# projects

application_id: 7049374
project_number: 5R01AI051377-05
project_title: Bcl-3 Oncoprotein in T Cell Survival
administering_ic: NIAID
award_notice_date: 2006-03-06
application_type: 5
activity_code: R01
ic: AI
serial_number: 051377
program_official: WINTER, DAVID B
project_start_date: 2002-04-01
project_end_date: 2007-03-31
study_section: Immunological Sciences Study Section[IMS]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Bcl-3 oncoprotein in T cell survival.          Immunization with antigen plus adjuvant results in the rapid proliferation and      clonal expansion of antigen-specific T cells. Failure to include adjuvants          during immunization ultimately results in clonal deletion rather than clonal       expansion because the responding T cells proliferate briefly but go on to die.     Understanding the mechanisms by which adjuvants promote T cell survival could       generate novel approaches to improve vaccines and prevent autoimmune diseases.      We previously studied adjuvant-induced T cell survival in mice given natural        adjuvants which are materials from microbes that trigger innate immune             responses. In activated T cells the oncoprotein Bcl-3 was induced by adjuvants     more than any other gene tested. Bcl-3 is a member of the NFkappaB/Rel/IKappaB      superfamily of transcription factors but its physiological function is             unknown. It is proposed that Bcl-3 regulates activated T cell survival through      an NFKB-dependent mechanism.                                                                                                                                            Specific aims: 1. Determine the extent of the Bcl-3 adjuvant effect on T cells.     The hypothesis that Bcl-3 regulates T cell survival rather than                    differentiation or proliferation will be tested via retroviral gene transfer.      These experiments will test the extent to which Bcl-3 expression alone is           sufficient to explain the effects of adjuvants on T cells and establish            parameters within which to study its survival effect. 2. Define the structural      domains and collaborating proteins needed for Bcl-3 to promote T cell survival.     The hypothesis that Bcl-3 functions through an NFkappaB-dependent mechanism         will be tested by assessing T cell survival after retroviral transduction of        Bcl-3 of deletion mutants of Bcl-3 and of other NFkappaB family members. These     experiments will identify NFKappaB proteins needed for Bcl-3 to promote             lymphocyte survival and will define domains of Bcl-3 that are necessary for it     to contribute to T cell survival. 3. Identify the cell populations that cause       impaired immunity in Bcl-3-deficient mice. Bc13-/- mice fail to produce             specific antibodies after vaccination and fail to clear model infections           patterns which are consistent with the idea that some or all of the immune          defects in these mice are caused by abortive T cell responses. Experiments with     these mice will identify those adjuvant effects on T cells for which Bcl-3          expression is required and which could therefore be targeted by drug                inhibition.

project_terms:
Retroviridae;T lymphocyte;cell growth regulation;gene deletion mutation;laboratory mouse;nuclear factor kappa beta;oncoproteins;protein structure function;tissue /cell culture;transcription factor;transfection


application_id: 7049331
project_number: 5F30NS051998-02
project_title: Role of Hsp90 Interactions in PC-12 Survival to Hypoxia
administering_ic: NINDS
award_notice_date: 2006-03-30
opportunity_number: PA-01-100
application_type: 5
activity_code: F30
ic: NS
serial_number: 051998
program_official: GOLANOV, EUGENE V
project_start_date: 2005-04-01
project_end_date: 2008-03-31
study_section: ZNS1-SRB-M(13)
contact_pi_person_id: 8088892
contact_pi: WIEGAND, CHRISTINA B
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):    Hypoxia is a primary factor in ischemic diseases such as stroke and traumatic brain disease. PC-12 cells have been widely used as a model to study signaling pathways of neuronal sensitivity to hypoxia notably the PI3K/Akt survival pathway. Hypoxia induces heat shock protein response in ischemic brain as well as in PC- 12 cells and HspQO has been implicated in the regulation of Akt activity. Thus hypoxia-induced HspQO may modulate PC-12 cell survival via protein binding regulated by phosphorylation. Proteomic techniques SDS-PAGE and MALDI-MS as well as site-directed mutagenesis translation co-immunoprecipitation and GST pull-down methods will be used to: (i) identify HspQO binding proteins in normoxic and hypoxic cells and determine their role in PC-12 survival to hypoxia; (ii) determine whether Akt and Akt-mediated phosphorylation events regulate HspQO protein binding and cell survival to hypoxia; (iii) determine whether HspQO regulation of cell survival to hypoxia involves shuttling its binding proteins to various subcellular compartments in an Akt dependent or independent manner. These studies will provide the groundwork for future intervention strategies aiming to prevent neuronal cell loss in diseases associated hypoxia.

project_terms:
PC12 cells;SDS polyacrylamide gel electrophoresis;binding proteins;biological signal transduction;cell growth regulation;cerebral ischemia /hypoxia;heat shock proteins;immunoprecipitation;matrix assisted laser desorption ionization;phosphatidylinositol 3 kinase;phosphorylation;protein binding;protein localization;protein protein interaction;protein quantitation /detection;protein structure function;proteomics;site directed mutagenesis


application_id: 7048688
project_number: 5R01GM047915-12
project_title: Modified Photoproteins as Labels and Molecular Switches
administering_ic: NIGMS
award_notice_date: 2006-03-30
application_type: 5
activity_code: R01
ic: GM
serial_number: 047915
program_official: EDMONDS, CHARLES G
project_start_date: 1995-01-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-BECM(01)S]
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Bioluminescent photoproteins afford high sensitivity of detection and have been employed as labels in bioanalysis. We propose to further expand the applications of these photoproteins by modifying them to possess unique bioluminescence properties. One of the goals of this work is to alter the electronic and H-bonding network within the chromophore-binding pocket of these photoproteins in order to shift their emission wavelengths. This will be achieved by incorporation of non-natural amino acids into the aequorin structure and by performing site-directed mutagenesis. The resulting proteins will be characterized in terms of their activity and structure-function relationship. We also propose to mimic the natural phenomenon that occurs in the jellyfish Aequorea Victoria where transfer of energy from aequorin to GFP results in the emission of green light. For that we propose to prepare protein-based "artificial jellyfish" by attaching a fluorophore to unique sites on aequorin close to  the coelenterazine binding pocket. This will allow transfer of energy from aequorin to the fluorophore thus shifting the wavelength of emission of the protein. "Molecular switches" that can be "turned on" in the presence of a target analyte will be prepared by constructing hybrid proteins between aequorin variants and a binding protein for a specific analyte. The hybrid proteins will be constructed by inserting the gene of the binding protein into the gene of aequorin. The conformational changes that occur in the binding protein upon ligand binding will bring the two parts of aequorin together allowing for the emission of bioluminescence. In addition "molecular switches" will be constructed by preparing fusion proteins of a dissected aequorin and genes that code for a pair of poplypeptides that can form a leucine zipper. The leucine zipper allows for aequorin to re-assembly and bioluminescence emission. When target DNA is present the leucine zipper is pulled apart; aequorin is disassembled with the subsequent loss of light. Applications of the above modified photoproteins in bioanalysis will be demonstrated by developing highly sensitive assays for panels of analytes that are important in disease diagnosis. Furthermore these assays based on aequorin variants with different emission wavelengths will be incorporated into a microcentrifugal microfluidic platform which should result in multiplex analysis with applications in point-of-care diagnostics and HTPS.

project_terms:
bioluminescence;biomarker;calcium indicator;chimeric proteins;chromophore;fusion gene;green fluorescent proteins;hydrogen bond;immunologic assay /test;ligands;luciferin monooxygenase;method development;polymerase chain reaction;protein structure;protein structure function;reagent /indicator;site directed mutagenesis


application_id: 7048525
project_number: 5R01HL069932-05
project_title: Postnatal Brain Susceptibility to Intermittent Hypoxia
administering_ic: NHLBI
award_notice_date: 2006-03-16
application_type: 5
activity_code: R01
ic: HL
serial_number: 069932
program_official: TWERY, MICHAEL
project_start_date: 2002-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-ALTX-1(01)]
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Obstructive sleep apnea syndrome (OSA) is      a frequent condition affecting up to 2 percent of the pediatric population at       ages that are characteristically associated with dynamic brain development and      acquisition of important neurocognitive functions. OSA is characterized by          repeated episodes of hypoxia during sleep and when untreated it is associated      with significant neurocognitive morbidities such as excessive restlessness and      irritability diminished intellectual performance attention span learning and     vigilance. However the relative contributions of chronic intermittent hypoxia      (CIH) to OSA-associated neurocognitive dysfunction in children remain unclear.      In adult rats a CIII profile that mimics the intermittent hypoxia observed in      patients with OSA during sleep leads to substantial reductions in spatial           learning and retention as well as diminished ability to induce long-term            potentiation in the CA1 region of the hippocampus. These neurobehavioral and        physiological alterations correlate with anatomical changes developing in           cortico-hippocampal regions. and we have found that such anatomical changes        are particularly prominent in developing rat pups at post-natal ages that           coincide with the peak prevalence of USA in children suggesting that this          period of brain maturation is uniquely vulnerable to CIH. We therefore              hypothesized that the detrimental effects of CIH on memory and learning             performances during this highly vulnerable developmental period are                 long-lasting and will be manifest even during adulthood long after the CIH        exposure has ceased. Furthermore these neurocognitive deficits will be             associated and correlated with parallel electrophysiological alterations in the     characteristics of long-term potentiation (LTP) of the CAl region of the            hippocampus as well as with disruption of normal ionotropic glutamate receptor     expression and binding characteristics within the cortex and hippocampus. We        propose to: (1) examine the short-term and long-term consequences of CIH on         behavioral patterning and on water maze task acquisition and retention. (2) To      assess the short-term and long-lasting effects of CIH on LTP characteristics of     the CA1 region of the hippocampus.; (3) To establish changes in NMDA glutamate      receptor expression and binding characteristics in neocortical and hippocampal      regions associated with CIH and following long-term recovery; (4) To determine     whether exposure to CIH during a critically-vulnerable period of development        will elicit time-dependent glial and neuronal stem cell proliferation within        cortical and hippocampal regions. These studies will characterize concomitant       structural and phenotypic changes induced by CIH in a developmental rodent          model of OSA and provide initial insights into the role of CIH in short-term       and long-term neurobehavioral morbidity of USA in children.

