_date: 2008-11-30
study_section: Special Emphasis Panel[ZRG1-ACTS(01)Q]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant):   The effectiveness of non-steroidal anti-inflammatory drugs and specific cyclooxygenase (COX)-2 inhibitors for treatment of arthritis provides clinical evidence that increased prostaglandin (PG) production in joint tissues contributes to symptoms of pain swelling and stiffness. PG biosynthesis requires the sequential action of COX and PG synthase enzymes. After stimulation with pro-inflammatory cytokines there is a preferential increase in PGE2 in many different cell types including synovial fibroblasts. We demonstrated that increased PGE2 in response to pro-inflammatory cytokines in human primary synovial cells is due to induction of microsomal PGE synthase (mPGES)-1. The overall goal of this proposal is to characterize the role of mPGES-1 and other PGE synthases in eicosanoid biosynthesis in immune inflammatory arthritis. We hypothesize a requirement for mPGES-1 to achieve maximal PGE2 production and a role for mPGES-1-derived PGE2 in shaping the immune inflammatory response. We propose to determine the specific role of mPGES-1 relative to other synthetic enzymes for biosynthesis of PGE2 in human synovial fibroblasts using specific COX enzyme inhibitors and inhibitory RNA (RNAi). We will investigate eicosanoid production pathways in cells from mice deficient for COX-1 COX-2 or mPGES-1. Expression of the COX and PGES enzymes in synovial tissues from patients with arthritis or non-arthritic subjects and their relative subcellular localization will be determined. In addition we will examine the consequences of mPGES-1 deficiency for innate and acquired immunity in genetically null mice. We will determine eicosanoid and cytokine profiles of macrophages splenocytes and dendritic cells in mPGES-1 null mice. We will determine the impact of mPGES-1 deficiency on dendritic cell phenotype and function. We will determine the role of PGE2 on immune versus inflammatory mechanisms of arthritis using the collagen-induced arthritis and K/BxN serum models. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.

project_terms:
RNA interference;cell line;clinical research;cytokine;eicosanoid metabolism;enzyme activity;enzyme inhibitors;fatty acid metabolism;free fatty acids;gene expression;genetically modified animals;high performance liquid chromatography;human subject;immune response;immunocytochemistry;inflammation;laboratory mouse;patient oriented research;prostaglandin E;prostaglandin endoperoxide synthase;protein isoforms;protein localization;rheumatoid arthritis;synovial membrane;synthetic enzyme


application_id: 7062446
project_number: 5R01NS037717-07
project_title: Molecular/genetic control of oligodendrocyte development
administering_ic: NINDS
award_notice_date: 2006-04-19
application_type: 5
activity_code: R01
ic: NS
serial_number: 037717
program_official: UTZ, URSULA
project_start_date: 2000-03-01
project_end_date: 2008-02-28
study_section: Molecular, Cellular and Developmental Neurosciences 2[MDCN-2]
contact_pi_person_id: 1906514
contact_pi: QIU, MENSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of oligodendrocytes. Although considerable insights have been gained into the molecular mechanisms that control the initial specification of oligodendrocytes it is still not clear how the terminal differentiation and myelination of oligodendrocytes are regulated during animal development. Recently we have demonstrated that oligodendrocyte progenitor cells start to acquire the expression of Nkx2.2 homeodomain transcription factor during their migration to their destination sites and expression of Nkx2.2 is required for oligodendrocyte differentiation and myelin gene expression. Here we hypothesize that Nkx2.2 plays a key role in controlling the timing of oligodendrocyte differentiation and myelination during animal development and the expression and activity of Nkx2.2 are tightly regulated by both intracellular and extracellular factors.  Specific aim 1 of this proposal is to test the hypothesis that Nkx2.2 and Sox10 interact physically and have synergistic actions on activating myelin gene expression and oligodendrocyte differentiation. Specific aim 2 is to test the hypothesis that Nkx2.2 expression in oligodendrocyte progenitor cells can be induced by extracellular factors (thyroid hormone) that promote oligodendrocyte differentiation. Specific aim 3 is to test the hypothesis that the Notch pathway controls the timing of oligodendrocyte differentiation by regulating Nkx2.2 expression in oligodendrocyte progenitor cells. Specific aim 4 is to test the hypothesis that Nkx2.2 regulates oligodendrocyte myelination at later stages of animal life in collaboration with Nkx6.2.  Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of oligodendrocytes and may provide theoretic basis for design of novel therapeutic approaches for prevention and treatment of motor neuron and oligodendrocyte atrophies.

project_terms:
biological signal transduction;cell differentiation;chick embryo;electroporation;gene expression;genetic regulation;immunoprecipitation;in situ hybridization;laboratory mouse;myelination;neurogenetics;oligodendroglia;protein protein interaction;spinal cord;stem cells;thyroid hormones;transcription factor


application_id: 7062154
project_number: 5R01AI051517-05
project_title: SV5 and Hendra virus F protein promoted membrane fusion
administering_ic: NIAID
award_notice_date: 2006-04-03
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: CASSETTI, CRISTINA
project_start_date: 2002-05-15
project_end_date: 2008-04-30
study_section: Experimental Virology Study Section[EVR]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA E.
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: 2006-05-01
project_abstract:
EXCEED THE SPACE PROVIDED.The paramyxovirus family contains both established major human pathogens including measles virus andrespiratory syncytial virus and newly emerged human pathogens the Hendra and Nipah viruses. The fusion (F) proteins from paramyxoviruses promote fusion of viral and cellular membranes an event that is both anessential step mediating entry of enveloped viruses into the host cell and an excellent model system for investigating the basic molecular events in membrane fusion processes. The long-term objective of this proposed research is to understand the precise mechanism(s) of the paramyxovirus F proteins in promotion ofmembrane fusion. The central hypothesis of this research proposal is that regions of the paramxyovirus F proteins that are critical for promotion of membrane fusion will be conserved between disparate members ofthe family and that analysis of these regions will aid in understandingthe precise mechanisms of the Fproteins in promotion of membrane fusion. The experiments in Specific Aim 1 will utilize transient expression systems and site-directed mutagencsis to analyzethe synthesis and processing of the F protein from Hendra virus a recently discovered human pathogen. The research proposed in Specific Aim 2 willcharacterize the membrane fusion event promoted by the Hendra virus F protein using several differentmembrane fusion assays which allow for examination of various stages of the reaction. Finally the experiments in Specific Aim 3 will examine the effect of mutations in the SV5 F and Hendra F proteins in regions that show amino acid conservation throughout the paramyxovirusfamily to determine whether thesechanges effect folding protein processing or promotion of membrane fusion. Accomplishing these goals willprovide crucial information on the processing and fusion-promotion activity of a paramyxovirus F proteinfrom a newly emerged virus. In addition conserved regions of the F proteins that are important in functionwill be identified. The results of all of these studies will provide significant new information relevant tounderstanding specific molecular events involved in membrane fusion processes.PERFORMANCE S1TE(S) (organization city state)University of Kentucky. Lexineton. KYKEY PERSONNEL. See instructionsName Rebecca Ellis Dutch Michael Sheehan Willie Craft Jr.Patrick Segeleonon Page 11. Use continuation pages as needed to provide the required information in the format shown below. Organization Role on Project University of Kentucky Principal Investigator University of Kentucky Graduate Student University of Kentucky Graduate Student University of Kentucky Senior Lab TechnicianPHS 398 (Rev. 4/98) Page 2 BBNumber pages consecutively at the bottom throughout the application. Donal usesuffixes such as 3a 3b.CC iS^HWrapcal Investigator/Program Director (Last first middle): P^i Rebecca EllisType the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications seeinstructions on page 6.)RESEARCH GRANTTABLE OFCONTENTSPage NumbersFace Page 1Description

project_terms:
Paramyxoviridae;clinical research;gene mutation;human subject;membrane fusion;protein biosynthesis;protein sequence;simian virus;site directed mutagenesis;virus infection mechanism;virus protein


application_id: 7062149
project_number: 5R01AI048850-04
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2006-03-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-SSS-F(01)S]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of aP2 and keratinocyte fatty acid binding protein (mal-1). AP2 and mal-1 are FABPs which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs) which include metabolites of cyclooxygenase and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands thus impacting macrophage gene expression and function. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed and the activity of transcription factors known to be regulated by PPARs will be analyzed in wild-type and FABP-deficient macrophages. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model will be employed to provide a means to analyze FABP function in vivo in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes.

project_terms:
biological signal transduction;enzyme activity;enzyme linked immunosorbent assay;experimental allergic encephalomyelitis;fatty acid binding protein;gel mobility shift assay;gene expression;keratinocyte;laboratory mouse;ligands;lipoxygenase;macrophage;multiple sclerosis;peroxisome proliferator activated receptor;prostaglandin endoperoxide synthase;tissue /cell culture;transcription factor


application_id: 7062147
project_number: 5R03AI057670-02
project_title: Role of an essential RNA chaperone in virus replication
administering_ic: NIAID
award_notice_date: 2006-04-13
opportunity_number: PA-02-038
application_type: 5
activity_code: R03
ic: AI
serial_number: 057670
program_official: PARK, EUN-CHUNG
project_start_date: 2005-05-15
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1-IDM-G(90)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: N
project_abstract:
DESCRIPTION (provided by applicant): RNA replication is the central step in the infection cycles of plus-strand RNA viruses which cause many diseases in humans animals and plants. In spite of its significance the mechanism of viral RNA replication is incompletely understood. Tractable model systems such as tombusviruses can contribute greatly to our understanding of viral RNA replication. Since the RNA-dependent RNA polymerase (RdRp) the key enzyme in replication is similar in tombusviruses and numerous other important human and animal viruses (hepatitis C virus flavivirus including West Nile virus and dengue virus pestiviruses) and plant viruses (luteo- and carmoviruses) understanding the mechanism of RNA replication in tombusviruses is expected to help studies on important but less amenable RNA viruses of humans animals and plants. In order to advance understanding of the mechanism of virus replication the investigator has developed an efficient in vitro RNA replication assay based on purified tombusvirus RdRp from yeast. In addition the investigator has established a novel RNA replicon based in vivo replication system in yeast. These advances make tombusviruses exceptionally suitable for studying the mechanism of RNA replication. One of the two essential replicase proteins coded by tombusviruses termed p33 is an RNA chaperone protein which influences many processes during infection including replication of genomic RNA and Dl RNA subgenomic RNA synthesis RNA recombination and Dl RNA formation. The aims of this application is to determine the functions of p33 in tombusvirus replication such as: (i) targeting the viral RNA template and the RdRp to the site of replication; (ii) template selectivity; (iii) stabilization of tombusvirus RNAs in cells; (iv) enhancement of synthesis of plus- and minus-strand RNAs; and (v) RNA structure unwinding and strand separation. The investigator will perform biochemical cellular experiments using yeast and whole plants in order to define the multiple functions of p33 during tombusvirus infection. Overall studies on tombusvirus replication will likely advance major scientific areas including: (i) mechanism of RNA replication and interference; (ii) template and RdRp recruitment to the site of replication; (iii) regulation of RNA synthesis by essential protein factors; (iv) RNA-protein and protein-protein interactions during replication; (v) template selection by the viral replicase; and (vi) development of novel antiviral agents.

project_terms:
RNA interference;RNA virus;biological models;molecular chaperones;nucleic acid biosynthesis;protein protein interaction;replicase;virus RNA;virus protein;virus replication


application_id: 7062138
project_number: 5R01HL076160-03
project_title: Direct Peritoneal Resuscitation from Hypovolemic Shock
administering_ic: NHLBI
award_notice_date: 2006-02-17
opportunity_number: RFA-HL-03-015
application_type: 5
activity_code: R01
ic: HL
serial_number: 076160
program_official: LIANG, ISABELLA Y
project_start_date: 2004-03-01
project_end_date: 2008-02-28
study_section: ZHL1-CSR-I(F1)
contact_pi_person_id: 7725997
contact_pi: GARRISON, RICHARD N
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The pathophysiology of Hemorrhagic shock consists of disruption of the cellular metabolic functions  endothelial barrier properties redistribution of body fluids and electrolytes a systemic inflammatory  response and a deleterious intestinal vasoconstriction and a disproportionate splanchnic hypoperfusion which persists even after adequate fluid replacement that restores and maintains hemodynamics. These pathophysiologic events cause local and remote tissue injury that culminates in multiple organ failure (MOF) by mechanisms which are poorly understood. It is hypothesize that initiation of direct intraperitoneal resuscitation (DPR) with a balanced physiologic salt solution supplemented with glucose (2.5%) at the time of conventional resuscitation (CR) from hemorrhagic shock can reverse the pathophysiology of this syndrome improving resuscitation outcome potentially preventing (MOF) and improving survival: a) by suppressing the hemorrhage-induced systemic inflammatory response b) by direct intestinal resuscitation to enhance visceral perfusion and cardiac output c) by improving endothelial cell responsiveness to vasodilators and d) by preventing the hemorrhage-induced water and electrolytes imbalance. To address this hypothesis we will utilize intravital microscopy and quantitative autoradiography (QAR) to perform in vivo studies in a rodent model of hemorrhagic shock which will be resuscitated with either CR or CR+DPR and determine the following: 1) Serum cytokines profile and level of prostanoid metabolites; 2) Endothelial cell function with dose-response curves to endothelial-dependent receptor-mediated and non-receptor mediated as well as endothelial-independent agonists; 3) The pattern of distribution of tissue water (intravascular thetaiv interstitial thetaif intracellular thetaic) in the gut and abdominal wall with QAR; 4) The role of neutrophils in the derangement of intestinal microvascular endothelium by measuring microvascular responses in the presence of anti-PMN serum and specific antibodies; and 5) The mechanisms involved in the ability of DPR to reverse the pathophysiology of the shock syndrome. Long-term objectives are to develop a pre-clinical protocol that utilizes DPR as a prelude to translation of the results to trauma patients and finally a clinical protocol that utilize DPR to prevent multiple organ failure in hemorrhage shock with resuscitation.