project_terms:
age difference;behavioral /social science research tag;cell proliferation;cerebral cortex;cerebral ischemia /hypoxia;developmental neurobiology;disease /disorder model;glutamate receptor;hippocampus;infant animal;laboratory rat;learning;long term potentiation;nerve stem cell;neuropsychological tests;neurotoxicology;respiratory airflow disorder;respiratory hypoxia;sleep apnea


application_id: 7046763
project_number: 5R01HL072936-04
project_title: Regulation of Calcium Channel Function by the Rem GTPase
administering_ic: NHLBI
award_notice_date: 2006-03-20
application_type: 5
activity_code: R01
ic: HL
serial_number: 072936
program_official: WANG, LAN-HSIANG
project_start_date: 2003-04-15
project_end_date: 2009-03-31
study_section: Pharmacology A Study Section[PHRA]
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Voltage-dependent calcium channels (VDCCs) serve two critical functions: the regulation of cellular excitability and the regulation of Ca2+ entry. Ca2+ dysfunction accompanies adult disease progression such as in cardiac hypertrophy. Thus it follows that the chronic regulation of voltage-dependent Ca2+ channel expression is critical to the function of the heart and skeletal muscle. The guiding hypothesis of this proposal is that the Ras-related GTPase Rem regulates Ca2+ channel activity in cardiac and skeletal muscle by the novel mechanism of interacting with the beta-subunits of voltage-gated Ca2+ channels to block their association with alpha1-subunits. We hypothesize that this inhibits channel activity by blocking trafficking of functional calcium channels to the plasma membrane. This hypothesis was motivated by the following pilot studies: 1) Rem is highly expressed in cardiac and skeletal muscle. 2) Rem binds to beta- subunits. 3) Over-expression of wild-type Rem inhibits ionic current expression in heterologous expression systems and importantly in primary ventricular myocytes. 4) T-type Ca 2+ channels do not require accessory subunits and Rem does not inhibit expression of currents through this family of channels. This suggests that Rem regulates Ca2+ channel activity in a beta-subunit-dependent fashion. 5) Rem-mediated regulation of CaV1 channels is not understood but initial studies have defined a crucial role for the Rem C-terminal domain in this process. We propose three specific aims to elucidate the function of Rem as a regulator of voltage-dependent Ca2+ channel activity. Specific Aim 1 will identify the amino acid sequences in Rem and the Ca2+ channel beta- subunit important for their interaction. Specific Aim 2 will determine if formation of the Rem:beta-subunit complex is regulated in vivo by 14-3-3 protein binding and GTPase activity. Studies will also examine the role of the C-terminal domain in Rem-mediated Ca2+ channel regulation. Specific Aim 3 will characterize the mechanism of Rem-mediated regulation of alpha1 channel activity by examining Rem effects on the association of alpha1 and beta-subunits and channel trafficking. These studies will advance knowledge by elucidating a new mechanism for controlling chronic Ca2+ channel activity as well as a novel mechanism for achieving cross talk between Ras-related GTPases and electrical signaling pathways. This knowledge could aid understanding of the regulation of voltage-dependent Ca2+ channels in both normal and disease states.

project_terms:
calcium channel;cardiac myocytes;cell membrane;computer simulation;genetic regulation;guanine nucleotide binding protein;intracellular transport;laboratory mouse;membrane activity;myocardium;protein protein interaction;protein sequence;protein structure function;site directed mutagenesis;striated muscles;voltage gated channel;yeast two hybrid system


application_id: 7046736
project_number: 5R03AI061437-02
project_title: Host factors involved in viral RNA recombination
administering_ic: NIAID
award_notice_date: 2006-04-25
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AI
serial_number: 061437
program_official: PARK, EUN-CHUNG
project_start_date: 2005-04-01
project_end_date: 2008-03-31
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): The host plays a role not only in replication of plus-stranded RNA viruses but also in viral RNA recombination although the role(s) of host factors in recombination is currently unknown. RNA recombination is an important mechanism for plus-strand RNA viruses because it contributes to the emergence of new pathogenic or drug-resistant viruses and strains. Accordingly RNA recombination has been demonstrated to occur for a large number of human animal and plant viruses including poliovirus dengue virus infectious bronchitis virus influenza A virus hantavirus hepatitis D virus Human Respiratory Syncytial Virus Corona- Rota- Flavi- Calici- Arteri- Astro- Entero-; and Alphaviruses. In order to advance understanding of the role of the host in viral RNA recombination the PI has recently developed a yeast-based recombination system for a model plant virus Cucumber necrosis tombusvirus (CNV). The CNV replicase is similar to the replicases of important human and animal viral pathogens such as hepatitis C virus Flaviviruses and Pestiviruses. CNV is exceptionally suitable for studying RNA recombination because numerous recombinants can easily and rapidly be recovered: (i) in yeast cells (ii) in whole plants and (iii) in the in vitro CNV RNA-dependent RNA polymerase (RdRp) assay. The central hypothesis tested in this work is that host factors may affect viral RNA recombination. The PI will use (Aim 1 and 2) the advanced genetics tools available for yeast a model host. Encouraged by preliminary data on the efficient replication and recombination of a Tombusvirus replicon in yeast the PI will use a high-throughput screen to test the effect of each host gene on viral RNA recombination based on the yeast deletion strain library (~ 5500 strains) in which each yeast gene was separately deleted. A partial screen of the library has already identified three host genes affecting RNA recombination thus confirming the feasibility of the approach. The identified host genes affecting viral RNA recombination will be further tested (Aim 3) to characterize their effect on viral recombinants. The research described here will lead to better understanding of the role of host genes in viral RNA recombination and the role of the host in virus evolution. Knowledge of recombination promises untold health benefits by providing means to limit virus infections and to develop safer vaccines.

project_terms:
RNA virus;Saccharomyces;biotechnology;fungal genetics;gene expression;genetic library;genetic screening;high throughput technology;host organism interaction;plant virus;protein structure function;recombinant virus;replicase;replicon;virus RNA;virus genetics;virus protein;virus replication


application_id: 7046182
project_number: 5R01CA049797-15
project_title: Mechansins of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2006-03-03
application_type: 5
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2010-02-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
RNA interference;carcinogenesis;chromatin immunoprecipitation;enzyme induction /repression;genetic regulatory element;genetically modified animals;laboratory mouse;neoplastic cell;neoplastic process;nucleic acid sequence;nucleic acid structure;oxidative stress;protein protein interaction;proteomics;skin neoplasms;small interfering RNA;superoxide dismutase;tissue /cell culture;transcription factor


application_id: 7046094
project_number: 5R01DK055030-06
project_title: LEUKOCYTE ADHESION IN COPPER DEFICIENT MICROCIRCULATION
administering_ic: NIDDK
award_notice_date: 2006-09-08
application_type: 5
activity_code: R01
ic: DK
serial_number: 055030
program_official: MAY, MICHAEL K
project_start_date: 1999-08-01
project_end_date: 2009-03-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 2291964
contact_pi: SCHUSCHKE, DALE A
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Regulation of the microvascular response to inflammatory stimuli is highly dependent upon the interactions between neutrophils and the endothelium. We have shown a significant role for dietary copper in various endothelial interactions in the inflammatory process including nitric oxide (NO)-mediated vasodilation macromolecular leakage and thrombosis. Recently we have studied the role of dietary copper in microvascular control mechanisms with an emphasis on leukocyte/endothelial adhesion. We have demonstrated that dietary copper restriction causes tissue-specific changes in neutrophil/endothelial adhesion and transmigration. Neutrophil accumulation the expression of the adhesion molecule ICAM-1 and the transcription factor NF-kappaB are all greater in the lungs of copper-deficient rats compared to copper-adequate controls. Based on these results we hypothesize that dietary copper deficiency has a priming effect on leukocytes and pulmonary vascular endothelial ceils such that the lung becomes hypersensitive to inflammatory stimuli and more susceptible to the development of acute lung injury. Therefore the specific aims of this study are to: 1) determine the role of dietary copper in leukocyte/endothelial cell interactions in the lung microcirculation; 2) determine the mechanisms by which copper deficiency primes cells for acute inflammation and 3) determine at what concentration of dietary copper the inflammatory mechanisms become enhanced in the in vivo animal microcirculation. Aim #1 will use both in vivo and in vitro models of the lung microcirculation to study leukocyte/endothelial cell adhesion and chemotaxis. Aim #2 will study the role of copper in the NF-kB signaling pathway and in neutrophil priming. Aim #3 will examine these mechanisms under conditions of copper-marginal diets. These experiments have particular relevance since analysis of typical Western diets suggest that 1/3 to 1/2 of those diets may provide less than the RDA of 900mg Cu/day.