project_terms:
autoradiography;cytokine;glucose;hemorrhagic shock;hypovolemia;immunologic assay /test;inflammation;intraperitoneal injections;intravital microscopy;laboratory rat;multiple organ failure;neutrophil;resuscitation;saline;vascular endothelium;vasoconstriction;vasodilation


application_id: 7062065
project_number: 5R01NR008135-04
project_title: Effect of Prehabilitation on Rehabilitation of TKA
administering_ic: NINR
award_notice_date: 2006-03-17
application_type: 5
activity_code: R01
ic: NR
serial_number: 008135
program_official: MARDEN, SUSAN F
project_start_date: 2003-08-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1-NURS(03)M]
contact_pi_person_id: 1862038
contact_pi: TOPP, ROBERT VINCENT
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
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): OA of the knee is a significant problem in later life which is associated with declines in functional capacity. This chronic condition is accompanied by increasing degrees of knee pain which is associated with decreasing levels of functional capacity. The increasing incidence of total knee arthroplasty (TKA) appears to indicate that conservative approaches have limited effectiveness in relieving symptoms of OA of the knee. Recovery following TKA surgery  appears empirically and theoretically positively linked to functional capacity prior to surgery. A large number of investigators have indicated that various exercise interventions can improve the functional capacity of knee OA patients. To date no study has yet demonstrated the efficacy of preoperative exercise training which improves functional capacity on the postoperative recovery of TKA patients. Preliminary studies in the area indicate the feasibility of TKA patients engaging in various types of exercise interventions preoperatively. These studies have been limited by a number of methodological flaws which may have contributed to their inconclusive findings that preoperative exercise had no effect on postoperative recovery among TKA patients. The proposed study will address these flaws by utilizing an urger sample and employing proven exercise interventions which have been shown to improve the functional capacity of patients with OA of the knee. The specific aim of this study is: to compare the knee pain ability to complete functional tasks and markers of prehabilitation among TKA patients who do and do not participate in an 8-week program of prehabilitation prior to their FKA surgery. To address this aim ninety-eight community dwelling subjects age 50 and older who are scheduled for a unilateral TKA will be recruited from a single orthopedic surgeon's practice. Subjects will be assessed prior to beginning interventions at baseline one week prior to their TKA surgery and 1 and 3 months following their TKA surgery. These assessments will include measures of knee pain the ability to complete functional tasks and markers of rehabilitation. Following baseline-testing subjects will be randomized into either a prehabilitation group (treatment) or a usual treatment group (control). Subjects in the treatment group will participate in three sessions of prehabilitation per week one supervised and 2 unsupervised for eight weeks prior to their TKA. The training will consist of resistance training flexibility exercises and step training. The three principle hypotheses of this study will be tested through repeated measures analysis of covariance. This statistic compares the two groups' dependent outcome measures at one week prior to their TKA and 1 and 3 months following the TKA procedure while adjusting for dependent measures taken at baseline and potential confounding variables between the groups. The outcomes of this study have the potential to reveal that  preoperative exercise can enhance post surgical recovery.

project_terms:
arthroplasty;biomarker;clinical research;exercise;functional ability;gait;human subject;human therapy evaluation;joint prosthesis;knee;medical implant science;medical rehabilitation related tag;musculoskeletal disorder therapy;nutrition;nutrition related tag;orthopedics;osteoarthritis;pain;patient oriented research;physical therapy;postoperative state;preoperative state;proprioception /kinesthesia;rehabilitation


application_id: 7062060
project_number: 5R01ES011314-04
project_title: Arsenic Induced Miotic Arrest Associated Apoptosis
administering_ic: NIEHS
award_notice_date: 2006-04-28
application_type: 5
activity_code: R01
ic: ES
serial_number: 011314
program_official: THOMPSON, CLAUDIA L
project_start_date: 2003-08-01
project_end_date: 2008-04-30
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_terms:
Chinese;aneuploidy;antisense nucleic acid;apoptosis;arsenic;basal cell carcinoma;cell growth regulation;chemical carcinogenesis;cyclins;flow cytometry;gene mutation;human genetic material tag;human tissue;p53 gene /protein;phosphorylation;squamous cell carcinoma;ultraviolet radiation


application_id: 7062054
project_number: 5R24RR016344-06
project_title: GENOME RESOURCES FOR MODEL AMPHIBIANS
administering_ic: NCRR
award_notice_date: 2006-02-12
application_type: 5
activity_code: R24
ic: RR
serial_number: 016344
program_official: CHANG, MICHAEL
project_start_date: 2002-08-16
project_end_date: 2007-03-31
study_section: Comparative Medicine Review Committee[RIRG-C]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (Provided by applicant):  Salamanders (urodele amphibians) are                                important model organisms in several areas of human health and disease              research including limb regeneration neural transmission vision renal           function embryo genesis heart development and olfaction.  The utility of         salamanders would be greatly extended if fundamental genome resources were          developed and made available to researchers.  The objective of the proposed         project is to characterize and determine the genomic position of expressed          sequences(ESTs)from regenerating limb and retina two focal salamander tissues      in biomedical research.  Also to make a more general contribution to               salamander researchers genes that correspond to previously published               salamander sequences in Genbank will be mapped.  The identification of ESTs         and development of a genome map will be an important resource over the short        term because it will allow: (1) construction of an EST database for salamander      traits that are of special interest; (2) gene homologies to be determined           between salamander and human; (3) candidate gene studies of existing                salamander mutants; (4) quantitative trait locus analyses of complex                phenotypes; and (5) reconstruction of vertebrate genome evolution.  With            respect to longer term goals the proposed project will spur development of         additional resources that will facilitate identification of salamander genes        of biomedical significance.

project_terms:
Internet;Urodela;clone cells;complementary DNA;evolution;gene expression;genetic library;genetic mapping;genetic markers;genetic models;genetic polymorphism;genetic strain;genome;limbs;linkage mapping;molecular biology information system;mutant;nucleic acid sequence;phenotype;quantitative trait loci;retina;tissue resource /registry


application_id: 7061701
project_number: 5R01CA107575-03
project_title: Anoikis Effect by Quinazolines on Prostate Growth
administering_ic: NCI
award_notice_date: 2006-04-11
application_type: 5
activity_code: R01
ic: CA
serial_number: 107575
program_official: ARYA, SURESH
project_start_date: 2004-05-01
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1-UROL(01)]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Loss of apoptotic control in prostate growth disorders involves the altered expression/activation of downstream intracellular effectors of apoptosis signaling pathways.  Re-instating functional apoptotic mechanisms by targeting specific components in this pathway are of high significance in the regulation of prostate growth.  Recent studies documented the ability for quinazoline-based a1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in human prostate smooth muscle benign and malignant epithelial cells via an a1-adrenoceptor independent mechanism and suppress tissue vascularity.  Our hypothesis is that quinazoline-based a1-adrenoceptor antagonists suppress prostate growth by inducing apoptosis (via induction of intracellular signaling effectors) and inhibit angiogenesis by promoting anoikis (via interference with extracellular matrix attachments).  To test this hypothesis the following aims are proposed: In Specific Aim 1 we will use DNA microarray analysis and proteomic analysis to identify intracellular signaling effectors of apoptosis induced by quinazoline-based a1-adrenoceptor antagonists in prostate benign and malignant cells.  Specific Aim 2 will identify the extracellular matrix components involved in quinazoline-induced anoikis in prostate epithelial and endothelial cells with focus on Fas-Fasligand-caspase-8 activation mechanism and integrin effectors.  Specific Aim 3 will establish that the quinazolines doxazosin and terazosin suppress prostate vasculature and inhibit tissue angiogenesis in patients after a1 blockade treatment. Immunohistochemical analysis will be performed on tissue specimens from BPH patients treated with a1 blockade (for obstructive symptoms) using antibodies against Factor VIII (microcrossed density) vascular endothelial growth factor (VEGF) and focal ashesion kinase (FAK).  The goal of the proposed studies is to determine the early response genes at the intracellular (TGF-beta) and extracellular matrix (integrins) environment underlying the quinazoline-mediated apoptosis targeted by this pharmacologic intervention in benign and malignant prostate growth.  Potential results will establish the apoptotic/anoikis effect by the quinazolines as a significant phenomenon with clinical relevance in development and progression of benign prostatic hyperplasia (BPH) prostate cancer.

project_terms:
angiogenesis;apoptosis;benign prostate hyperplasia;biological signal transduction;cell growth regulation;cell line;coagulation factor VIII;cysteine endopeptidases;enzyme activity;enzyme mechanism;extracellular matrix;focal adhesion kinase;gel mobility shift assay;gene expression profiling;human tissue;immunocytochemistry;integrins;male;microarray technology;prazosin;prostate neoplasms;proteomics;quinazolines;smooth muscle;transforming growth factors;vascular endothelial growth factors


application_id: 7061327
project_number: 5R01DA011551-08
project_title: Structure and Function of CB2 Cannabinoid Receptor
administering_ic: NIDA
award_notice_date: 2006-04-08
application_type: 5
activity_code: R01
ic: DA
serial_number: 011551
program_official: HILLERY, PAUL
project_start_date: 1998-09-30
project_end_date: 2009-04-30
study_section: Molecular, Cellular and Developmental Neurosciences 5[MDCN-5]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this research proposal is to identify the molecular basis underlying the functions of the CB2 cannabinoid receptor. To achieve this purpose the following steps will be taken. In Aim 1 and 2 the interactive mutagenesis molecular modeling and new compound testing studies will be carried out. This combined approach has advanced our understanding and should continue to reveal new insights on how cannabinoid ligands are recognized by their receptors the origin of receptor subtype-selectivity and how these receptors are activated/inactivated. Cannabinoid receptors share many of the conserved sequence motifs seen in other well-studied G protein-coupled receptors (GPCRs) such as rhodopsin and biogenic amine receptors. However several helix-bending residues and motifs and a key disulfide bridge present in many other GPCRs are missing in cannabinoid receptors. In Aim 3 Ligand binding crevice exposure of two transmembrane domains of CB2 cannabinoid receptor will be mapped using substituted-cysteine accessibility method. This approach should elucidate structural and functional consequences of the sequence divergence in these trasmembrane domains of cannabinoid receptors.   In Aim 4 Disulfide bond formation of CB2 receptor will be determined directly by the state-of-art methodologies of mass spectrometry. Investigating the unique disulfide bond or absence of a disulfide bond should provide important helix folding information of CB2 receptor and this will have important implications regarding ligand binding crevice and activation mechanisms of this receptor. Finally in Aim 5 effort will be devoted to over-express and purify large amounts of functional CB2 receptor. This challenging task if successfully completed should have a significant impact by providing the badly needed pure receptor proteins for future high-resolution biophysical studies. Overall This study should help us to understand in more molecular detail the structure and function of CB2 receptor. CB2 is primarily distributed in the immune system. It is very important for the immune-modulatory effects of marijuana. In the long run this study should also help us to develop better cannabinoid mimetics for the treatment of immune system illnesses such as inflammation and autoimmune diseases. The drugs that specifically targeted at CB2 should be devoid of psvchoactive side effects of marijuana.