project_terms:
anemia;biological signal transduction;cell cell interaction;chemotaxis;copper;dietary mineral;enzyme linked immunosorbent assay;flow cytometry;free radical oxygen;gel mobility shift assay;gene expression;inflammation;laboratory rat;leukocyte activation /transformation;leukocyte adhesion molecules;lung injury;malnutrition;microcirculation;neutrophil;nuclear factor kappa beta;nutrient requirement;nutrition related tag;polymerase chain reaction;respiratory circulation;vascular endothelium;video microscopy


application_id: 7046077
project_number: 5R01HL038120-14
project_title: Alpha-1 Adrenergic Subtypes and Vascular Smooth Muscle
administering_ic: NHLBI
award_notice_date: 2006-03-17
application_type: 5
activity_code: R01
ic: HL
serial_number: 038120
program_official: LIN, MICHAEL
project_start_date: 1987-04-01
project_end_date: 2008-04-30
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 1894945
contact_pi: PIASCIK, MICHAEL 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-05-01
project_abstract:
DESCRIPTION (provided by applicant):  The alpha1-adrenergic receptors (alpha1-ARs) play a vital role in the regulation of systemic arterial blood pressure blood flow cardiac contraction and as mediators of growth responses. Three receptors the alpha1A the alpha1B and the alpha1D-ARs have been isolated cloned and characterized. This is an application to continue studies designed to increase our understanding of the cardiovascular regulatory biology of the alpha1-ARs. We will focus our studies on the alpha1B and alpha1D-ARs. The alpha1B-AR has properties typical of a G-protein coupled receptor (GPCR). In contrast the alpha1D-AR has many characteristics that are atypical for a GPCR. Specific Aim # 1 builds on observations made by us and others that there are significant differences in the basal cellular localization agonist mediated receptor internalization and desensitization between the alpha1b and alpha1D-ARs. We will test the hypothesis that these differences are due to sequence diversity between these receptors in key subdomains particularly the C-terminus. Specific Aims # 2 and 3 will focus on the regulatory activities of the alpha1B and alpha1D ARs and will utilize vascular smooth muscle cells cardiomyocytes in vitro responses in isolated blood vessels the isolated heart and in vivo measurements. We will also use newly developed lines of transgenic mice in assessing these hypotheses. Aim # 2 will focus on the alpha1D-AR and evaluate the hypothesis that this receptor is a specific regulator of vascular smooth muscle contraction with minimal effects on cardiomyocytes. In Aim # 3 we will test the hypothesis that the alpha1B-AR plays an important role in mediating growth responses and as a regulator of contractile function in the heart. We will show that the alpha1B-AR has limited involvement in the contraction of vascular smooth muscle. We have proposed a comprehensive experimental design that applies contemporary molecular biologic genetic cellular and immunologic approaches in combination with in vitro and in vivo assessment of physiologic function. Specific hypotheses will be evaluated in a fashion that will yield definitive mechanistic conclusions. Considering the health-related risks of hypertension and heart failure a better understanding of the role of the alpha1-ARs in these pathophysiologic conditions is highly relevant. Knowledge of the role of these receptors in these disorders can also aid in the development of newer and safer drug therapies.

project_terms:
alpha adrenergic receptor;cardiac myocytes;cell growth regulation;genetically modified animals;heart contraction;laboratory mouse;membrane activity;protein isoforms;protein localization;receptor coupling;receptor sensitivity;tissue /cell culture;vascular smooth muscle;vasoconstriction


application_id: 7039357
project_number: 3P50NS039787-05S2
project_title: RESTORATION OF DOPAMINE FUNCTION IN PARKINSON'S DISEASE
project_terms: Parkinson&apos;s disease;dopamine;nervous system regeneration;neurotrophic factors
administering_ic: NINDS
award_notice_date: 2005-03-29
opportunity_number: NS99-004
application_type: 3
activity_code: P50
ic: NS
serial_number: 039787
suffix: S2
program_official: MURPHY, DIANE
project_start_date: 1999-09-30
project_end_date: 2005-08-09
study_section: ZNS1
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
project_abstract:
The neuroestorative and neuroprotective tropic actions of GDNF on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease.  As with many tropic factors optimum success of this tropic factor depends on focal and controlled delivery of the protein to affect the function of DA neurons without producing unwanted side effects.  It is our central hypothesis that chronic intracerebroventricular or intraputamenal GDNF willproduce effects on damaged DA neurons with greater efficacy potency and reduced side effects as compared to other methods of delivery. 1.  We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-lesioned monkey to evaluate two sites of delivery:  the lateral ventricle and the putamen. 2.  We will also investigate washout of GDNF and re-instatement of the trophic factor in both infusion paradigms. The different highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons and form the foundation for a Parkinson's Disease Center of Excellence. Project 1 will use microdialysis in vivo electrochemistry and postmortem HPLC-EC methods to study the nigrostriatal pathway of unilateral MPTP-lesioned monkeys that have received chronic infusions of GDNF.  Project 2 will investigate the behavioral consequences of the GDNF infusions and study potential functional changes to DA neurons using fMRI methods.  Project 3 will carryout tract tracing and immunohistochemical measures of DA neurons in the same groups of chronically treated monkeys.  The Cores A-D will all provide needed support for the experiments outline in Projects 1-3.  These studies will answer key questions regarding the chronic delivery of a trophic factor in freely-moving and behaving rhesus monkeys.  Such data could lay the foundation for the use of trophic molecules for the treatment of Parkinson's disease in humans.


application_id: 7039134
project_number: 5R01AG025047-07
project_title: Neuroendocrine mechanisms of reproductive aging
administering_ic: NIA
award_notice_date: 2006-02-23
application_type: 5
activity_code: R01
ic: AG
serial_number: 025047
program_official: SUNEJA, SANOJ
project_start_date: 1999-06-01
project_end_date: 2010-03-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1891759
contact_pi: JENNES, LOTHAR H
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_terms:
NMDA receptors;aging;biological signal transduction;estradiol;estrogen receptors;estrus;female;gene expression;genetically modified animals;glutamates;gonadotropin releasing factor;green fluorescent proteins;hypothalamus;immunocytochemistry;in situ hybridization;laboratory mouse;luteinizing hormone;microarray technology;neuroendocrine system;neurogenetics;neurohormones;neurons;polymerase chain reaction;radioimmunoassay;reproductive system


application_id: 7039008
project_number: 5R01EY014821-04
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2006-03-21
application_type: 5
activity_code: R01
ic: EY
serial_number: 014821
program_official: OBERDORFER, MICHAEL
project_start_date: 2003-04-01
project_end_date: 2007-07-31
study_section: Biobehavioral and Behavioral Processes 4[BBBP-4]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): A significant proportion of human activities involving space orientation locomotion and action occur over a critical span of space of about 2 to 25m from the observer. Yet the mechanisms underlying the abilities to flawlessly perform these activities in the intermediate distance range are not well understood though appreciated whenever the abilities are impaired due to brain injuries. How is space perception impaired? A key to answering this question is to understand how human perception in the intermediate distance range is referenced relative to the physical space. An early theoretical answer to this question was provided by Gibson (1950) who proposed that space perception in the intermediate distance range is highly influenced by the structure of the ground surface. The current proposal presents some empirical evidence to support the ground reference idea in addition to presenting new hypotheses to uncover the perceptual mechanisms underlying space perception in the intermediate distance range. Three broadly defined issues will be addressed. These are: 1. How does the visual system define the ground surface reference frame for distance judgment? 2. How is the eye level determined and calibrated? 3. How is an object above the ground surface localized? This research will be conducted both in the real and virtual reality environments. The latter not only provides for a controlled stimulus environment but will also provide valuable insights into designing virtual reality systems with high immersion quality which will be of benefit to those interested in the vocational and therapeutic usage of the virtual reality systems. Above all this research will advance the knowledge of how the ground surface is represented by the brain and how it is employed as a reference frame for localizing objects which is an important step to understanding space perception and cognition.

project_terms:
attention;behavioral /social science research tag;binocular vision;clinical research;computer human interaction;computer simulation;cues;form /pattern perception;human subject;judgment;neural information processing;retinal adaptation;space perception;vision tests;visual depth perception;visual fields;visual pathways;visual stimulus


application_id: 7037906
project_number: 2R01AI049367-05A1
project_title: Blockade of host apoptosis by Toxoplasma gondii
administering_ic: NIAID
award_notice_date: 2006-02-09
opportunity_number: PA-04-119
application_type: 2
activity_code: R01
ic: AI
serial_number: 049367
suffix: A1
program_official: WALI, TONU M
project_start_date: 2001-03-01
project_end_date: 2011-02-28
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Toxoplasma gondii infected cells exhibit a profound blockade of apoptosis that manifests at multiple points in the apoptotic cascade. Our studies have shown an essential role for the hose transcription factor NFKB in the establishment of the parasite-directed anti-apoptotic state. Activation of NFxB by diverse cellular pathways occurs via the phosphorylation of specific Ser residues on its inhibitor kB. This phosphorylation event is  
catalyzed by a unique cellular kinase complex defining the kB kinase signalosome (IKK). In T. gondii infected cells Phospho-kB localizes at the parasitophorous vacuole membrane (PVM) the organelle defining the intracellular replication-permissive niche. The detection of P-kB at the PVM in cells devoid of all IKK activity suggested the presence of a parasite-encoded kinase (TglKK) is responsible. We find just such an activity in parasite extracts and PVM-enriched fractions. We focus here on identifying the gene(s) encoding the TglKK activity and examining its role both in NFxB activation and the blockade of apoptosis. Our data indicate that TglKK activity alone is not sufficient to drive NFKB gene expression in cells with defects in IKK. Initial studies examining the temporal nature of NFxB activation reveal a biphasic pattern of NFKB expression suggesting independent but temporally linked contributions of the host and parasite IKK activities. We propose to use host cell lines with specific lesions in pathways upstream of IKK as well as  
cell lines "locked" into a defined expression profile to better characterize the pertinent cellular pathways subverted by T. gondii infection. Finally we have developed a genetic screen to identify parasite genes involved in NFKB activation. Initial results bear out the evidence that the mechanism to subvert NFKB is multifactorial. Identification of these parasite genes and the elucidation of their roles in NFKB activation in the context of the studies on the cellular components will help define the signaling networks subverted by the parasite. Dissection of these pathways is particularly important given the targets of NFKB many of the cytokines implicated both in the pathogenesis of acute toxoplasmosis and the development of immunity to the parasite.

project_terms:
Toxoplasma gondii;antigen antibody reaction;apoptosis;cell growth regulation;cellular immunity;cysteine endopeptidases;enzyme activity;flow cytometry;gene targeting;genetically modified animals;host organism interaction;laboratory mouse;mitochondria;nuclear factor kappa beta;protozoal antigen;protozoal infection;vesicle /vacuole;western blottings;yeast two hybrid system


application_id: 7037552
project_number: 5R01AA013168-04
project_title: Alcohol apoptosis and lung opportunistic infection
administering_ic: NIAAA
award_notice_date: 2006-03-21
application_type: 5
activity_code: R01
ic: AA
serial_number: 013168
program_official: VELAZQUEZ, JOSE M
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
contact_pi_person_id: 8535326
contact_pi: D'SOUZA EL-GUINDY, NYMPHA BRUNA
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): The long-term objective of this proposal is to elucidate the mechanisms by which chronic alcohol (EtOH) ingestion predisposes the host to pulmonary infections.  In spite of years of extensive research the precise mechanisms whereby pulmonary infections develop in alcoholics are not fully elucidated.  Therefore novel approaches need to be undertaken to further our understanding of how these infections develop.  Based on the gaps in our understanding of why alcoholics have a greater propensity to acquire lung infections and the recently discovered pivotal role for apoptosis in health and diseases the project proposes to test three hypotheses: 1) EtOH alters basal rate of lung apoptosis.  The primary targets of this EtOH effect are the alveolar macrophages (AM) and during an infection also infiltrating cells; 2) EtOH alters apoptosis of lung immune cells by modulating the amount and interaction of apoptotic protein adapters; and 3) The EtOH-induced apoptotic death of lung cells overwhelms the inherent clearance mechanisms in the lung. As a result the uncleared dead cells undergo secondary necrosis leading to persistent lung inflammation.  Accordingly the proposal has four specific aims: 1) to determine the temporal relationship between EtOH-altered rate of lung apoptosis and severity of infection; 2) to determine the lung cell types undergoing apoptosis following EtOH ingestion and infection; 3) to determine the mechanism(s) underlying EtOH effects on lung immune cell apoptosis and 4) to determine the temporal relationship between EtOH-induced alterations in the kinetics of lung apoptosis and the ability of AM to remove apoptotic cells. To achieve these goals mice will be fed EtOH for various periods and infected with Streptococcus pneumoniae (SP).  These mice will be used to assess the apoptotic and pathologic state of the lung.  To evaluate the potential deleterious effects of EtOH enhanced lung cell apoptosis the lung propensity to clear an SP infection will be evaluated in presence and absence of apoptosis inhibitors.  By applying biochemical molecular and cell biology techniques the steps of apoptotic signaling pathway where EtOH acts will be established.  Finally the project will determine if there is a correlation between EtOH-induced apoptosis decreased phagocytosis and increased inflammation.  The project will provide essential and novel information to: 1) broaden our understanding of how EtOH increases the hosts' susceptibility to pulmonary infections and 2) pave the way to developing therapeutic interventions to control pulmonary infections.

project_terms:
Streptococcus pneumoniae;alcoholic beverage consumption;alcoholism /alcohol abuse;alveolar macrophages;apoptosis;biological signal transduction;ethanol;inflammation;laboratory mouse;necrosis;opportunistic infections;phagocytosis;respiratory infections


application_id: 7037536
project_number: 5F31AA015676-02
project_title: Ethanol withdrawal HIV-1 and corticosterone
administering_ic: NIAAA
award_notice_date: 2006-02-27
opportunity_number: PA-04-032
application_type: 5
activity_code: F31
ic: AA
serial_number: 015676
program_official: LUCAS, DIANE
project_start_date: 2005-03-01
project_end_date: 2006-06-30
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 9444496
contact_pi: SELF, RACHEL L
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): Alcohol-withdrawal induced neurotoxicity and viable options for its treatment have not yet been fully elucidated. However research indicates a role for polyamine-sensitive sites on the NMDA receptor (NMDAr) system and glucocorticoids in ethanol withdrawal (EWD)-induced neurodegeneration. Further estimates indicate that approximately 75% of HIV-positive individuals fulfill DSM-IV criteria for alcohol and/or substance abuse. Excessive glucocorticoid release has also been shown to exacerbate certain health problems including those that contribute to neurodegeneration. Therefore these studies will examine the role of glutamate and corticosteroid receptors in mediating the superadditive neurotoxic effects of ethanol withdrawal and the HIV- 1 viral protein Tat. For these experiments adolescent rats will implanted with intra-hippocampal cannula into the CA1 region via stereotaxic surgery. The animals will then be chronically exposed to ethanol and undergo withdrawal with or without co-exposure to Tat. A subsequent study will investigate the efficacy of novel NMDAr polyamine-site and glucocorticoid receptor antagonists in blocking any resultant neurotoxicity. Brains will be extracted and examined for damage via immunohistochemistry and autoradiographic imaging.

project_terms:
AIDS dementia complex;NMDA receptors;autoradiography;behavior test;corticosteroid inhibitor;corticosteroid receptors;corticosterone;drug withdrawal;ethanol;hippocampus;hormone regulation /control mechanism;human immunodeficiency virus 1;immunocytochemistry;laboratory rat;neuropathology;neurotoxicology;neurotransmitter antagonist;predoctoral investigator;psychoneuroimmunology;radioimmunoassay;stereotaxic techniques;transcription factor;virus protein


application_id: 7037396
project_number: 5K08EY016120-02
project_title: PROTEOMIC ANALYSIS OF AGE-RELATED MACULAR DEGENERATION
administering_ic: NEI
award_notice_date: 2006-03-23
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: EY
serial_number: 016120
program_official: MARIANI, ANDREW P
project_start_date: 2005-04-01
project_end_date: 2008-03-31
study_section: ZEY1-VSN(06)
contact_pi_person_id: 7936607
contact_pi: TEZEL, TONGALP H
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): Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population in the Western world. So far several "destructive" treatment modalities have been tried in vain to improve the central vision in patients with AMD. The failure of developing effective treatment stems from the inadequacy of our knowledge of cellular mechanisms in AMD pathogenesis. Several epidemiological studies indicate aging as the predominant risk factor for AMD. Experimental data suggest that post-translational modifications of cellular proteins by glycation phosphorylation or oxidation may be responsible for age related retinal cell loss. However the exact mechanisms involved in age-related retinal cell loss and macrostructural alterations leading to AMD have not yet been identified. Identification of these pathogenetic pathways will help us to develop rational strategies to block the cellular events leading to AMD. Proposed experiments aim to identify the differential in situ protein expressions of RPE choriocapillaris and photoreceptor cells in the macula and periphery of the (1) young (<50) normal donors (2) normal old (>65) donors without any retinal pathology (3) old donors with age-related maculopathy (ARM) and (4) old donors with AMD. Comparison of these proteome maps will reveal the topographical and age-related variations in protein expression of each cell type. Such proteome maps will also be useful in detecting the differentially expressed proteins in ARM and in AMD. Using bioinformatic techniques possible pathological events and related pathways will be identified. Proposed studies will also yield topographical and age-correlated specific proteome maps of each tissue which can be used for future research in the field. Results of this proposal will undoubtedly improve our understanding of the precise mechanisms of cell death in AMD and facilitate efforts to develop more specific treatment techniques aimed at identified pathological pathways.

project_terms:
aging;bioinformatics;cell cycle proteins;glycation;human tissue;macular degeneration;oxidation;phosphorylation;posttranslational modifications;proteomics;retinal pigment epithelium;two dimensional gel electrophoresis;visual photoreceptor


application_id: 7037009
project_number: 1R01GM072756-01A1
project_title: Dissection and Reconstitution of Human Mismatch Repair
administering_ic: NIGMS
award_notice_date: 2005-12-22
application_type: 1
activity_code: R01
ic: GM
serial_number: 072756
suffix: A1
program_official: PORTNOY, MATTHEW
project_start_date: 2006-01-01
project_end_date: 2009-12-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanism of human mismatch repair (MMR) and its impact on human health and disease. The importance of MMR is underscored by the fact that defects in MMR genes lead to genomic instability and eventually to cancer predisposition. Despite the fact that the excision-step of the human MMR reaction has been recently reconstituted using purified proteins including MutS alpha MutL alpha EXO1 and RPA many fundamental questions in MMR still remain unanswered. For example how mismatch-provoked excision initiates and terminates and what role MutL alpha plays in MMR are unknown. Through the reconstitution of the 5' nick-directed human MMR reaction we found that MutL alpha negatively regulates mismatch-provoked EXO1-catalyzed excision and terminates it immediately upon mismatch removal. Given the dependency of the EXO1-catalyzed mismatch excision on MutS alpha and physical interactions among EXO1 MutS alpha and MutL alpha we hypothesize that mismatch-provoked excision is precisely regulated through interactions among these proteins. Specifically in the presence of a mismatch MutS alpha preferentially interacts with EXO1 to promote excision; but the removal of the mismatch by EXO1 allows EXO1 to preferentially interact with MutL alpha which then terminates the excision. To test this hypothesis a series of EXO1 MutS alpha MutL alpha mutant proteins that disrupt the interaction of EXO1 with one Mut protein but not the other will be constructed expressed and purified. These mutant proteins will be tested in an in vitro reconstitution system for their ability to perform mismatch-provoked excision at the initiation and at the termination. Analysis of the excision intermediates in each reaction will reveal how the interactions among MutS alpha and MutL alpha and EXO1 regulate a particular step of the excision reaction. Finally to understand how efficiently the MMR system terminates mismatch-provoked excision the excision termination sites for heteroduplexes with different sequence contents and distances separating the mismatch and the strand break will be precisely determined. In addition to revealing the molecular mechanism of mismatch-provoked excision this study will provide important clues to understand many puzzling phenomena in mlh1 null mutants regarding 5' directed MMR meiotic cell apoptosis and anti-recombination.

project_terms:
DNA binding protein;DNA repair;exodeoxyribonuclease;genetic transcription;molecular cloning;nucleic acid sequence;phosphoester ligase;protein protein interaction;protein purification;protein structure function;site directed mutagenesis;southern blotting;transcription termination


application_id: 7036311
project_number: 1R01AI064421-01A1
project_title: Analyzing and modulating immunoregulatory defects in autoimmune disease
administering_ic: NIAID
award_notice_date: 2005-12-30
application_type: 1
activity_code: R01
ic: AI
serial_number: 064421
suffix: A1
program_official: RIDGE, JOHN P
project_start_date: 2006-01-01
project_end_date: 2010-12-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimmunity. Although the thymus appears to be a major site of CD4+CD25+ T cell development it is still unclear whether there are also peripheral sites of development. We have found recently that CD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in the periphery. Conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells may be a very important mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenance and a defect in this process could contribute to autoimmune disease development. We have found that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in the thymus but a significantly lower percentage in the periphery. Furthermore NOD CD4+CD25- T cells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function strongly suggesting that NOD mice may have a defect in this conversion process and may therefore be unable to maintain this regulatory population. The central hypothesis of this proposal is that enhanced conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice can prevent diabetes. We will test this hypothesis by studying the mechanisms and defects in conversion in NOD mice determine whether this process can be restored and whether restoration is associated with amelioration of disease. By understanding the defects in conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells in NOD mice it may be possible to devise strategies to overcome these defects and thereby develop therapies to prevent or treat autoimmune disease.