project_terms:
active sites;cannabinoid receptor;chemical models;computer simulation;disulfide bond;ligands;mass spectrometry;molecular dynamics;protein purification;protein reconstitution;protein structure function;receptor expression;site directed mutagenesis


application_id: 7060822
project_number: 5R01CA100656-03
project_title: Integrating Innate & Adaptive Immunity in Cancer Therapy
administering_ic: NCI
award_notice_date: 2006-04-25
application_type: 5
activity_code: R01
ic: CA
serial_number: 100656
program_official: HECHT, TOBY T
project_start_date: 2004-05-21
project_end_date: 2006-12-31
study_section: Experimental Immunology Study Section[EI]
contact_pi_person_id: 2793463
contact_pi: EGILMEZ, NEJAT K
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant): The slow release of IL-12 and GM-CSF from biodegradable microspheres into a single primary tumor nodule promotes the development of potent systemic anti-tumor immunity and the complete eradication of disseminated tumor nodules in a metastatic murine tumor model. The immune mechanisms that mediate the eradication of systemic disease have not yet been defined in this model. Our hypothesis is that the local and sustained release of IL-12 and GM-CSF into the tumor microenvironment promotes the activation of the tumor-associated effector memory T-cells which then initiate a cascade of local inflammatory events that result in the development of a systemic anti-tumor immunity. To this end in Aim 1 we will phenotypically and functionally define the T cells that are present in the primary tumor microenvironment and characterize the downstream events that follow their activation. Studies proposed in Aim 2 will address the continuing hypothesis that the induction of inflammatory activity within the primary tumor will prime the development of a long-term systemic anti-tumor T-cell response that effectively infiltrates and suppresses metastatic tumors.   
Preliminary observations suggest that a systemic NKT/NK cell response is also involved in the suppression of metastatic tumors. In Aim 3 we will test the notion that activation of a systemic but transient NKT/NK response accompanies the early local immune events and that co-induction of innate and adaptive immunity is critical to effective eradication of systemic disease. Finally in Aim 4 we will test the hypothesis that the intensity of the immediate effector memory T-cell response that is induced within the primary tumor microenvironment determines the efficacy of long-term cure in individual mice. The information derived from these studies is expected to provide valuable insights for the design of an effective cytokine-based immunotherapeutic strategy for the treatment of cancer patients.

project_terms:
T lymphocyte;antineoplastics;cell mediated cytotoxicity;cell migration;cellular immunity;colony stimulating factor;drug delivery systems;flow cytometry;genetically modified animals;histology;immunologic memory;inflammation;interleukin 12;laboratory mouse;leukocyte activation /transformation;metastasis;microcapsule;natural killer cells;neoplasm /cancer immunology;neoplasm /cancer immunotherapy;nonhuman therapy evaluation;polymerase chain reaction;slow release drug;tumor infiltrating lymphocyte


application_id: 7060791
project_number: 5R21DE016644-02
project_title: Cooperative roles of Tat & k-cyclin Kaposi's sarcoma
administering_ic: NIDCR
award_notice_date: 2006-05-19
opportunity_number: RFA-DE-05-001
application_type: 5
activity_code: R21
ic: DE
serial_number: 016644
program_official: MCINNES, PAMELA M
project_start_date: 2005-06-01
project_end_date: 2008-05-31
study_section: ZDE1-PZ(08)
contact_pi_person_id: 9185054
contact_pi: LI, MENGTAO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kaposi's sarcoma is a malignant tumor of endothelial origin and the most frequent cancer in AIDS patients. Sixty percent of AIDS-associated KS initiate in the oral cavity representing a serious problem in oral health. Despite identification of human Herpesvirus 8 (HHV-8) as the etiological agent for all forms of KS the extraordinarily higher prevalence of KS in HIV-infected patients suggests a cooperative interaction between HIV and HHV-8 in the development of KS. HIV Tat is one of the key regulating factors for viral gene expression and plays many roles in HIV-associated pathogenesis. Tat causes dysfunction and transformation of cultured endothelial cells and induces KS-like lesions in transgenic animals. HHV-8 k-cyclin a homologue of cellular cyclin D disrupts cell growth control by aberrantly activating Cdk6 and accelerating the G1/S transition of the cell cycle. The expression of k-cyclin promotes proliferation of endothelial cells. We have found that Tat interacts with k-cyclin in vivo providing evidence of pathological links between HIV and HHV-8. Here we propose to study the cooperative roles of Tat and k-cyclin in the development of KS by using immortalized primary endothelial cells. Using this in vitro model we will dissect steps that are responsible for the HHV-8-infected endothelial cells to progress toward the development of KS malignancy. The specific aims are: (1) define the molecular interaction between Tat and k-cyclin and examine kinase activities associated with these two proteins (2) determine cooperative effects of Tat and k-cyclin in promoting the proliferation of endothelial cells (3) demonstrate roles of Tat in enhancing HHV-8 infection and HHV-8-induced cell transformation. These studies will increase our understanding of the pathogenesis of AIDS-associated KS the cooperative role of Tat and k-cyclin and suggest a strategy in combating this tumor.

project_terms:
Kaposi&apos;s sarcoma;cell proliferation;clinical research;cyclins;enzyme activity;human herpesvirus 8;human immunodeficiency virus;human tissue;neoplastic transformation;protein kinase;protein protein interaction;tissue /cell culture;transcription factor;vascular endothelium;virus genetics;virus virus interaction


application_id: 7060613
project_number: 7R01NS045131-04
project_title: Pathology of traumatic injury to CNS axons
administering_ic: NINDS
award_notice_date: 2005-05-10
application_type: 7
activity_code: R01
ic: NS
serial_number: 045131
program_official: KLEITMAN, NAOMI
project_start_date: 2002-12-15
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-01
project_abstract:
EXCEED THE SPACE PROVIDED. Traumatic brain injury afflicts 2 million people each year in the United States many of whom suffer persistent neurological disability as a result of diffuse axonal injury. Shearing or stretching of axons during traumatic brain injury initiates progressive axonal damage ultimately leading to axotomy and neuronal death. Because traumatic injury most often causes delayed rather than immediate axotomy the opportunity exists to intervene therapeutically prior to axotomy. To elucidate the cellular mechanisms underlying traumatic axonal injury and identify therapeutic targets we will perform dynamic optic nerve stretch injury in mice accurately replicating the biomechanics of injury experienced by axons in the human brain during traumatic injury. We propose to use this established model of central nervous system axonal injury to test our working hypothesis that activation of calpains after traumatic axonal injury causes microtubule damage and impairment of axonal transport which unless reversed will lead to axotomy and neuronal apoptosis. In Aim 1 we will evaluate anterograde and retrograde fast axonal transport as a function of injury severity and establish the time course of transport impairment relative to axotomy. In Aim 2 we will establish a mechanistic link between calpain activation and interruption of axonal transport via degradation of microtubule-related proteins. In Aim 3 we will test our hypothesis that prolonged disruption of axonal transport in optic nerve axons leads to apoptosis of retinal ganglion cells (RGCs). In Aim 4 we will use IGF-1 overexpressing mice and exogenous IGF-1 treatment to determine whether elevation of IGF-1 levels can reverse transport impairment after axonal injury by delaying RGC apoptosis and upregulating cytoskeletal protein synthesis. Because regeneration of central nervous system axons remains an elusive goal it is vital to intervene in the pathologic cascade of traumatic axonal injury before axotomy occurs. The optic nerve stretch injury model allows correlations between axonal pathology and either mechanical injury parameters or the cell body response that are not currently possible in whole-brain axonal injury models. By exploiting these unique advantages we hope to identify key mediators in axonal pathology and novel therapeutic strategies to effectively sustain the vulnerable neuron and repair axonal damage prior to axotomy. PERFORMANCE SITE ========================================Section End===========================================


application_id: 7060396
project_number: 5R01CA113932-02
project_title: Increasing Clorectal Cancer Screening in Rural Kentucky
administering_ic: NCI
award_notice_date: 2006-04-27
application_type: 5
activity_code: R01
ic: CA
serial_number: 113932
program_official: BRESLAU, ERICA S
project_start_date: 2005-05-01
project_end_date: 2010-04-30
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: 2006-05-01
project_terms:
behavioral /social science research tag;clinical research;colorectal neoplasms;community health services;focus groups;health behavior;health care service availability;health care service utilization;health disparity;health services research tag;human subject;interview;low socioeconomic status;medical records;medically underserved population;neoplasm /cancer diagnosis;neoplasm /cancer education;primary care physician;rural area;rural health


application_id: 7060018
project_number: 5R25AT000682-05
project_title: Interdisciplinary CAM Curriculum Model
administering_ic: NCCIH
award_notice_date: 2006-04-14
opportunity_number: PAR-00-027
application_type: 5
activity_code: R25
ic: AT
serial_number: 000682
program_official: KHALSA, PARTAP SINGH
project_start_date: 2002-07-15
project_end_date: 2010-04-30
study_section: ZAT1-G(07)
contact_pi_person_id: 7875359
contact_pi: ELDER, WILLIAM GIBBS
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This comprehensive project will evaluate innovative methods and structures to incorporate CAM knowledge and experiences into medical school education residency training and five disciplines of CE.  A multidisciplinary Advisory Committee will incrementally weave multiple CAM modalities into a spectrum of learning contexts taught in an interdisciplinary manner by conventional and CAM providers.  Experiential components include a student wellness and health beliefs activity that incorporates CAM experiences into a wellness program with a subgroup participating mind-body skills training.  Commitments exist for integration of CAM into 12 of 24 medical school coursed.  Experiences include clinical applications on several clerkships and residency rotations.  Project personnel have a strong commitment to CAM education and practice and significant expertise in curriculum and organizational development.  Process and summative evaluative techniques will be used to ensure project objectives are met.  The originating department has strong faculty development capabilities.  Because difficulties should be expected in identifying conventional and CAM practitioner faculty qualified to teach CAM this project will develop and certify and explicit evidence-based CAM content development process.  CAM practitioners will receive community faculty appointments and participate in a faculty development program.  In year four after curricula have been demonstrated in the College of Medicine methodology will be applied to a broader range of learners in the College of Allied Health: physical therapists physician assistants and nutritionists.  The University of Kentucky Chandler Medical Center and the originating medical department have a successful history of training and meeting Federal obligations.  This project has the endorsement of Medical Center leadership course directors students and community CAM practitioners.

project_terms:
alternative medicine;attitude;bias;clinical research;curriculum;education evaluation /planning;health care personnel education;information dissemination;medical education;physicians;preference;role model


application_id: 7059328
project_number: 5U01DE014543-04
project_title: 'Multicenter Trial of CPE for Maxillofacial Prosthetics'
administering_ic: NIDCR
award_notice_date: 2006-04-21
application_type: 5
activity_code: U01
ic: DE
serial_number: 014543
program_official: ATKINSON, JANE C
project_start_date: 2003-08-21
project_end_date: 2008-05-31
study_section: ZDE1-GH(08)
contact_pi_person_id: 1963729
contact_pi: GETTLEMAN, LAWRENCE M.
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-06-01
project_abstract:
DESCRIPTION (provided by applicant): Maxillofacial prosthetics is a subspecialty of prosthodontics providing the clinical rehabilitation treatment of patients who have lost parts of the face due to cancer trauma or birth defects. It is an orphan field a) offering fundamental rehabilitation and improvement in the quality of life to patients who may have exhausted personal or third party funding b) treating so few patients that it makes the field unprofitable for manufacturers and c) provides a dental solution to an essentially medical problem.  Silicone rubber materials have been used for facial rehabilitation for more than 4 decades with few improvements. There is a clear need for new alternative and more economic materials for extraoral maxillofacial prostheses. Research at Gulf South Research Institute in New Orleans by the Principal Investigator and others in the 1970s and 1980s developed an alternative low-cost thermoplastic material (chlorinated polyethylene CPE) that met all toxicological (safety) and physical (effectiveness) requirements.  A limited clinical trial at the time yielded equivocal results when compared to conventional but costly silicone rubber products.  This research will conduct a randomized single-crossover double-blinded Phase III clinical trial to evaluate a) experimental thermoplastic CPE and b) control silicone (Silastic Adhesive A/MDX4-4210) materials for non-inferiority of CPE based on functional & subjective characteristics and on the quality of life.  Both prostheses will be attached with a skin adhesive.   In the clinical trial the patient's missing anatomy will be sculpted and a gypsum mold made. The silicone and the CPE prosthesis will be fabricated and delivered in random order to 50 patients at M.D. Anderson Cancer Center University of Texas Houston 30 patients at Toronto Sunnybrook Regional Cancer Centre and 20 patients at J.G Brown Cancer Center University of Louisville (100 total) to be worn for 4 months each.  Detailed questionnaires will be filled out by the anaplastologist/laboratory technician clinicians before and after the prostheses are worn and the patient. Quality-of-life before and after wearing each prosthesis will be tested with the Toronto Outcomes Measure for Craniofacial Prosthetics. These methods were designed to test future materials and techniques.  The power analysis that determined that 100 patients would be needed used a non-inferiority approach from data in the previous study. The final analysis of the proposed clinical trial will also test for non-inferiority of CPE (experimental) compared to silicone rubber (control). The outcome will determine if the new material is at least equivalent to conventional silicone in important features. Longevity will be estimated by following patients. Material properties their cost and processing characteristics will affect use in underserved areas or developing countries.