project_terms:
CD28 molecule;CD40 molecule;MHC class II antigen;NOD mouse;antigen presenting cell;developmental immunology;disease /disorder prevention /control;flow cytometry;genetically modified animals;helper T lymphocyte;immunologic memory;immunoregulation;insulin dependent diabetes mellitus;interferon gamma;phenotype;selectins;tissue /cell culture;transforming growth factors


application_id: 7036017
project_number: 1R01HL078976-01A1
project_title: Saturated Fatty Acid and Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2006-03-15
application_type: 1
activity_code: R01
ic: HL
serial_number: 078976
suffix: A1
program_official: ERSHOW, ABBY
project_start_date: 2006-03-15
project_end_date: 2011-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The central hypothesis to be tested in this proposal is that binding of saturated fatty acid to SR-BI activates AMP kinase which results in the production of eNOS-dependent peroxynitrite and subsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heart disease for decades; however numerous studies have demonstrated that the type of fat may be more important than the total amount of fat in the diet. Unsaturated fats such as n-3 and n-6 fatty acids are thought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e. myristic acid and palmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenic in part by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearly influence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorial disease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause an increase in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal is to determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasma cholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acids that involve SR-BI caveolin AMP kinase and eNOS which subsequently results in the generation of the pro- atherogenic compound peroxynitrite. Three specific aims are proposed. Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolin and to determine the domain within caveolin that interacts with SR-BI. Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains within caveolin and AMP kinase that interact. Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fatty acid-induced peroxynitrite production and subsequently atherosclerosis.

project_terms:
adenylate kinase;atherosclerotic plaque;caveolins;cholesterol;dietary lipid;fatty acid binding protein;fatty acid transport;genetically modified animals;laboratory mouse;myristates;nitric oxide synthase;nutrition related tag;palmitates;pathogenic diet;peroxynitrites;phosphorylation;protein structure function;saturated fatty acids;scavenger receptor;tissue /cell culture


application_id: 7035933
project_number: 5K23AA014235-04
project_title: Suppression of CYP2E1 in drug induced liver injury
administering_ic: NIAAA
award_notice_date: 2006-03-17
application_type: 5
activity_code: K23
ic: AA
serial_number: 014235
program_official: VELAZQUEZ, JOSE M
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: ZAA1-DD(01)
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
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):   The long-term career goals are to develop the clinical discipline of pharmacogenomies and the short-term goal is to develop an independent patient-oriented research career focusing on the validation and development of pharmacogenentic diagnostics. Environment: The University of Louisville has adopted pharmacogenetics as one of seven key areas for development. The Pharmacogenetic Diagnostics Laboratory (founded by Dr's Valdes and Linder) is one of the first CLIA certified clinical pharmaeogenetic laboratories in the world. Dr C. McClain (Co-mentor) is Director of the newly established Clinical Research Center at the University of Louisville Hospital. Preliminary findings: Within the proximal promoter of the CYP2E1 gene is a nucleotide sequence (cytokine response element) responsible for gamma-interferon (gamma-IFN)-dependent suppression of gene transcription. A naturally occurring polymorphisrn G(-71)T within this sequence renders the CYP2E1 promoter insensitive to suppression by gamma-IFN. Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter. Polymorphism within the promoter sequence interrupts this feedback and leads to increased toxicity from reactive intermediate products. Approach: To test this hypothesis we will; i) Investigate  the mechanism of IFN-gamma mediated CYP2E1 suppression in humans ii) Evaluate the influence of IFN-gamma on the LD 50 of CYP2E 1 substrates which undergo metabolic bioactivation iii) Characterize the molecular detail of IFN-gamma dependent suppression of CYP2E1 and iv) Evaluate the relationship between the CYP2E1*7B allele and selected human diseases influenced by the catalytic properties ofCYP2E1. Significance: This research will identify a novel mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1. These findings may lead to development of a diagnostic test for identifying susceptible individuals and provide insight into potential therapeutic or preventive approaches.

project_terms:
acetaminophen;clinical research;cytochrome P450;drug metabolism;enzyme activity;enzyme biosynthesis;enzyme induction /repression;free radical oxygen;gel mobility shift assay;gene frequency;genetic polymorphism;genetic promoter element;genetic transcription;hepatotoxin;high performance liquid chromatography;human subject;inflammation;interferon gamma;liver disorder;necrosis;patient oriented research;pharmacogenetics;polymerase chain reaction;protein tyrosine kinase;transfection;western blottings


application_id: 7035753
project_number: 5R01HL062053-08
project_title: Host response to P. carinii in neonatal mice
administering_ic: NHLBI
award_notice_date: 2006-03-07
application_type: 5
activity_code: R01
ic: HL
serial_number: 062053
program_official: PEAVY, HANNAH H
project_start_date: 1990-07-01
project_end_date: 2008-03-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Pneumocystis carinii (PC) pneumonia continues to be a significant problem among immunosuppressed individuals. Moreover neonatal animals have been shown to harbor subclinical PC infections and more recently it has been shown that a significant proportion of human infants also are either infected or colonized with PC. Very little is known about lung immune responses to PC or other fungal pathogens in neonates. We observed that neonatal mice challenged with an intranasal inoculation of PC fail to mount an inflammatory response before about 3 weeks of age whereas adult mice mount a response in a matter of a few days. Our goal in the previous funding period was to determine whether this delay in response was due to immaturity of neonatal lymphocytes or whether the neonatal lung environment is suppressive. We established that neonatal lymphocytes are functional when transferred into an adult lung environment and could stimulate clearance of PC infection. However transfer of adult cells to neonates did not alter the kinetics of inflammation nor clearance of the organisms suggesting that the neonatal lung environment could not support an immune response to PC. There was a significant deficit in the production of proinflammatory cytokines and chemokines in PC-infected neonatal lungs; whereas TGFI3 and IL-10 mRNA were constitutively expressed in neonatal lungs at levels similar to PC-infected adult lungs. These data suggested that the growth factors involved in postnatal lung development may also be immunosuppressive. For this proposal we have chosen to focus on this immunosuppressive lung environment with the goal of determining whether there is active suppression of inflammation in postnatally developing lungs. We hypothesize that the neonatal lung environment impacted on by growth factors and innate immune cells is immunosuppressive toward inflammatory responses against PC. This results in suppressed proinflammatory cytokine and chemokine production and delayed clearance of organisms. The following aims are designed to address this hypothesis: 1) to determine whether lung developmental growth factors are expressed at the protein level in response to PC in infant mice; 2) to determine whether immaturity of innate immune cells and mediators in the lungs suppress immune responses to PC; and 3) to determine whether interruption of negative regulators of immune function in neonatal lungs will promote inflammatory responses to PC. Very little is known regarding the development of immunity in the lungs and understanding this process is vital for protecting young children from potentially life-threatening infections.

project_terms:
Pneumocystis carinii;Pneumocystis pneumonia;SCID mouse;age difference;alveolar macrophages;biological signal transduction;cell surface receptors;confocal scanning microscopy;corticosterone;dendritic cells;developmental immunology;disease /disorder model;gene expression;growth factor;immune response;immunocytochemistry;immunofluorescence technique;immunosuppression;inflammation;interleukin 10;laboratory mouse;lung development;newborn animals;transforming growth factors


application_id: 7035369
project_number: 5R01HL068509-05
project_title: HIV Protease Inhibitors and Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2006-03-13
application_type: 5
activity_code: R01
ic: HL
serial_number: 068509
program_official: MCDONALD, CHERYL
project_start_date: 2002-04-15
project_end_date: 2007-03-31
study_section: AIDS and Related Research 6[AARR-6]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION: (provided by applicant) We hypothesize that HIV protease               inhibitors alter macrophage class B scavenger receptor-dependent uptake and         efflux of cholesterol thereby promoting the formation of lipid-laden                macrophages and atherosclerotic lesions. A major drawback to the use of HIV         protease inhibitors is that they promote the development of dyslipidemia which     is an established risk factor for the development of atherosclerosis. Numerous      reports have suggested a causal link between protease inhibitor therapy and         atherosclerosis; however this has not been unequivocally demonstrated in a         large-scale clinical trial. The dyslipidemia which is primarily an increase in     triglycerides is unlikely to completely account for the development of             atherosclerotic lesions in HIV patients because atherosclerosis is a                multifactorial disease that is not controlled by a single factor. Our               preliminary data demonstrate that HIV protease inhibitors have direct effects       on macrophages which are critical cellular mediators in atherosclerotic lesion     development. The generation of lipid-laden macrophages is a key event in            atherogenesis and is thought to be due in part to unregulated uptake of           modified lipoproteins. Such aberrant cholesterol accumulation is influenced by      the functions of the class B scavenger receptors SR-BI and CD36. Both              receptors are found in atherosclerotic lesions and on macrophages. In addition     both receptors can mediate the uptake of lipoprotein cholesterol and the efflux     of cellular cholesterol. Our preliminary data demonstrate that peritoneal           macrophages isolated from LDL receptor null mice given the HIV protease             inhibitors amprenavir indinavir or ritonavir contain more SR-BI and CD36        than aged-matched controls. In addition all three protease inhibitors              increased SR-BI and CD36 levels in THP-1 cells our macrophage cell model           system. The protease inhibitors also increased the cellular cholesterol content     in both the in vivo and in vitro model systems which is consistent with our        hypothesis. Importantly mice given amprenavir indinavir or ritonavir had         significantly more atherosclerotic lesions than control mice. We will test two      Specific Aims. Aim 1 : To determine the effects of HTV protease inhibitors on       SR-BI and CD36 dependent cholesterol uptake and efflux. Aim 2: To determine the     leukocyte (i.e. macrophages etc.) specific effects of HIV protease inhibitors     on atherosclerotic lesion formation in LDL receptor null mice that have been        transplanted with bone marrow from SR-BI x LDLR and CD36 x LDLR null mice.