project_terms:
biomaterial development /preparation;biomaterial evaluation;clinical research;clinical trial phase III;cooperative study;cost effectiveness;human subject;medical implant science;oral facial restoration;oral facial restoration material;oral pharyngeal neoplasm;patient oriented research;plastics;prosthesis;quality of life;questionnaires;silicone rubber;training


application_id: 7059320
project_number: 5R01DE012205-07
project_title: Selective Aggregation and Sorting of Salivary Proteins
administering_ic: NIDCR
award_notice_date: 2006-04-14
application_type: 5
activity_code: R01
ic: DE
serial_number: 012205
program_official: SHUM, LILLIAN
project_start_date: 1999-08-01
project_end_date: 2008-04-30
study_section: Oral Biology and Medicine Subcommittee 1[OBM-1]
contact_pi_person_id: 1878918
contact_pi: DARLING, DOUGLAS S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION: The long-term goal of this research is to determine the mechanisms for sorting and storage of regulated secretory proteins in salivary glands. The answer to this question is important for our understanding of the regulation of protein secretion from salivary glands and hence the composition of saliva. Significant progress towards this goal was made in the first grant period. It was shown that calcium- and pH-mediated aggregation do not contribute significantly to the storage of secretory proteins in parotid secretory granules suggesting that sorting in this gland differs from that of other endocrine and exocrine glands. Indeed it was demonstrated that sulfated proteoglycans are necessary for efficient storage of secretory proteins in secretory granules of rat parotid acinar cells. The sulfated proteoglycan appears to buffer the internal pH of secretory granules. These results led to the hypothesis that sulfated proteoglycans act as buffering agents that regulate protein sorting and storage in parotid acinar cells. Specific Aim 1 will test if sulfated proteoglycans act as buffering agents in parotid secretory granules. Aim 2 will test if expression and) post-translational modification of the proteoglycan core proteins regulates the sorting and storage of other) parotid secretory proteins. These Aims will employ isoproterenol treatment to overexpress acidic and basic PRPs in rat parotid glands combined with in vitro tissue culture approaches. As an alternative we will use transgenic mice that overexpress PRPs in salivary glands. In Aim 3 it will be tested if sulfated proteoglycans play a role in protein or membrane binding of PSP. Specific Aim 4 will test if sulfated proteoglycans or other acidic proteins are involved in sorting and storage of secretory proteins in the submandibular gland a current target for gene therapy protocols. The proposed research will use cell biological and molecular methods in salivary cells and protein expression experiments in intact animals. The results of this research will provide insight into the unique sorting mechanisms that function in salivary glands. This will lead to a better understanding of the formation of saliva and provide the basis for efficient delivery of therapeutic proteins from salivary glands.

project_terms:
SDS polyacrylamide gel electrophoresis;acidity /alkalinity;acinar cell;affinity chromatography;calcium;cell aggregation;cell sorting;endocrine gland /system;granule;high performance liquid chromatography;laboratory rat;parotid gland;polymerase chain reaction;protein structure function;proteoglycan;salivary glands;secretory protein;tissue /cell culture


application_id: 7058439
project_number: 1R01DP000214-01
project_title: Agri-Pharmaceutical Cancer Therapeutics
administering_ic: NCCDPHP
award_notice_date: 2005-07-15
opportunity_number: RFA-DP-05-120
application_type: 1
activity_code: R01
ic: DP
serial_number: 000214
project_start_date: 2005-07-15
project_end_date: 2007-07-14
study_section: ZDP1-SRC(99)
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-15
project_abstract:
The development of modern genomics and proteomics has created an opportunity for the development of rational peptide-based cancer therapeutics. Using plant-biomass production systems it is now possible to generate therapeutic peptides and proteins quite inexpensively and in large quantities. The overall goal of this proposal is to develop peptide-based cancer therapeutics which can be produced by plant biomass particularly tobacco. In collaboration with Large Scale Biology Inc. scientists at the James Graham Brown Cancer Center have developed the ability to express peptides and proteins in tobacco plants. The Large Scale Biology processing plant at Owensboro Kentucky has the capability of GMP production of tobacco-based therapeutics. This proposal will take advantage of the Brown Cancer Center expertise in cancer drug and vaccine development and the Large Scale Biology expertise in plant molecular biology and expression technology to accomplish the following specific aims:1. To identify growth inhibitory peptide aptamers targeted to nucleolin and alpha-enolase two cellular proteins expressed on the surface of cancer cells.2. To develop effective human papillomavirus vaccines that can be produced in tobacco.The unique and complementary experience of Dr. Miller in aptamer development and Dr. Jenson in vaccine creation will ensure the success of this project. The accomplishment of these goals will have the duel advantage for Kentucky of developing new compounds with therapeutic potential and generating revenue for farmers who participate in the program. The development of a viable agripharmaceutical industry in the state will have additional benefits. The experiments which are proposed in this grant will allow Brown Cancer Center scientists to translate their laboratory observations into early phase clinical trials.

project_terms:
RNA binding protein;bioreactors;biotechnology;cell surface receptors;cervix neoplasms;combinatorial chemistry;dogs;drug design /synthesis /production;drug screening /evaluation;growth inhibitors;human papillomavirus;laboratory mouse;laboratory rabbit;neoplasm /cancer pharmacology;neoplasm /cancer vaccine;neutralizing antibody;nonhuman therapy evaluation;peptides;phosphoproteins;phosphopyruvate hydratase;plant genetics;protein binding;tobacco;vaccine development;viral vaccines


application_id: 7058072
project_number: 1F32HD050043-01A1
project_title: Heat Shock Factor Function in Spermatogenesis
administering_ic: NICHD
award_notice_date: 2006-05-01
opportunity_number: PA-03-067
application_type: 1
activity_code: F32
ic: HD
serial_number: 050043
suffix: A1
program_official: RANKIN, TRACY L
project_start_date: 2006-05-01
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1 F06 (20)]
contact_pi_person_id: 8179373
contact_pi: WILKERSON, DONALD C.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The work presented in this grant is focused on the long term goal of better understanding the roles of HSF1 and HSF2 in spermatogenesis and early embryogenesis. According to the Center for Disease Control (CDC) infertility affects approximately 6.1 million women and their partners in the United States. Defective expression of heat shock factors leads to several phenotypes including infertility in both males and females. To identify the role(s) of HSF1 and HSF2 in reproduction these factors must be thoroughly characterized in vivo at various stages of spermatogenesis. The role of HSF2 bookmarking the hsp70i gene in mature spermatozoa must be evaluated. Finally all gene targets bound by HSF1 and HSF2 must be identified.

project_terms:
DNA binding protein;cell cycle;chromatin immunoprecipitation;deoxyribonuclease I;developmental genetics;enzyme activity;fertility;gel mobility shift assay;genetic promoter element;genetic regulation;heat shock proteins;immunofluorescence technique;laboratory mouse;meiosis;phosphoprotein phosphatase;postdoctoral investigator;protein protein interaction;protein structure function;spermatogenesis;western blottings


application_id: 7057746
project_number: 5R01NS049954-03
project_title: Novel Imging and Physiological Evaluation of Human SCI
administering_ic: NINDS
award_notice_date: 2006-07-01
opportunity_number: RFA-NS-04-004
application_type: 5
activity_code: R01
ic: NS
serial_number: 049954
program_official: KLEITMAN, NAOMI
project_start_date: 2004-09-15
project_end_date: 2009-04-30
study_section: ZNS1-SRB-R(06)
contact_pi_person_id: 7900826
contact_pi: VITAZ, TODD W
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The decision to surgically decompress the spinal cord following spinal cord injury (SCI) is controversial as is the timing of decompression. Multicenter randomized controlled studies of early surgical decompression have not been performed in humans. MR images of the spine reflect the anatomical picture of the spinal cord but do not reflect metabolic status of the tissue or the CSF surrounding the spinal cord and thus may not indicate the precise degree of compression on the spinal cord. We hypothesize that:    
1) quantitative cine phase-contrast magnetic resonance imaging (C-MR) which non-invasively measures flow velocity of cerebrospinal fluid (CSF) above and below the injury will provide additional objective data to assist the decision-making process for surgical decompression and whether use of this data results in better long-term functional outcome following SCL. Within 8 hours after admission all patients will undergo T1- and T2-weighted MR scans followed immediately by a C-MR. Patients with cord compression and evidence of CSF block will undergo immediate decompression surgery. Patients with no MR evidence of spinal cord compression or CSF block will be treated with the best medical care (non-surgical). Patients in whom the anatomical picture (MR scan) and CSF flow pattern (C-MR) are not concordant will be randomized into surgical and non-surgical groups. A variety of functional outcome measures will be performed on admission weekly for one month and at 3 6 9 12 18 and 24 months following SCI to determine whether use of C-MR data results in a better functional outcome.  
2) integrated PET/CT can determine the metabolic status at the site of the injury (as early as possible but within 3 days) after the injury. We will use 18F-deoxyglucose to assess uptake and utilization. This information will attempt to assess whether the injury is complete (irreversible) or incomplete (reversible). We will answer the question if PET/CT is performed early can it be used to predict the outcome of spinal decompression surgery?  
3) tcMMEP and SSEP can be used as non-invasive tools to assess spinal compression. We will measure them on the day of admission and after decompression and correlate them post hoc with the MR and C-MR data all of which will be entered into an NIH-sponsored national SCI database. We will also assess whether these tests can be used to more accurately determine if decompressive surgery can improve the long-term functional outcome by performing these tests weekly for one month and at 3 6 9 and 12 months following SCI.  
4) oximetry at the site of SCI can be used over the first week as a non-invasive monitor of cord ischemia that results from compression and thus as a decision-making tool for decompression. This can be done by correlating the data of each patient  
post hoc with other measures of Aims 1-3.

project_terms:
bioimaging /biomedical imaging;cerebrospinal fluid;clinical research;diagnosis design /evaluation;functional ability;human subject;human therapy evaluation;ischemia;longitudinal human study;magnetic resonance imaging;nerve decompression;nervous system disorder diagnosis;patient oriented research;positron emission tomography;spinal cord imaging /visualization;spinal cord injury;spinal cord mapping


application_id: 7057507
project_number: 1F31MH074245-01A1
project_title: Comparing Personality Disorder Models: FFM and DSM-IV
administering_ic: NIMH
award_notice_date: 2005-09-05
opportunity_number: PA-04-032
application_type: 1
activity_code: F31
ic: MH
serial_number: 074245
suffix: A1
program_official: WYNNE, DEBRA K
project_start_date: 2005-12-17
project_end_date: 2008-12-16
study_section: Special Emphasis Panel[ZRG1 F12B (20)]
contact_pi_person_id: 8087519
contact_pi: SAMUEL, DOUGLAS B
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed study will allow the current DSM-IV categorical model of personality disorders to be compared directly to the Five-Factor model (FFM) of personality on the basis of temporal stability within a clinical setting convergent and discriminant validity and clinical utility. The FFM is the most heavily researched of the dimensional models that have been proposed as an alternative for the current DSM-IV system. The DSM- IV and FFM ratings will be assessed in a group of 75 self-referred individuals who are currently receiving outpatient psychotherapy for a personality disorder using the four primary methods of assessment used in clinical practice: unstructured clinical interview by the client's therapist semi-structured interview by a trained researcher self-report inventory and informant report. Additionally the same participants will be assessed again after six months to examine the temporal stability of each model. Finally the therapists who are treating these clients and providing the unstructured clinical interview ratings will also provide feedback on the clinical utility of each model. It is hoped that this research will help to better conceptualize personality difficulties and ultimately a more coherent and useful diagnostic system.