project_terms:
amprenavir;antiAIDS agent;antiatherogenic agent;atherosclerosis;atherosclerotic plaque;blocking antibody;bone marrow transplantation;cardiovascular disorder risk;cholesterol;drug adverse effect;genetically modified animals;high performance liquid chromatography;hypertriglyceridemia;indinavir;laboratory mouse;low density lipoprotein receptor;macrophage;protease inhibitor;receptor binding;receptor expression;ritonavir;scavenger receptor;tissue /cell culture;virus infection mechanism


application_id: 7034599
project_number: 5R43DK070374-02
project_title: A Uroguanylin Based ELISA for Salt Sensitivity
administering_ic: NIDDK
award_notice_date: 2006-06-02
opportunity_number: PA-03-123
application_type: 5
activity_code: R43
ic: DK
serial_number: 070374
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2005-04-01
project_end_date: 2007-03-31
study_section: Special Emphasis Panel[ZRG1-RUS-B(10)B]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: Pewee Valley
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: This proposal is submitted in response to the program announcement PA-03-123 "Development of diagnostic screening test for salt sensitivity (SBIR/STTR)" from the National Institute of Diabetes and Digestive and Kidney Diseases. The overall hypothesis of our laboratory is the principle that NaCl homeostasis is maintained in part by an entero-renal endocrine axis in which renal NaCI excretion is rapidly regulated by uroguanylin (UGN) and guanytin (GN) to altered NaCI intake AND that these intestinally-derived peptides can fhodulate acute renal function in response to oral NaCi loads. It is well established in both humans and in experimental animals that orally-administered NaCI loads can be excreted more rapidly (within four hours) than equivalent salt loads administered intravenously suggesting that an enteric factor may be capable of acute-regulation of renal function. Evidence from this and other laboratories suggests that UGN and GN are involved in and contribute to this response. However methods to quantitatively and routinely determine the levels of UGN GN and their pro-hormones in biological fluids (i.e. serum urine) have not been developed. Thus lack of the reagents required for the quantitative assessment of these peptides has limited our knowledge of their role in pathologic conditions such as saltsensitive hypertension congestive heart failure and edema. To establish proof of principle we will in Aim 1 develop monoclonal antibodies to UGN to be used in a quantitative capture ELISA for murine UGN. In Aim 2 we will validate this ELISA in a mouse model developed in our laboratory in which the renal response and the serum and urinary levels of UGN will be measured prior to and after (1) intravenous doses of UGN and (2) intra-gastric (oral) salt loading; UGN wiH be measured by ELISA and confirmed by HPLC and Western blotting. We predict that the development of this quantitative ELISA will allow us to determme the rote of guanylin peptides in the acute renal response to oral NaCI  loading.

project_terms:
analytical chemistry;clearance rate;diagnosis design /evaluation;diagnostic tests;dietary sodium;enzyme linked immunosorbent assay;gastrointestinal hormones;guanylate cyclase;high performance liquid chromatography;intravenous administration;kidney function;laboratory mouse;monoclonal antibody;oral administration;peptide hormone;sodium chloride;technology /technique development;western blottings


application_id: 7033929
project_number: 5R01ES011594-04
project_title: Metabolism and Detoxification of Base Propenals
administering_ic: NIEHS
award_notice_date: 2006-03-30
application_type: 5
activity_code: R01
ic: ES
serial_number: 011594
program_official: THOMPSON, CLAUDIA L
project_start_date: 2003-06-01
project_end_date: 2008-03-31
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
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): The long-term goal of this project is to elucidate the metabolic pathways that regulate the cytotoxic and mutagenic potential of base propenals (BP) generated from oxidant-induced DNA damage. BP are derived from selective hydrogen abstraction from C4' of the deoxyribose ring and their formation leads to strand scission. High concentrations of BPs are generated by anticancer drugs such as bleomycin and environmental agents such as Cr (VI). BPs have also been detected in normal untreated human cells suggesting that they are produced from background DNA damage. The BPs are highly reactive unsaturated aldehydes which readily attack cellular nucleophiles such as glutathione and guanine. At high concentrations BPs are cytotoxic and cytostatic whereas at low concentrations they form potentially mutagenic DNA adducts. Propenal-derived DNA adducts have been detected in high abundance in normal and cancerous human tissues and it has been suggested that they are derived mainly from BPs originating from oxidant-mediated DNA damage. Nonetheless the metabolic processes that regulate the cytotoxic and mutagenic potential of BPs are not well understood. Based on our preliminary data and literature evidence we propose that glutathione S-transferase (GSTP1-1) and aldose reductase (AR) are the major enzymes that participate in the metabolism of base propenals and that the sequential biotransformation by these enzymes prevents the toxicity and mutagenicity of base propenals. To test this hypothesis we will identify the major cellular and urinary metabolites of base propenals generated by COS-7 and HepG2 cells or mice exposed to radiolabeled adenine and thymine propenals (Aim 1). Next we will delineate the contribution of AR and GSTP1-1 to the overall metabolism of base propenals using pharmacological and molecular strategies and elucidate the metabolism of propenal in AR-inhibitor treated or GSTP1-1 null mice (Aim 2). To test the catalytic efficiency of AR and GSTP1-1 we will examine their steady-state kinetic properties and determine whether product or substrate inhibition limits propenal metabolism via this pathway (Aim 3). Finally to delineate the role of GSTP1-1 and AR in preventing the acute toxicity of base propenals and their ability to form DNA adducts (Aim 4) we will test whether inhibition or overexpression of these enzymes prevents base propenal cytotoxicity and adduct formation and whether the mutagenic burden due to base propenal exposure is altered in GSTP1-1-null or AR inhibitor-treated mice. The results of these studies will provide a better understanding of the cytotoxic effects of DNA degradation products and the mechanism by which they indirectly induce potentially mutagenic DNA lesions. Our results may also help in designing more effective and targeted anticancer interventions and could lead to the identification of organ systems and individuals more sensitive to endogenous and environmental oxidants.

project_terms:
DNA damage;adduct;aldehyde reductase;biotransformation;cytotoxicity;detoxification;electrospray ionization mass spectrometry;enzyme activity;enzyme inhibitors;genetically modified animals;glutathione transferase;high performance liquid chromatography;laboratory mouse;tissue /cell culture;toxin metabolism


application_id: 7032986
project_number: 5R01HL074369-03
project_title: Monocarboxylate transporter in hypoxic preconditioning
administering_ic: NHLBI
award_notice_date: 2006-03-09
application_type: 5
activity_code: R01
ic: HL
serial_number: 074369
program_official: DENHOLM, ELIZABETH M
project_start_date: 2004-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-ALTX-4(02)M]
contact_pi_person_id: 1885973
contact_pi: WANG, YANG
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Tissue/organ hypoxia impacts on the progression and outcome of a variety of human disorders whereas environmental hypoxia threatens the life of healthy individuals such as high altitude sojourners. We have recently discovered a novel protective mechanism in unacclimatized mice that significantly prolongs survival of these animals when exposed to lethal hypoxia. The robust protection was induced by a simple procedure of whole-body hypoxic preconditioning (WHPC) became effective shortly after the induction and was accompanied by improved organ functions in the lung including reduced lung cytotoxicity vascular permeability and pulmonary edema and ameliorated gas-exchange function. Further we found that the lung consumed lactate under both normoxic and hypoxic conditions and that WHPC enhanced the uptake and metabolism of lactate in the lung. This enhancement appeared to depend on the upregulation of monocarboxylate transporter 2 (MCT2) a member of the transporter gene family responsible for lactate movement across the cellular and the mitochondrial membranes. We therefore hypothesize that WHPC protects the entire organism against hypoxia by improving organ functions in the lung and that the latter results from enhanced capacity of the lactate-metabolism machinery in this organ. To test this hypothesis we will (1) characterize the beneficial effect of WHPC on cellular integrity by measuring overall cytotoxicity markers and cell-specific markers for endothelial and epithelial cells. We will also examine whether the beneficial effect of WHPC on cellular integrity is correlated with tissue ATP content in the lung; (2) determine the role of lactate in energy metabolism in the lung by exploring lactate and glucose kinetics in the lung under normoxic and hypoxic conditions with or without WHPC. We will also examine whether disruption of lactate metabolic pathway attenuates the protective effects of WHPC; (3) delineate temporal expression patterns of MCT2 under normoxic and hypoxic conditions with or without WHPC pretreatment We will also delineate spatial expression patterns of MCT2 at the cellular and the subcellular levels; and (4) establish a cause-effect relationship between the upregulation of MCT2 and the protection afforded by WHPC by examining whether inhibition of MCT2 using pharmacological agents and siRNA-mediated gene silencing attenuates the protective effects of WHPC and whether overexpression of MCT2 in a transgenic mouse model mimics the protective effects of WHPC. Insights into the cellular and molecular basis of WHPC will underpin future efforts for exploiting this protective mechanism for therapeutic purposes.

project_terms:
adenosine triphosphate;bioenergetics;carboxylate;cytoprotection;gene expression;genetic regulation;genetically modified animals;glucose transport;ischemic preconditioning;laboratory mouse;lactates;lung ischemia /hypoxia;mitochondrial membrane;small interfering RNA;transport proteins


application_id: 7032436
project_number: 5K02AI059023-03
project_title: T CELL ADJUVANTS FOR BIODEFENSE
administering_ic: NIAID
award_notice_date: 2006-03-08
application_type: 5
activity_code: K02
ic: AI
serial_number: 059023
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2004-03-01
project_end_date: 2009-02-28
study_section: Allergy, Immunology, and Transplantation Research Committee[AITC]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Significance of the research. Vaccination with recombinant proteins is the safest way to immunize people against biological weapons and infectious diseases. However the use of mild adjuvants with low levels of inflammatory side effects that make subunit vaccines desirable for immunization may also be responsible for their relatively poor efficacies. This is true because inflamed environments help promote the survival of activated T cells which in turn promote long-term immunity. It is proposed that identification and description of adjuvant mechanisms that promote T cell survival will improve biodefensive vaccine design by favoring ways to maximize antigen-specific T cell yield while limiting inflammation. Research goals. This K02 application is organized around two research goals to be pursued in tandem over the next five years. The award will make possible Dr. Mitchell's scientific direction of experiments designed to determine i) the mechanisms by which Toll-like receptor (TLR) adjuvants promote T cell immunity via interactions with antigen-presenting cells and ii) the signaling pathways in T cells that result from upstream interactions and that cause prolonged cellular survival. The hypothesis that TLR adjuvants boost the numbers of antigenspecific T cells by improving their survival through activities of the NF-kappaB/IkappaB factor Bcl-3 will be tested.  Multiple aspects of this hypothesis will be tested using mouse models of T cell responses and infectious disease microarray analyses retroviral gene transfer and biochemical analyses of experimentally modified T cells in order to rationally enhance the establishment of immunity. Career development. Dr. Mitchell was first trained as a virologist and then as a T cell immunologist. He has an eight year history of studying the effects of adjuvants on T cells and is poised to make significant advances in this subdiscipline. Career development will occur at the University of Louisville's Department of Microbiology and at the Institute for Cellular Therapeutics a center of excellence where the Mitchell laboratory is housed. The University of Louisville is a state-supported institution with a rapidly expanding basic research program. External salary support will lessen the load of non-research duties such that conceptual advances in vaccine design for biodefense can be made.