project_terms:
behavioral /social science research tag;clinical research;diagnosis quality /standard;disease /disorder classification;health care personnel performance;human subject;interview;mental disorder diagnosis;mental health personnel;personality disorders;predoctoral investigator;psychological models;psychometrics;psychotherapy;questionnaires


application_id: 7057360
project_number: 5R01MH063817-04
project_title: Neuroimaging of shape similarity in object recognition
administering_ic: NIMH
award_notice_date: 2006-03-30
application_type: 5
activity_code: R01
ic: MH
serial_number: 063817
program_official: QUINN, KEVIN J
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: Biobehavioral and Behavioral Processes 4[BBBP-4]
contact_pi_person_id: 1911365
contact_pi: JOSEPH, JANE E
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): The goal of the proposed research is to determine the neural substrates associated with visual recognition. An area of the human brain referred to as ventral temporal cortex (VTC) is implicated in visual recognition based on evidence from electrophysiological and lesion studies with non-human primates and on clinical observations that visual recognition abilities are lost when this region of the brain is damaged. In addition human lesion studies and recent functional neuroimaging findings suggest that different regions of VTC may preferentially respond to different object categories. A popular interpretation of these results is that specialized neural subsystems are dedicated to recognizing different object classes. Cognitive behavioral studies however have demonstrated that object recognition depends critically on processing information about an object's shape and that shape information drives category organization. Consequently the thesis of the present proposal is that category-specific patterns of brain activation in VTC may in fact reflect varying degrees of shape information processing that is crucial for object identification. For example manufactured object categories like tools and furniture do not overlap much in shape whereas faces overlap tremendously in shape. Brain areas that appear to be specific to face processing may instead be involved in resolving high degrees of shape similarity. Functional magnetic resonance imaging (fMRI) is used in the present proposal to examine blood-flow changes in VTC during object recognition. The first goal is to determine the role of VTC in processing shape information associated with objects. One hypothesis is that posterior VTC is critically involved in mapping perceptual information onto stored information about object form. Another hypothesis examines the magnitude and spatial distribution of fMRI response in VTC as shape similarity parametrically increases among objects. Posterior VTC regions are likely involved when shape similarity is low (as in the case of manufactured object categories) but anterior VTC regions are likely recruited to resolve high degrees of shape similarity (as in the case of faces). The second goal is to compare the efficacy of this shape similarity framework with two other popular approaches to category specificity - a taxonomic category account and a categorization-level account. Shape similarity may explain both taxonomic category differences and categorization level differences in brain activation patterns in VTC. Isolating the proper cognitive processing components of visual recognition and mapping these components to functional neuroanatomy is invaluable for understanding the nature of visual recognition deficits following brain damage and for leading to potential therapies for rehabilitation and recovery of function.

project_terms:
bioimaging /biomedical imaging;brain imaging /visualization /scanning;clinical research;form /pattern perception;human subject;interview;magnetic resonance imaging;neural information processing;questionnaires;temporal lobe /cortex;visual perception


application_id: 7057344
project_number: 5R03EY015134-03
project_title: OCULAR SURFACE MUCIN ppGaNTase GLYCOSYLTRANFERASES
administering_ic: NEI
award_notice_date: 2006-05-12
opportunity_number: PAR-01-007
application_type: 5
activity_code: R03
ic: EY
serial_number: 015134
program_official: SHEN, GRACE L
project_start_date: 2004-05-01
project_end_date: 2008-04-30
study_section: ZEY1-VSN(01)
contact_pi_person_id: 1898346
contact_pi: YOUNG, WILLIAM W
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mucus layer secreted primarily by the conjunctival goblet cells but also by the corneal and conjunctival epithelia is a critical protective layer for the ocular surface; shielding it from pathogenic and environmental challenges. Mucins are a heterogeneous group of highly glycosylated proteins that  are present both on the ocular surface cells and as major soluble components of tear fluid. The first and rate-limiting step of O-glycosylation of mucins requires the action of at least one isoform of the UDPGalNAc: polypeptide N-Acetylgalactosaminyltransferase (ppGaNTase) family of glycosyltransferases.  Without glycosylation mucins would lack the viscoelastic properties required for proper function. The hypothesis of this project is that one cause of dry eye disease is abnormal mucin glycosylation due to altered expression of ppGaNTase isoforms. In the first aim we will compare the levels of mRNA expression of ppGaNTase isoforms in normal and dry eye patients by real-time PCR using the Taqman technique. The results will provide the first complete analysis of the expression of this critical glycosyltransferase family in human ocular tissues and point to one possible cause of human dry eye disease.    In the second aim we will determine which ppGaNTase isoforms are responsible for glycosylation of specific mucin types using RNA interference and inhibitors of ppGaNTase action. First we will determine which ppGaNTase isoforms are expressed at the mRNA level in human corneal and conjuncrival cell lines by real-time PCR. Second we will use gene silencing by small interfering RNAs (siRNA) to specifically silence each ppGaNTase isoform and then determine by Western blotting whether silencing of one ppGaNTase isoform results in altered glycosylation of each mucin type. As a positive control for ablation of mucin glycosylation we will treat cells with inhibitors of the ppGaNTase family. The results of RNA interference will enable us to obtain the first evidence in whole ocular cells as to which ppGaNTase isoforms are required for the glycosylation of particular mucin types.

project_terms:
RNA interference;clinical research;corneal epithelium;galactosyltransferases;gene expression;glycosylation;glycosyltransferase;goblet cells;human tissue;in situ hybridization;keratoconjunctivitis sicca;mucins;polymerase chain reaction;protein isoforms;proteoglycan;small interfering RNA;tear;western blottings


application_id: 7057290
project_number: 5R24EY015636-03
project_title: Vision Research Infrastructure Development
administering_ic: NEI
award_notice_date: 2006-03-23
opportunity_number: PAR-02-050
application_type: 5
activity_code: R24
ic: EY
serial_number: 015636
program_official: CHIN, HEMIN R
project_start_date: 2004-05-01
project_end_date: 2009-04-30
study_section: ZEY1-VSN(03)
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Although the Department of Ophthalmology and Visual Sciences at the University of Louisville has a large cadre of NEI funded vision scientists it has not previously had funding for core module services.  The purpose of this application is to provide our scientists with additional shared support to enhance their individual research capabilities and enhance further collaboration. Additionally it is oriented to enhance the research capability of the University of Louisville for conducting vision research by encouraging collaborative studies and attracting other scientists to vision research. These goals will be met by operating two research modules which will provide the following services:    l. The Image Acquisition and Analysis Module will provide technical support and expertise in  histological procedures such as conventional histological processing processing frozen tissue  samples/blocks and immunohistochemical staining confocal microscopy etc.  Additionally it will  provide assistance and expertise in the acquisition manipulation and analysis of digital images  captured using various imaging devices such as confocal bright field and fluorescence microscopy.    II. The Flow Cytometry Module will help investigators identify specific cell types in mixed cell populations. Such studies include but are not limited to estimation of subsets of T-cells determination of mitotic state and studies of cell surface receptors and markers.    These services and resources will enhance vision research at the University of Louisville by extending the capability of NEI funded scientists promoting collaboration and attracting new scientist to vision research.

project_terms:
bioimaging /biomedical imaging;biomedical facility;cell type;confocal scanning microscopy;digital imaging;flow cytometry;fluorescence microscopy;histology;imaging /visualization /scanning;immunochemistry;mixed tissue /cell culture;tissue /cell preparation;vision


application_id: 7056280
project_number: 1F31NS052012-01A1
project_title: Substance P and the tectothalamic pathway
administering_ic: NINDS
award_notice_date: 2005-12-23
application_type: 1
activity_code: F31
ic: NS
serial_number: 052012
suffix: A1
program_official: CHEN, DAOFEN
project_start_date: 2006-01-01
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1 F02B (20)]
contact_pi_person_id: 7390903
contact_pi: MASTERSON, SEAN P
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of the proposed experiments is to determine the causes of attention impairment during disease. However it is first necessary to understand the organization of circuits that may contribute to attention mechanisms in the normal brain. Many studies have implicated the pulvinar nucleus as an area that may regulate visual attention. The rodent lateral posterior (LP) nucleus is a region comparable to inferior regions of the primate pulvinar nucleus. The rodent LP nucleus is innervated by fibers which contain the neuropeptide substance P a neuromodulator known to facilitate neuronal firing properties. The LP nucleus receives visual input from projection cells within an area of the superior colliculus that is substance P- immunoreactive. A combination of tract tracing immunocytochemistry electron microscopy and in vitro electrophysiology will be used to examine the synaptic organization and functional properties of the tecto- thalamic pathway. Concomitant release of substance P with glutamate from tecto-thalamic terminals might enhance and potentiate glutamatergic input from the superior colliculus. Because the LP nucleus projects to the visual cortex the tecto-thalamic pathway could affect visual attention by modulating cortical circuitry.

project_terms:
attention;electron microscopy;electrophysiology;gamma aminobutyrate;glutamates;immunocytochemistry;interneurons;laboratory rat;neural information processing;neuroanatomy;neuropeptide receptor;neuroregulation;predoctoral investigator;pulvinar thalami;receptor expression;substance P;superior colliculus;synapses;thalamic nuclei;thalamus;visual cortex;visual pathways;voltage /patch clamp


application_id: 7056070
project_number: 5R01CA102102-02
project_title: BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
administering_ic: NCI
award_notice_date: 2006-04-28
application_type: 5
activity_code: R01
ic: CA
serial_number: 102102
program_official: FU, YALI
project_start_date: 2005-05-01
project_end_date: 2010-04-30
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: N
budget_start_date: 2006-05-01
project_terms:
aminoglycoside antibiotics;antifungal antibiotics;antineoplastic antibiotics;drug design /synthesis /production;enzyme induction /repression;enzyme structure;gene expression;isoquinolines;microorganism metabolism;pharmacokinetics;polyketide synthase


application_id: 7054951
project_number: 1R43HL083586-01
project_title: A counterpulsation device to promote myocardial recovery
administering_ic: NHLBI
award_notice_date: 2006-02-20
application_type: 1
activity_code: R43
ic: HL
serial_number: 083586
program_official: BALDWIN, TIM
project_start_date: 2006-02-20
project_end_date: 2007-02-19
study_section: Special Emphasis Panel[ZRG1 SBTS-E (10)]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-20
budget_end_date: 2007-02-19
assistance_listing_number: 93.837
project_abstract:
DESCRIPTION (provided by applicant): The incidence of congestive heart failure (CHF) is increasing worldwide with over one million new cases diagnosed annually. Over the past 30 years counterpulsation with an intra-aortic balloon pump (IABP) has been widely and successfully used as a short-term treatment for cardiac dysfunction. However counterpulsation is limited by its location within the descending thoracic aorta to short durations of therapy typically less than 14 days. To overcome this limitation Superficial Counterpulsation Research (SCR) Inc. has invented a novel device for long-term application of counterpulsation therapy for heart failure. The counterpulsation device (CPD) is designed to be implanted via a surface operation in the shoulder area (pacemaker pocket) by attaching it to the subclavian artery. This approach would give the patient nearly complete mobility. The first prototype CPD developed was a 40-ml valveless sac that fills and empties with each cardiac cycle. In acute studies in a calf with diminished cardiac function (DCF) the 40-ml CPD successfully reduced ventricular workload and augmented myocardial perfusion. In a cadaver fit study a problem with proper fit of the device in patients was revealed. To solve this problem a smaller second generation device (30-ml CPD) was developed. The 30-ml CPD provides a better fit and more comfortable implantation in the shoulder area but its stroke volume is reduced by 25% and this change requires verification that it can provide sufficient hemodynamic support. This 30-ml CPD is ready for in vivo testing. The goal of this Phase 1 SBIR proposal is to compare the hemodynamic efficacy of the new ergonomic 30- ml CPD to the 40-ml CPD prototype. We will also demonstrate that the 30-ml CPD will not damage the artery or blood. This will be accomplished by completing the following specific aims: Aim-1: Demonstrate the efficacy of the 30-ml CPD in reducing ventricular workload and augmenting diastolic perfusion to the heart and vasculature in acute experiments using the DCF calf model. Aim-2: Perform a safety evaluation of the 30-ml CPD by examining possible pathological and hematologic changes in the artery and blood (i.e. hemolysis). In Phase II we will propose chronic in vivo testing (30-day and 90-day DCF calf model) to demonstrate long-term effectiveness of the 30-ml CPD.