project_terms:
BCL2 gene /protein;T lymphocyte;biological signal transduction;enzyme linked immunosorbent assay;flow cytometry;genetic transcription;immune response;immunomodulators;laboratory mouse;lipopolysaccharides;microarray technology;nuclear factor kappa beta;toll like receptor


application_id: 7032289
project_number: 5R01GM042476-16
project_title: Function of snRNP particles in pre-mRNA splicing
administering_ic: NIGMS
award_notice_date: 2006-03-16
application_type: 5
activity_code: R01
ic: GM
serial_number: 042476
program_official: RHOADES, MARCUS M
project_start_date: 1989-07-01
project_end_date: 2008-03-31
study_section: Cell Development and Function 1[CDF-1]
contact_pi_person_id: 1898350
contact_pi: RYMOND, BRIAN C.
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): The pre-mRNA transcripts of most mammalian genes contain multiple introns that must be precisely removed before the mRNA can be used in protein synthesis. For many genes this pre-mRNA splicing reaction is regulated by developmental or environmental signals. Errors in the splicing pathway can have devastating health consequences and account for approximately 15% of all known human genetic disorders. The diagnosis and treatment of splicing-related disorders will profit by a better understanding of the cellular rules governing intron removal. The pre-mRNA splicing enzyme or spliceosome is a large ribonucleoprotein complex composed of over 70 proteins and 5 small nuclear RNAs. A widely cited model of spliceosome assembly activation and disassembly (or the spliceosome cycle) has evolved from the results of in vitro experimentation conducted over the last 15 years. The modulation of splicing efficiency and alterative splice site selection often can be explained by changes in spliceosome assembly observed in the presence or absence of specific regulator proteins (or cis-acting elements). The recent isolation from yeast of a U2U5U6 ribonucleoprotein (RNP) complex reminiscent of a late stage or post-catalytic spliceosome supports this spliceosome cycle model. In contrast the identification of what appears to be a fully assembled but pre-mRNA-free "penta-snRNP" spliceosome from yeast raises the question of whether spliceosome disassembly actually occurs in vivo. We will address this apparent discrepancy by tests of two hypotheses. First that a spliceosome cycle occurs within cells and progresses through a series of splicing factor-dependent assembly and disassembly steps. Second that the Clf1p assembly factor facilitates integration of the prespliceosome with the U4/U6.U5 tri-snRNP particle through branchpoint reorganization that includes the recruitment of RNA export factors. This work will provide new experimental tools for the analysis of RNA processing and generate conceptual frameworks from which to view spliceosome assembly and the integration of the pre-mRNA splicing and RNA export pathways in living cells.

project_terms:
RNA splicing;fungal genetics;intermolecular interaction;introns;microarray technology;molecular assembly /self assembly;nucleic acid sequence;precursor mRNA;protein structure function;small nuclear ribonucleoproteins;spliceosomes;yeasts


application_id: 7032237
project_number: 5R21AI063052-02
project_title: Proteolytic cleavage of the Hendra virus fusion protein
administering_ic: NIAID
award_notice_date: 2006-02-13
opportunity_number: PA-03-080
application_type: 5
activity_code: R21
ic: AI
serial_number: 063052
program_official: CASSETTI, CRISTINA
project_start_date: 2005-03-15
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1-IDM-G(90)S]
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
project_abstract:
DESCRIPTION (provided by applicant): Hendra virus and the closely related Nipah virus are zoonotic paramyxoviruses with high mortality rates in humans and both have been placed on the NIAID priority pathogens list. The fusion (F) protein of Hendra virus promotes both virus-cell and cell-cell membrane fusion thereby mediating a critical first step in viral infection. This important viral protein undergoes proteolytic cleavage of the precursor form F0 to the disulfide-linked form F1 and F2 a process that has been shown to be required for fusogenic activity of all paramyxovirus F proteins characterized to date. It is clear that the cellular secretory protease furin known to cleave other paramxyovirus F proteins is not involved in proteolytic activation of the Hendra F protein. At present neither the cellular localization of this crucial cleavage event or the identity of the protease involved is known. The long-term objective of this proposed research is to understand the processing of the Hendra F protein and to identify host cell factors involved in these events. The specific hypothesis to be tested is that the protease involved in cleavage of the Hendra F protein represents a novel class of cellular proteases that could serve as a target for anti-viral therapies. In our preliminary results we demonstrate that proteolytic activation occurs in either secretory vesicles budding from the trans-Golgi network or at the cell surface. In addition we find that proteolytic processing is not affected by Ca2+ levels but is extremely sensitive to changes in intracellular pH. The experiments in Aim 1 will identify the cellular location of proteolytic processing of the Hendra F protein and the amino acid sequence requirements for cleavage. The research proposed in Aim 2 is directed towards purification of the protease responsible for proteolytic processing of the Hendra F protein with subsequent identification using N-terminal sequencing or proteomic techniques. This research will provide important information about basic processes within the secretory pathway. In addition identification of the enzyme(s) involved in the proteolytic cleavage of the Hendra and Nipah F proteins will set the stage for development of new antiviral therapies for these recently emerged paramyxoviruses.

project_terms:
Golgi apparatus;Nipah virus;Saccharomyces cerevisiae;Vero cells;acidity /alkalinity;bioterrorism /chemical warfare;cell membrane;chemical cleavage;emerging infectious disease;endopeptidases;enzyme mechanism;equine morbillivirus;fluorescence spectrometry;host organism interaction;immunoprecipitation;membrane fusion;protease inhibitor;protein localization;protein sequence;proteolysis;proteomics;secretory protein;virus infection mechanism;virus protein;zoonosis


application_id: 7032234
project_number: 5R01AI052381-04
project_title: Leukotriene B4 Receptors in Rheumatoid Arthritis
administering_ic: NIAID
award_notice_date: 2006-02-09
application_type: 5
activity_code: R01
ic: AI
serial_number: 052381
program_official: PEYMAN, JOHN A
project_start_date: 2003-03-01
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1-GMA-1(01)Q]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Neutrophils are found in large numbers in rheumatoid synovium and have been suggested to be involved in clinical signs of inflammation and pain associated with RA. Neutrophil activation during host defense and inflammation is mediated by G-protein coupled receptors (GPCRs) for chemoattractants. Leukotriene B4 (LTB4) a potent chemoattractant for neutrophils activates its receptor (BLT-1) to mediate diverse physiological effects in neutrophils. A second LTB4 receptor (BLT-2) with distinct antagonist specificity and tissue distribution was recently described. GPCRs are regulated by receptor phosphorylation leading to desensitization as well as down regulation. We will test the hypothesis that LTB4 acting through the high affinity receptor BLT-1 mediates its effects on neutrophils in RA while LTB4 acting through BLT-2 modulates T-lymphocyte activation and function in RA. The goal of the current studies is to develop comprehensive in vivo and in vitro models to determine the role of LTB4 and the relative contributions of BLT-1 and BLT-2 in the development of murine RA. In specific aim 1 we will define the role of BLT-1 in the development and progression of collagen induced arthritis in the BLT-1 deficient mice we have already generated by targeted gene disruption. In specific aim 2 we will use the well-established RBL-2H3 cell model to determine the differences in signaling desensitization internalization and antagonist specificity of BLT-1 and BLT-2. These studies take advantage of the novel video microscopy and live cell imaging methods we have recently developed.    Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis atherosclerosis RA and asthma. Understanding the precise function of distinct LTB4 receptors in mice deficient in specific receptors and defining the role of these receptors in RA will identify novel targets for therapeutic intervention of RA.

project_terms:
cell surface receptors;chemotaxis;confocal scanning microscopy;gene targeting;genetically modified animals;inflammation;laboratory mouse;leukocyte activation /transformation;leukotrienes;membrane activity;neutrophil;pathologic process;protein structure function;receptor sensitivity;rheumatoid arthritis;video microscopy


application_id: 7032231
project_number: 5R01AI050656-04
project_title: Molecular Mechanisms Controlling KIR Genes in NK Cells
administering_ic: NIAID
award_notice_date: 2006-02-17
application_type: 5
activity_code: R01
ic: AI
serial_number: 050656
program_official: MILLER, LARA R
project_start_date: 2003-09-01
project_end_date: 2008-02-29
study_section: Experimental Immunology Study Section[EI]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Natural killer (NK) cells use killer cell immunoglobulin-like receptors (KIR) to distinguish normal cells from infected and malignant cells. NK cells express an apparently random assortment of KIR genes. Our LONG RANGE GOAL is to use NK cells to treat cancer and infectious diseases. Our CURRENT OBJECTIVE is to identify how developing NK cells initiate and then maintain selective KIR gene expression. Supported by strong preliminary data our CENTRAL HYPOTHESIS is that promoter methylation controls locus-specific and allele-specific KIR gene expression. The RATIONALE for the proposed research is that understanding KIR gene regulation could lead to effective immunotherapy of cancer and infectious diseases. Furthermore our research will test the central paradigm of tissue-specific gene expression. The proposed research is a COLLABORATION between investigators at two universities. The principal investigator has an established record of research in NK ceils immune recognition of HLA class I molecules and molecular biology. The other investigators are leaders in gene expression control and in human NK cell development. The collaboration will produce a synergistic effect that is not easily matched by a single investigator. Our SPECIFIC AIMS are to 1. Test the molecular mechanisms of KIR gene expression control. 2. Define cis acting elements and trans-acting factors that control KIR gene expression. 3. Elucidate how developing NK cells initiate selective KIR gene expression. Our approach is INNOVATIVE. We have produced unique new data and we will combine several cutting-edge research techniques to rigorously test our hypotheses. It is our EXPECTATION that 1) we will develop a clear understanding of how NK cells maintain stable KIR expression; 2) we will define several important cis-acting elements and trans-acting factors that regulate KIR transcription; 3) we will identify what signals developing NK cells use to initiate KIR gene expression. Our results will be highly SIGNFICANT because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Of broader significance elucidation of KIR gene expression control will provide an important model for gene choice in development and offer insights into birth defects and cancer.