project_terms:
aortic balloon pump;auxiliary heart prosthesis;bioengineering /biomedical engineering;biomaterial compatibility;biomedical equipment development;biomedical equipment safety;cardiovascular disorder therapy;carotid artery;congestive heart failure;cow;heart ventricle;hemodynamics;immature animal;medical implant science;medical rehabilitation related tag;miniature biomedical equipment;myocardium disorder;nonhuman therapy evaluation;rehabilitation;therapy design /development


application_id: 7054764
project_number: 5R01AG020917-05
project_title: Genes affecting aging stem cell populations
administering_ic: NIA
award_notice_date: 2006-03-15
opportunity_number: RFA-AG-01-006
application_type: 5
activity_code: R01
ic: AG
serial_number: 020917
program_official: FLORES, ROBERTO L
project_start_date: 2002-04-01
project_end_date: 2008-03-31
study_section: ZAG1-FAS-9(J2)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Advancing age is characterized by the functional decline of multiple organ systems.  At first glance the blood-forming system does not seem to reflect the effects of aging in that normal blood cell counts are maintained into old age.  However an age-related decline in function is apparent in the response to stresses requiring accelerated blood cell formation.  The hematopoietic stem cell population lies at the heart of this response and while able to maintain steady-state blood formation its response to increased demand is blunted.  Despite the key role of the stem cell population in blood formation and increasing knowledge about its function in the young there are large gaps in our knowledge of aging stem cells.  We hypothesize that deleterious changes in the lympho-hematopoietic stem cell population and perhaps in stem cells of other organs limit organismal longevity. We have mapped a genetic locus in the mouse that regulates stem cell numbers in old animals but not in young animals.  It thus qualifies as an 'aging gene'.  Allelic differences at this locus prescribe over a 3-fold increase in stem cells during aging of long-lived C57BL/6 (B6) mice and a 20 percent decline in stem cells during the same period in short-lived DBA/2 (DBA) mice.  We hypothesize that this locus is an important determinant of the response of stem cells to hematopoietic demands in old animals and thus influences organismal longevity. The goal of this project is to genetically fine map the locus at a resolution that will permit positional cloning at the molecular level in the next phase.  To this end we have generated a B6 strain congenic for the DBA-derived telomeric segment of Chr. 2 harboring the locus.  We propose to create a large number of recombinations within the congenic interval and thus to create congenic sub-strains enabling us to narrow the locus to less than 0.5 cM.  Preliminary studies of the existing congenic strain have shown that the effect of the locus can be observed in stem cells of young animals under the rigorous demands of bone marrow transplantation.  Thus to aid in the future study of this locus we propose developing a surrogate measure of the aging phenotype in young mice by using a transplantation assay.

project_terms:
aging;alleles;animal old age;biotechnology;bone marrow;bone marrow transplantation;cell growth regulation;cell population study;genetic mapping;genetic recombination;genetic regulation;genotype;hematopoiesis;hematopoietic stem cells;inbreeding;juvenile animal;laboratory mouse;linkage mapping;longevity;phenotype;quantitative trait loci;tissue mosaicism


application_id: 7054759
project_number: 5R01DE013958-05
project_title: Periodontitis and Preterm Birth:Nonhuman Primate Model
administering_ic: NIDCR
award_notice_date: 2006-04-10
opportunity_number: PA-99-045
application_type: 5
activity_code: R01
ic: DE
serial_number: 013958
program_official: KUSIAK, JOHN W
project_start_date: 2002-06-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1-OBM-1(02)Q]
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Current human epidemiologic reportsindicate a positive association between preterm birth/low birth weight(PTB/LBW) neonates and periodontal disease prevalence in the mother. Sixtypercent of infant mortality (not attributable to congenital/anatomical defects)is linked with PTB/LBW. It is the objective of this project to investigatepotential mechanisms of the association between PTB/LBW and periodontitis in anin vivo model system. The baboon Papio anubis which has a >95 percent genetichomology to humans will be used to investigate Aims testing hypotheses that: (1)the incidence and severity of periodontitis results in an increased incidenceof PTB/LBW neonates; (2)  the progression of periodontitis is characterized by anincrease in pathogenic subgingival microbial species and systemic expression ofplaque pathogenicity which correlate with an increased incidence of PTB/LBWneonates; and (3)  the progression of periodontitis is characterized by localand systemic inflammatory biomarkers which correlate with an increasedincidence of PTB/LBW neonates. 400 female baboons housed at the SouthwestFoundation for Biomedical Research (SFBR) a NIH Regional Primate Center willbe randomized into two groups. Following baseline sample collection (bloodcrevicular fluid (GCF) subgingival plaque clinical assessment) from allbaboons ligature will be placed (one maxillary/one mandibular quadrant; 6molar teeth) in the experimental group (n=200). Both groups will then beintroduced to males. Pregnancy will be confirmed and gestational age determinedusing ultrasound at approximately 3 months. Oral samples will be collected atthis time point followed by placement of ligatures on the contralateralmaxillary and mandibular quadrants of the experimental group to extend theexposure variable (i.e. periodontitis). Animals will be sampled atapproximately 30 days following the completion of the pregnancy and ligaturesremoved. In both experimental and control groups dates of birth and post-natalweights will be obtained within 14 days of birth. Blood IGCF samples will beassayed for acute phase reactants and endotoxin activity. Sera will also beanalyzed for IgG antibody to oral microorganisms. Differences in clinical andlaboratory parameters will be assessed between outcome (PTB/LBW vs. normalneonates) and between groups (experimental vs. control). Results from thisinvestigation will describe mechanisms of this linkage and contribute to thedevelopment of therapeutic and clinical intervention strategies.

project_terms:
animal birth weight;baboons;birth;dental plaque;dental research;disease /disorder model;disease /disorder proneness /risk;endotoxins;model design /development;newborn animals;nucleic acid hybridization;oral bacteria;pathologic process;periodontitis;premature infant animal;premature labor;radiography;tooth extraction


application_id: 7053449
project_number: 1R41DE017265-01
project_title: Identification of anti-cariogenic/low-glycemic activity factors from Lo Han Kuo
project_terms: aging;children;emotions;family;health;oral health;sucrose;sweetening agents
administering_ic: NIDCR
award_notice_date: 2006-04-13
application_type: 1
activity_code: R41
ic: DE
serial_number: 017265
program_official: MCINNES, PAMELA M
project_start_date: 2006-05-01
project_end_date: 2007-04-30
study_section: Special Emphasis Panel[ZRG1 MOSS-K (11)]
contact_pi_person_id: 8367053
contact_pi: HUANG, CHIFU BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 140647046
duns_number: 140647046
fips: US
organization_id: 10002330
organization_name: ORACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405032916
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
budget_end_date: 2007-04-30
project_abstract:
DESCRIPTION (provided by applicant): While there exist numerous artificial sweeteners that are commercially available designed to provide zero- or low-calorie artificial alternatives to sucrose/high fructose corn syrup there remain concerns regarding potential health concerns in the general population or unique subsets of individuals (e.g. phenylketonurics and diabetics). Moreover altered sugar alcohol substitute sweeteners i.e. sorbitol xylitol that have been marketed as noncariogenic sweeteners and more recently as sweeteners for low carbohydrate diets have been observed to have the potential for gastrointestinal disturbances in some individuals. Thus there appears to remain a viable market for the identification of novel sweetening agents that can be: (1) used by the general population; (2) demonstrate a anti-cariogenic capacity; (3) have a low glycemic index and negligible negative health effects; (4) has high sweetening index so low amounts can be used; (5) have a chemical structure that maintains its sweetening ability with heating (i.e. baking cooking) acid conditions (i.e. carbonated drinks) withstand freezing (i.e. ice cream) and can be used as a tabletop sweetening agent; and (6) are natural with many health benefit. This proposal describes studies evaluating a novel zero-calorie high intensive natural sweetener Lo Han Kuo (LHK) extract derived from the Chinese Lo Han Kuo fruit (Momordica grosvenori). LHK extract is 300 times sweeter than sucrose and has recently been isolated on an industrial scale; however little critical research has been conducted to elucidate the sweetening function coupled with biological parameters as related to potential health benefits. A composite of our preliminary studies provides evidence that LHK extract has antibacterial activity against oral microorganisms and has a low-glycemic capability in vitro. In this Phase I proposal bioactive components will be isolated from LHK extract and their chemical structures determined. These components will be evaluated for their potential anti-caries anti-periodontitis and insulin-inductive properties. This proposal is to develop and document methods that will allow the active components of LHK extract to be isolated and characterized. The development of purification and screening methods for functional properties represents the deliverables for Phase I of this STTR. Success of this STTR will define the potential to commercialize a valuable sweetener with therapeutic oral and general health benefits.


application_id: 7053206
project_number: 2R44EY014728-03
project_title: A Real Time Monitoring System to Measure IOP in Glaucoma
administering_ic: NEI
award_notice_date: 2006-04-21
application_type: 2
activity_code: R44
ic: EY
serial_number: 014728
program_official: WUJEK, JEROME R
project_start_date: 2003-05-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1 BDCN-F (12)]
contact_pi_person_id: 7678043
contact_pi: JACKSON, DOUG J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 602020195
duns_number: 602020195
fips: US
organization_id: 10000059
organization_name: ASSENTI, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402170191
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
budget_end_date: 2007-04-30
assistance_listing_number: 93.867
project_abstract:
DESCRIPTION (provided by applicant): Assenti LLC is a 10-person start-up company formed out of collaborative research teams from the University of Louisville's Speed School of Engineering and the Department of Ophthalmology & Visual Sciences along with key industry partners. Assenti's enclosed SBIR Phase II application will allow us to continue our significant progress and momentum towards becoming the first company to bring a MEMS (Micro-Electrical-Mechanical Systems) based device to market for treating glaucoma patients. This revolutionary technology has the potential to eliminate the root cause of blindness for patients with glaucoma by providing continuous non-invasive monitoring of Intra-Ocular Pressure (IOP). Our near term goal for commercialization is to develop our Gen I "Smart IOP" monitor that will strictly monitor IOP so patients can self-administer eye drops to reduce pressure which will lead to the elimination of optic nerve damage and hence prevention of blindness from glaucoma. However our eventual longer term goal is to develop a self contained system that will either release hypotensive medication to reduce IOP or use a switch controlled MEMS valve to create a totally autonomous system requiring no patient intervention. Recent studies have shown that applying topical ocular hypotensive medication was effective in delaying or preventing the onset of primary open-angle glaucoma [12]. Assenti has met or exceeded all three specific aims from our funded SBIR Phase I and we anxiously look forward to build upon this progress in Phase II. We have identified the following three specific aims to accomplish for Phase II: 1. Develop a reliable production ready battery-free IOP monitoring system using an ultra-miniature MEMS pressure sensor as well as a telemetry 1C whose combined size measures less than 2mm x 2mm x 0.5mm (75% volume reduction from the phase I device) for FDA animal and eventual human trials. 2.Implementation of our strategic FDA test plan developed by Arkios LLC to obtain our IDE and lead Assenti towards a PMA of our Smart IOP monitor. S.Research into our longer term goal of combining Assenti's Smart IOP monitor with an invivo IOP reducing mechanism that can lead to autonomous control of the entire system and completely eliminate patient intervention.

project_terms:
assistive device /technology;bioengineering /biomedical engineering;biomedical equipment development;glaucoma;intraocular pressure;laboratory rabbit;microprocessor /microchip;miniature biomedical equipment;optic nerve disorder;patient monitoring device;telemetry


application_id: 7052088
project_number: 5R01HL071098-04
project_title: Group V sPLA2 in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2006-04-30
application_type: 5
activity_code: R01
ic: HL
serial_number: 071098
program_official: WASSEF, MOMTAZ K
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: Pathology A Study Section[PTHA]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): A critical event in early atherogenesis is the retention of low-density lipoprotein (LDL) particles in the subendothelium through their binding to intimal proteoglycans. These retained lipoprotein particles are exposed to several modifying enzymes in the arterial wall including lipases oxidizing enzymes and proteases. A multitude of biological responses to such modified LDL including the recruitment and lipid loading of macrophages leads to the initiation and progression of atherosclerosis. The extracellular matrix (ECM) appears to play an active role in this process by not only mediating the retention of LDL particles but by also modulating the activity of various enzymes towards LDL. Thus in regions where LDL is being accumulated the co-localization of LDL ECM and LDL modifying enzymes leads to a self-perpetuating cascade of events that culminates in atherosclerosis. The identification and characterization of molecules and the manner in which they interact to contribute to this process is central to our understanding the mechanisms that underlie susceptibility to lesion formation. This proposal aims to study a novel form of secretory phospholipase A2 Group V sPLA2 which we now show is present in human and mouse atherosclerotic lesions specifically associated with macrophages. We hypothesize that Group V sPLA2and LDL in the proximity of macrophages leads to the localized production of aggregated and/or fused lipoprotein particles which consequently leads to foam cell formation. To test this hypothesis the following specific aims are proposed: Specific Aim 1): To test the hypothesis that Group V sPLA2 produces modifications in LDL particles that lead to increased uptake by macrophages. This will be accomplished by analyzing LDL particles after hydrolysis by Group V sPLA2 to determine particle composition density and extent of aggregation and/or fusion; quantifying the effect of Group V sPLA2 hydrolysis on the delivery of LDL lipid to macrophages and determining whether other factors in the arterial subendothelium namely sphingomyelinase and ECM promote Group V sPLA2-mediated effects. Specific Aim 2): To test the hypothesis that macrophage expression of Group V sPLA2 in the vessel wall results in increased atherosclerosis. This will be achieved by transplanting fetal liver hematopoetic stem cells over-expressing wild-type Group V sPLA2 or a mutant form of the enzyme that is deficient in proteglycan binding into LDL receptor-/- mice. Measuring lesion size and cholesterol/cholesterol ester content will assess the extent of atherosclerosis.

project_terms:
atherosclerosis;atherosclerotic plaque;cholesterol;cholesterol esters;chromatography;clinical research;electron microscopy;extracellular matrix;flow cytometry;high performance liquid chromatography;human tissue;hydrolysis;laboratory mouse;low density lipoprotein;low density lipoprotein receptor;macrophage;phosphodiesterases;phospholipase A2;proteoglycan;sphingomyelin phosphodiesterase;vascular endothelium


application_id: 7052033
project_number: 5R01AI058842-02
project_title: Nanoparticle HIV Protein Vaccines for Cellular Responses
administering_ic: NIAID
award_notice_date: 2006-01-17
application_type: 5
activity_code: R01
ic: AI
serial_number: 058842
program_official: AHLERS, JEFFREY D
project_start_date: 2005-04-15
project_end_date: 2009-12-31
study_section: HIV/AIDS Vaccines Study Section[VACC]
contact_pi_person_id: 7876835
contact_pi: MUMPER, RUSSELL J
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): Currently there is no effective vaccine for HIV infection. HIV vaccines can potentially be used for prevention of infection or therapeutically to control the level of HIV replication post-exposure. The overall goal of this 5-year research proposal is to develop nanoparticle-based HIV-1 vaccines to elicit enhanced Th1 cytotoxic T lymphocyte (CTL) and humoral immune responses to recombinant Tat (1-72) and Gag p24 proteins. The immunogenicity of the developed nanoparticle-based HIV-1 Tat (1-72) and Gag p24 vaccine will further be enhanced by 1) the attachment of a dendritic cell targeting ligand mannopentaose to the nanoparticles and 2) coating the nanoparticles with CpG to target the toll-like receptor-9 (TLR-9). Optimized nanoparticles vaccines will be compared to a heterologous prime boost strategy based on vaccinia expressing antigen and adjuvanted protein. Recombinant HIV Tat (1-72) and Gag p24 proteins and his-tagged proteins will be synthesized and purified to homogeneity by Dr. Nath's laboratory at Johns Hopkins and tested for bioactivity. In Dr. Mumper's laboratory at the University of Kentucky the proteins will be either coated on anionic nanoparticles (Type 1) or attached to nanoparticles made with a small amount of accessible nickel at the surface (Type 2). Both types of solid nanoparticles (<100 nm) will be made from novel oil-in-water microemulsion precursors. Dr. Mumper's lab will characterize the nanoparticles perform in-vitro uptake and activation studies in mouse and human dendritic cells and perform animal experiments to determine the humoral immune responses of the nanoparticle-based formulations and perform immunohistochemical analyses. Dr. Woodward's laboratory at the University of Kentucky will be responsible for ELISPOT CTL multi-probe ribonuclease tetramer cell proliferation assays as well as confocal microscopy and flow cytometry experiments.  Dr. Nath's laboratory will perform studies demonstrating that sera from immunized mice can suppress Tat-induced LTR-transactivation and will assess the effect of Tat and Gag p24 antisera on HIV replication. In addition Dr. Nath's lab will produce vaccinia expressing antigen.

project_terms:
AIDS vaccines;confocal scanning microscopy;cooperative study;dendritic cells;enzyme linked immunosorbent assay;flow cytometry;gag protein;human immunodeficiency virus 1;immunocytochemistry;laboratory mouse;nanotechnology;nickel;peptide chemical synthesis;protein purification;recombinant proteins;surface coating;tissue /cell culture;vaccine development;vaccinia virus;virus protein;virus replication


application_id: 7051961
project_number: 5R01NS049901-03
project_title: Role of Intraspinal Plasticity in Autonomic Dysreflexia
administering_ic: NINDS
award_notice_date: 2006-06-07
opportunity_number: RFA-NS-04-004
application_type: 5
activity_code: R01
ic: NS
serial_number: 049901
program_official: KLEITMAN, NAOMI
project_start_date: 2004-08-02
project_end_date: 2009-04-30
study_section: ZNS1-SRB-R(06)
contact_pi_person_id: 6146950
contact_pi: RABCHEVSKY, ALEXANDER GEORGE
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): Autonomic dysreflexia is a potentially life-threatening complication of spinal cord injury (SCI) that is characterized by episodic hypertension (high blood pressure) due to sudden massive discharge of the sympathetic neurons in the injured spinal cord. The sympathetic neurons enable the 'fight or flight' response of an individual (e.g. more blood flow to the muscles). The reason the sympathetic neurons are so sensitive is that descending inhibitory pathways from higher brain centers are interrupted as a result of the SCI. In spinal injured patients autonomic dysreflexia is frequently triggered by distension of or activity within pelvic viscera (bladder or bowel). Therefore distension of the bladder or bowel sends a signal via sensory neurons to the sacral spinal cord (the lower back). From here the signal is relayed to thoracic and lumbar sympathetic neurons (chest region of the cord) by relay neurons. Because there is no modulating influence from the higher brain the action of the sympathetic neurons is unopposed. As a result the sudden increase in their activity following visceral stimulation causes a sudden rise in blood pressure (up to 200 mmHg) that can cause potentially fatal brain or spinal hemorrhage seizures as well as severe headache shivering sweating and anxiety. Unfortunately little is known about the anatomical or functional relationships between the visceral sensory neurons the spinal relay neurons and the sympathetic neurons. We propose to use a variety of histological and physiological techniques in a well-defined rat model of autonomic dysreflexia to discover the anatomical connections between these three types of neurons that are critical for the development of autonomic dysreflexia. It is currently not known how visceral sensory information entering the lumbosacral spinal cord is relayed to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the thoracolumbar cord. Since nociceptive afferent sprouting after SCI is NGF-dependent and is correlated with the incidence of autonomic dysreflexia we have injected temperature sensitive adenoviruses (Adts) encoding nerve growth factor (NGFAdts) into thoracic lumbar and sacral spinal cord to trigger sprouting to determine which regions are critical for eliciting autonomic dysreflexia. Overexpression of NGFAdts only in the T13/L1 and L6/S 1 segments produced significant increases in arterial blood pressure evoked by colorectal distension versus injured controls injected with GFPAdts. This suggests that following spinal transection pelvic visceral information is relayed from its input site in the lumbosacral dorsal horn to the IML via unidentified projection pathways. This proposal has 4 goals. Firstly we will use anterograde tracing of biotinylated dextran amine (BDA) from the L6/S 1 cord and retrograde transsynaptic tracing of pseudorabies virus (PRV) from sympathetic pre-vertebral ganglia to identify the neural pathways that transmit visceral information from lumbosacral to thoracic cord after SCI. Secondly since NGFAdts exacerbate dysreflexia we will establish whether this correlates with increased pathway sprouting. Thirdly since it is possible that NGF-independent afferents play a role in autonomic dysreflexia we will inject Adts encoding other growth factors FGF-2 NT-3 BDNF and GDNF into multiple levels of the lumbosacral cord. We will also assess their direct influence on lumbar propriospinal neurons by injecting them in the distal thoracic cord. Finally based on our recent evidence we will inject chemorepulsive semaphorin3aAdts after injury into the lumbosacral spinal cord in an attempt to thwart early sprouting events and minimize dysreflexia as well as establish whether chronic injections are capable of inducing retraction of established sprouts. This information will form the basis for developing potential treatments for this common and debilitating complication of SCI.

project_terms:
Adenoviridae;autonomic disorder;central neural pathway /tract;dextrans;disease /disorder model;fluorescence microscopy;gene therapy;immunocytochemistry;laboratory rat;nerve growth factors;nervous system disorder therapy;neural plasticity;neurogenic hypertension;neuronal guidance;spinal cord injury;suid alphaherpesvirus 1


application_id: 7051958
project_number: 5R01NS045734-03
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2006-06-07
application_type: 5
activity_code: R01
ic: NS
serial_number: 045734
program_official: KLEITMAN, NAOMI
project_start_date: 2004-05-03
project_end_date: 2009-04-30
study_section: Special Emphasis Panel[ZRG1-CNNT(01)Q]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Contusive spinal cord injury (SCI) causes local endothelial cell damage resulting in vascular leakage and edema and the initiation of inflammation. These processes may lead to later tissue loss and functional deficits. Vascular endothelial growth factor (VEGF) is induced by SCI and may contribute to the leakage. VEGF may initiate detrimental processes as we have shown that VEGF injections after SCI in adult rats increases tissue loss seen at six weeks. Pharmacological inhibition of VEGF reduces edema inflammation and tissue loss in stroke models. Angiopoietin 1 (Ang1) induces vessel maturation and reduces leakage in many systems and is reduced after SCI. Therefore in aim la a VEGF trap and/or Ang1 will be administered early after SCI to test whether reduction of early leakage edema and inflammation reduces later loss of selected white matter tracts. In aim lb) the contribution of endothelial cell loss to secondary damage will be evaluated by protecting the cells with Ang1 plus VEGF or integrin agonist as these can promote endothelial cell survival in vitro. From 3-7 days after SCI an angiogenic response occurs in the injured cord. New vessels may counteract degeneration by increased tissue perfusion while their leakage may cause damage. Thus in aim 2a Ang1 will be administered during the angiogenic phase to promote maturation and maintenance of the new vasculature possibly resulting in better tissue protection. The new blood vessels regress between day 7 and 14 as secondary spinal tissue loss (cavitation) begins. This angiogenic failure may contribute to the secondary damage. In aim 2b the protective effects of maintaining the new blood vessels will be assessed by treating with Ang1 plus VEGF or Ang1 plus integrin agonist. The central hypothesis is that by enhancing stable and mature angiogenesis we will ultimately be able to reduce loss of important white matter tracts and improve functional sensory and motor outcome after SCI.

project_terms:
angiogenesis;angiopoietins;edema;flow cytometry;histology;inflammation;integrins;laboratory rat;neuropharmacology;spinal cord injury;statistics /biometry;terminal nick end labeling;vascular endothelial growth factors;vascular endothelium;white matter


application_id: 7051657
project_number: 1R43HD050006-01A1
project_title: STIMULATION-AUGMENTED EXERCISE AND NEUROMOTOR THERAPY
administering_ic: NICHD
award_notice_date: 2006-04-21
application_type: 1
activity_code: R43
ic: HD
serial_number: 050006
suffix: A1
program_official: SHINOWARA, NANCY
project_start_date: 2006-05-01
project_end_date: 2008-02-29
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
budget_end_date: 2008-02-29
project_abstract:
DESCRIPTION (provided by applicant): This project proposes to develop an electrical stimulation augmented exercise device for individuals with incomplete spinal cord injury (iSCI). The device will provide a closed-chain load bearing lower extremity exercise that has the potential to increase muscle mass strength and endurance and may additionally reverse or slow the rate of loss of bone mineral density. The user will be encouraged to voluntarily perform the exercise which will be augmented with electrical stimulation to complete the prescribed exercise range of motion. The stimulation controller will continuously adjust the stimulation profile to provide only the stimulation that is necessary to complete the exercise while encouraging the user to contribute their best volitional effort on each exercise cycle. We hypothesize that this exercise may provide motor retraining benefits to some users in addition to exercising lower extremity muscles and bones. In Phase I we propose: 1) to modify our existing adaptive stimulation controller for use by individuals with iSCI who have the ability to voluntarily active the stimulated muscles 2) to develop a simple visual feedback display to facilitate coordination between the user and stimulation controller 3) to validate the display paradigm in a study with subjects without neuromotor deficits and 4) to demonstrate feasibility of our approach by testing the device in a study with subjects with iSCI. In Phase II we will further develop the adaptive stimulation controller develop simple user-friendly visual feedback paradigms to improve user/stimulation coordination and demonstrate efficacy of the approach in a long-term study where individuals with incomplete SCI use the device in a motor retraining setting. The target market for the device is clinics who serve individuals with neuromotor disabilities such as incomplete SCI traumatic brain injury or stroke. The device will be competitively priced within the electrical stimulation-based exercise equipment market.   
RELEVANCE TO PUBLIC HEALTH: This project in relevant to public health because it may lead to development of a practical exercise device for individuals with iSCI that may prolong the onset of osteoporosis in the long bones of the legs and may lead to improved voluntary control of paralyzed lower extremity muscles when used as one component of a comprehensive post-SCI rehabilitation program.

project_terms:
bioengineering /biomedical engineering;biomedical equipment development;clinical research;computer human interaction;computer program /software;electronic stimulator;electrostimulus;exercise;human subject;human therapy evaluation;information display;medical rehabilitation related tag;nervous system disorder therapy;neuromuscular stimulator;paralysis;physical therapy;spinal cord injury;therapy design /development


application_id: 7050206
project_number: 5K08MH070840-03
project_title: ADHD Stimulants and D4 Knockout Mice
administering_ic: NIMH
award_notice_date: 2006-03-08
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: MH
serial_number: 070840
program_official: CHAVEZ, MARK RAY
project_start_date: 2004-04-01
project_end_date: 2009-03-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1915629
contact_pi: GLASER, PAUL E A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dr. Glaser is a dedicated physician/scientist who is strongly committed to a career as an academic physician. He is currently an Assistant Professor on a tenure-track at the University of Kentucky. His scientific goal is to understand the neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD) and its treatments. With his joint appointments in Psychiatry and Anatomy & Neurobiology he will be receiving laboratory and resource support from both departments. During the entire award period Dr. Glaser will be spending 75% of his time with laboratory related activities. In addition to research he will be spending 15% of his time pursuing clinical activities primarily in the areas of Child Psychiatry and Pediatrics in the treatment of children and adults with symptoms of ADHD. 10% of his time will be devoted to the teaching of residents and students as well as educational activities. His sponsor Dr. Gerhardt is a leader in the field of neuropsychopharmacology of dopamine modulating medications as well as a recent co-collaborator in the field of ADHD. The neuroscience community at the University of Kentucky will also provide a rich source for collaboration and intellectual support. Additional support will be provided by co-sponsor Dr. F. Xavier Castellanos at NYU a leader in translational ADHD research. The primary goal of Dr. Glaser's proposal is to investigate physiologically-relevant differences in dopaminergic activity evoked by different isomers of amphetamine found in clinically prescribed medications for ADHD using a novel combination of voltammetric and microdialysis in the mouse striatum and nucleus accumbens. A secondary goal is to investigate the possible contribution that dopamine D4 receptors (D4R) may have to dopaminergic function in the mouse.  Dr. Glaser will utilize mice designed by Dr. Grandy at the Oregon Health Sciences University that are missing the D4R (D4R knockout mice) to specifically investigate differences in their baseline behavior and stimulant induced behaviors. The integrated training mentorship research and teaching of Dr. Glaser provided by this award will allow him to develop as an independent investigator dedicated to using basic neuroscience to solve important problems which physicians face everyday in the treatment of children and adults with ADHD and potentially will lead to better understanding and superior treatments for ADHD thus reducing its burden on today's schools health systems and society.

project_terms:
amphetamines;attention deficit disorder;behavioral /social science research tag;corpus striatum;dextroamphetamine;dopamine;dopamine receptor;electrochemistry;gene targeting;genetically modified animals;laboratory mouse;mental disorder chemotherapy;methylphenidate;microdialysis;neuropharmacology;norepinephrine;nucleus accumbens;prefrontal lobe /cortex


application_id: 7050122
project_number: 5R01HL076794-03
project_title: Hematopoietic Stem Cell Therapy for Myocardial Regenerat
administering_ic: NHLBI
award_notice_date: 2006-03-16
application_type: 5
activity_code: R01
ic: HL
serial_number: 076794
program_official: BUXTON, DENIS B
project_start_date: 2004-04-01
project_end_date: 2008-03-31
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Recent reports that HSCs can regenerate infarcted myocardium have unleashed a tidal wave of enthusiasm for translating these findings to the clinical arena.  A number of institutions have already initiated studies of cytokine or HSC therapy in patients with acute MI.  It is our opinion that this rush to clinical trials is not only premature but possibly counterproductive and that further careful preclinical investigation is necessary to establish the efficacy of various treatment protocols and the underlying mechanisms.  For example nothing is currently known regarding whether i.v. HSC administration is effective which cytokine or combination of cytokines is more likely to succeed how long the window of efficacy is and whether HSCs are effective in the context of reperfusion.  Similarly nothing is known regarding the nature of the integrin/adhesion molecule interactions that underlie the homing of HSCs or the potential synergistic role of accessory calls specifically the FCs.  Our fundamental hypothesis is that both i.v.  injected and cytokine-mobilized HSCs can regenerate infarcted myocardium and that this process is mediated by a well-defined cascade of molecular interactions that involve specific adhesion molecules (ICAM-1 VCAM-1 P-selectin and E-selectin) integrins (VLA-4 VLA-5 and LFA-1) chemokines (SDF-1) and chemokine receptors (CXCR-4).  We further propose that FCs exert an important potentiating effect on HSC-dependent cardiac reqeneration and that this process can be further enhanced by FL These hypotheses will be tested in a well-established murine model using a broad multidisciplinary approach that will encompass diverse techniques (integrative physiology protein chemistry biochemistry pathology confocal microscopy immunohistochemistry molecular immunology molecular biology and gene therapy).  Aim I will assess the effectiveness of two clinically-relevant forms of HSC therapy (i.v.  HSCs and cytokines) in two different models designed to simulate reperfused and nonreperfused MI and will define the time-window of efficacy.  Three clinically-applicable cytokines (G-CSF SCF FL) will be tested alone or in combination.  Using gene targeted mice and immunologic blockade of integrins Aim 2 will systematically investigate the role of four specific adhesion molecules (VCAM-1 ICAM-1 P-selectin and E-selectin) and three specific integrins (VLA-4 VLA-5 and LFA-1) in HSC migration to the infarcted myocardium.  Aim 3 will decipher the role of SDF-1/CXCR-4 interactions in HSC homing and infarct repair using adenovirus-mediated gene transfer of SDF-1 and CXCR-4.  Aim 4 will explore the differential regenerative capacity of HSCs and FCs harvested from bone marrow vis-a-vis peripheral blood and the underlying mechanisms.  Aim 5 will determine whether FCs induce allogeneic graft tolerance to HSCs via a Th2 cytokine (IL-4 and IL-10)-dependent mechanism.  This proposal will yield novel information regarding the ability of i.v.  HSCs and various cytokine regimens to regenerate infarcted myocardium the molecular mechanisms for HSC homing the potential role of FCs and the beneficial effects of FL. The results may eventually lead to the development of novel therapeutic strategies in patients with ischemic heart disease.

project_terms:
biological models;cell adhesion molecules;chemokine;confocal scanning microscopy;cytokine;cytokine receptors;gene targeting;gene therapy;genetically modified animals;hematopoietic stem cells;homologous transplantation;human therapy evaluation;immunocytochemistry;integrins;intermolecular interaction;laboratory mouse;myocardium;protein protein interaction;protein structure function;regeneration;stem cell transplantation;transfection


application_id: 7049826
project_number: 2R01DA013519-05
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2005-09-26
application_type: 2
activity_code: R01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2010-08-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-30
project_terms:
analog;binding sites;chemical synthesis;computer simulation;conformation;dopamine;dopamine transporter;drug abuse;drug addiction antagonist;drug design /synthesis /production;drug screening /evaluation;high throughput technology;laboratory rat;membrane transport proteins;methamphetamine;neurotransmitter transport;nicotinic receptors;protein protein interaction;synaptic vesicles


application_id: 7049459
project_number: 5R01AI020941-22
project_title: Glycobiology of Leishmania
administering_ic: NIAID
award_notice_date: 2006-02-09
application_type: 5
activity_code: R01
ic: AI
serial_number: 020941
program_official: ROGERS, MARTIN J
project_start_date: 1985-09-01
project_end_date: 2008-02-29
study_section: Tropical Medicine and Parasitology Study Section[TMP]
contact_pi_person_id: 7875234
contact_pi: TURCO, SALVATORE J
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by the applicant): Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis a major health problem worldwide. Leishmania have evolved a unique family of phosphoglycan (PG)- containing glycoconjugates including the GPI-anchored prototype lipophosphoglycan (LPG). The abundance location and uniqueness of the Leishmania glycoconjugates have implicated these molecules in critical roles for the parasite's survival in their harsh digenetic life cycle. Unfortunately the wide distribution of PG units and GPI domains across a considerable number of diverse glycoconjugates has hindered a comprehensive assessment of their individual functions and the enzymes responsible for their biosynthesis. In a separately funded grant we have surmounted this dilemma by isolating relevant genes via functional complementation of glycosylation mutants and cross-species manipulations. These studies have progressed sufficiently to enable us to focus this grant on the enzymology of the encoded proteins involved in glycoconjugate biosynthesis and expression which in turn represent indispensable opportunities toward scrutinizing the molecular pathways of glycoconjugate assembly in Leishmania. By fully characterizing key proteins encoded by selected genes we expect to meaningfully advance our understanding of how Leishmania assemble such an assortment of complex interrelated glycoconjugates and how they are biochemically involved in the parasite's life cycle.  The specific aims of this competing renewal application are:  1. to investigate the family of Golgi nucleotide-sugar transporters.  2. to characterize the multiple mannosylphosphoryltransferases (MPTs) involved in PG synthesis.  3. to determinate the relationship of a chaperone with galactosylation of PG repeat units.  4. to examine the proteins involved in controlling LPG length and side chain sugar modifications

project_terms:
Leishmania;biochemistry;carbohydrate transport;chemical conjugate;enzyme activity;glycolipids;glycoprotein biosynthesis;glycoprotein structure;glycoproteins;glycosylation;glycosylphosphatidylinositols;glycosyltransferase;leishmaniasis;lipid structure;molecular assembly /self assembly;molecular chaperones;nucleic acid repetitive sequence;posttranslational modifications;protein purification;protein reconstitution;sugar phosphates


application_id: 7049388
project_number: 5R01AI033481-13
project_title: Iron Transport and Regulation in Yersinia Pestis
administering_ic: NIAID
award_notice_date: 2006-03-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 033481
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-07-01
project_end_date: 2008-03-31
study_section: Bacteriology and Mycology Subcommittee 1[BM-1]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):  For over two thousand years Yersinia pestis the causative agent of bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Modern more contained epidemics are common in South America and Madagascar. In addition Y. pestis is a category A bioterrorism agent with natural zoonotic foci as readily available sources of the organism on nearly every continent. The ability of pathogens to acquire iron from their hosts is one critical parameter in the outcome of the infectious process. Y. pestis encodes nine potential inorganic iron transport systems and two heme/hemoprotein transport systems. Of these the siderophore-dependent yersiniabactin (Ybt) iron transport system and the Yfe ABC transporter are the most important systems for acquisition of inorganic iron. Ybt is essential in the early stages of bubonic plague and mutations in this system are avirulent in mice infected subcutaneously (SC). However Ybt- mutants are fully virulent via an intravenous (IV) route of infection. Yfe plays an important role during the later stages of the infection - a Ybt-Yfe- mutant is completely avirulent in mice by IV injection. By SC injection a Yfe- mutant is 75-fold less virulent than its Yfe+ parent suggesting that the Ybt system can partially compensate for a lack of the Yfe system but it is clearly not as effective in the later stages of disease. Expression of both systems is repressed by iron through the iron-responsive regulatory protein Fur. In addition the Ybt system is activated by an AraC-type regulator YbtA possibly acting in concert with the Ybt siderophore. The Yfe system is also repressed by excess manganese through the Fur protein. In vivo repression by manganese and Fur is a unique regulatory mechanism. The specific aims of this proposal are to continue characterizing genetic and biochemical aspects of 1) the Ybt and 2) the Yfe transport systems and 3) to analyze the expression of these two systems in vivo and determine their roles in systemic spread of the disease. We will identify any remaining elements necessary for the function of these systems examine the regulatory components controlling expression of these systems in vitro and in vivo and determine the role of these systems in the infectious disease process of plague. An understanding of the components and functions of these two-transport system may lead to their use as protective antigens or as targets for new drugs. Our studies will also provide insights into the role of Ybt and Yfe in the pathogenesis of plague and other disease-causing organisms and into the general importance of iron acquisition in bacterial disease processes.

project_terms:
Yersinia pestis;Yersinia pestis disease;bacterial genetics;bacterial proteins;biological transport;bioterrorism /chemical warfare;electroporation;fusion gene;gel mobility shift assay;gene expression;gene mutation;genetic regulation;genetic regulatory element;high performance liquid chromatography;iron metabolism;laboratory mouse;matrix assisted laser desorption ionization;molecular cloning;nuclear magnetic resonance spectroscopy;pathologic process;polymerase chain reaction;reporter genes;siderophores;virulence