project_terms:
antibody receptor;biological signal transduction;clinical research;flow cytometry;gel mobility shift assay;gene expression;gene induction /repression;genetic promoter element;genetic regulatory element;human subject;immunoprecipitation;infection;methylation;molecular genetics;molecular shape;natural killer cells;neoplasm /cancer immunotherapy;nucleic acid probes;polymerase chain reaction;regulatory gene;tissue /cell culture


application_id: 7031875
project_number: 2R01AI044254-06A1
project_title: Analysis of Borrelia burgdorferi Erp Proteins
administering_ic: NIAID
award_notice_date: 2006-03-15
application_type: 2
activity_code: R01
ic: AI
serial_number: 044254
suffix: A1
program_official: PERDUE, SAMUEL S
project_start_date: 2000-03-01
project_end_date: 2011-02-28
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
project_abstract:
DESCRIPTION (provided by applicant): 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 of the novel DNA binding proteins we discovered that specifically bind to erp operator DNA. Results of our studies will provide important insight into the mechanisms by which B. burgdorferi infects humans.

project_terms:
Borrelia;antibacterial antibody;bacteria infection mechanism;bacterial proteins;gene expression;genetic promoter element;genetic regulation;genetic transcription;laboratory mouse;laboratory rabbit;messenger RNA;microorganism culture;nonblood lipoprotein;polymerase chain reaction;ticks;tissue /cell culture


application_id: 7031625
project_number: 5R01CA094853-05
project_title: Mechanisms of Redox Mediated Cardioprotection
administering_ic: NCI
award_notice_date: 2006-03-14
application_type: 5
activity_code: R01
ic: CA
serial_number: 094853
program_official: WOLPERT, MARY K
project_start_date: 2002-04-01
project_end_date: 2009-03-31
study_section: Special Emphasis Panel[ZRG1-PTHC(03)M]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION: (provided by applicant) The goal of this study is to identify          novel mechanisms leading to cardioprotection during cancer treatment. In            cardiac tissue both cytotoxic and cytoprotective actions are implicated in the     action of tumor necrosis factor alpha (TNFalpha). Although a variety of cancer      therapeutic agents have been shown to induce rapid expression of TNFalpha and       both types of TNF receptors (p55 and p75) are expressed in cardiomyocytes the      role of this cytokine and its associated receptors in cardiac response to           cancer therapy is unknown. The anti-estrogen tamoxifen (TAM) has been shown to      have a beneficial effect not only in the reduction of contralateral breast          cancer but also to result in a reduced incidence of heart disease in cancer         patients. Tamoxifen is generally thought to act as an anti-estrogen in breast       cancer to inhibit tumor growth. However the cardioprotective effect observed       in various clinical trials suggests that the mechanism of action of                 anti-estrogens is complex and cannot be described simply as an estrogen lacking     TNF receptors are more sensitive to ADR-induced cardiac injury and that             pre-treatment with TAM results in a dose-dependent reduction of the p75 TNF         receptor and suppression of TNFalpha-induced mitochondrial injury. These            results suggest that low levels of endogenous TNF may be cardioprotective           whereas high levels of TNFalpha are cardiotoxic. We hypothesized that 1)            endogenous TNFalpha serves a cardioprotective role by rapid activation of the       block. Our preliminary data indicate that mutant mice lacking nuclear factor        kappa Beta (NFkBeta) with subsequent induction of protective proteins; 2) high      levels of TNFalpha cause excessive TNF-receptors mediated-induction of              mitochondrial injury; and 3) enhancement of mitochondrial antioxidant capacity      improves TAM-induced cardioprotection. The role of TNFalpha and TAM in cardiac      injury will be established in animals isolated mitochondria and isolated          cardiomyocytes. Genetically modified animals will be used to investigate the        link between TNF/TAM and mitochondrial antioxidant status in cardioprotection.                                                                                          The proposed studies will provide fundamental information concerning the role       of TNF and TAM in cardiac injury. The results should also provide insights into     the link between mitochondrial antioxidant status and TAM. The results could        lead to the development of selective approaches to improve protection of the        heart thus reducing the toxicity of free radical-associated anti-cancer            agents.

project_terms:
antioxidants;cardiac myocytes;cardiotoxin;cytokine receptors;cytoprotection;dosage;doxorubicin;laboratory mouse;mitochondria;nuclear factor kappa beta;oxidative stress;tamoxifen;tissue /cell culture;tumor necrosis factor alpha


application_id: 7031572
project_number: 5R01CA112197-02
project_title: Mutagenesis as a novel target for cancer prevention
administering_ic: NCI
award_notice_date: 2006-03-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 112197
program_official: OKANO, PAUL
project_start_date: 2005-04-01
project_end_date: 2009-02-28
study_section: Chemo/Dietary Prevention Study Section[CDP]
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
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):  The overall aim of this project is to apply new knowledge of fundamental mechanisms of mutagenesis to directly test the somatic mutation hypothesis of cancer and to translate this knowledge into a clinically useful regimen to reduce the incidence of sunlight-associated skin cancer. Mutations in DNA are generally considered to have an etiologic role in the development of cancer but until recently it has not been possible to directly examine the relative contribution of mutagenesis and epigenetic alterations in cellular physiology induced by carcinogen exposure. We hypothesize that mutations induced by ultraviolet light (UV) in the DNA of actively dividing skin cells are causally involved in skin carcinogenesis and reducing the frequency of such mutations will reduce the risk of skin cancer induced by UV. There is now abundant evidence that virtually all mutations induced by UV in eukaryotic cells are dependent on the gene products encoded by the REV1 and REV3 genes. We showed further that targeting the mRNA of one of these genes (REV1) with gene-specific ribozymes virtually abolishes UV mutagenesis. To test our hypothesis we propose to expose newly-developed REV3-depleted transgenic mice to UV. We anticipate that these mice will have a greatly reduced risk of developing skin cancer compared with control animals. Further we propose to translate our data into a practical method to prevent UV-induced skin cancer. We will develop and optimize gene-specific ribozymes expressed in cultured cells using several different systems to target them to the cytoplasm or to the nucleus. Then we propose to deliver such ribozyme expression vectors into mouse skin cells. These ribozymes will specifically target REV1 mRNA a protein that may coordinate the activity of several proteins that are required for the mutagenic replication of UVdamaged DNA. The mice and the appropriate controls will be exposed to UV protocols that are known to induce skin cancer. Our hypothesis predicts that reducing the level of this protein will reduce the mutagenic response of skin cells to UV and will result in a greatly reduced incidence of skin cancer. If so these data will provide the experimental rationale to develop similar strategies to reduce the incidence of skin cancer in humans. Most importantly such a strategy should be successful as a preventive measure after UV exposure and prior to appearance of disease symptoms.

project_terms:
DNA directed DNA polymerase;biotechnology;cancer prevention;chemoprevention;disease /disorder model;enzyme activity;gene delivery system;gene therapy;genetic promoter element;genetically modified animals;laboratory mouse;lipids;mutagens;neoplasm /cancer genetics;nonhuman therapy evaluation;plasmids;radiation carcinogenesis;reporter genes;ribozymes;skin neoplasms;therapy design /development;tissue /cell culture;transfection /expression vector;ultraviolet radiation


application_id: 7031570
project_number: 5R01CA113735-02
project_title: Development of Nucleolin targeted Anticancer Compounds
administering_ic: NCI
award_notice_date: 2006-03-28
application_type: 5
activity_code: R01
ic: CA
serial_number: 113735
program_official: LEES, ROBERT G
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-04-01
project_terms:
analytical ultracentrifugation;antineoplastics;chemical binding;chemical stability;chemical structure function;conformation;drug design /synthesis /production;nuclear magnetic resonance spectroscopy;nuclear proteins;nucleolus;oligonucleotides;phosphoproteins;solubility;thermodynamics


application_id: 7031532
project_number: 5R01AI051476-05
project_title: Spread of HSV-1 mediated by the gD receptor nectin-1
administering_ic: NIAID
award_notice_date: 2006-02-23
application_type: 5
activity_code: R01
ic: AI
serial_number: 051476
program_official: BEISEL, CHRISTOPHER E
project_start_date: 2002-09-30
project_end_date: 2008-02-28
study_section: Virology Study Section[VR]
contact_pi_person_id: 7875122
contact_pi: GERAGHTY, ROBERT JAMES
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: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infection of epithelial cells often leads to spread of virus within the epithelium and to neurons for the establishment of a latent infection. Reactivation results in spread of virus from neurons back to epithelial cells. The virus can spread destructively in an epithelium often in the presence of neutralizing antibodyresulting in the formation of a characteristic lesion. HSV spreads from an infected cell to an uninfected cell in three ways. First extracellular virus binds cell-surface receptors on the adjacent cell and enters by fusion of the viral and cellular membranes (viral entry). Second viral glycoproteins on the surface of the infected cell induce fusion with adjacent uninfected cellsresulting in giant-multinucleated cells called syncytia (cell fusion). The third form of viral spread occurs between contiguous cells in the presence of neutralizing antibody and absence of syncytium formation (cell-cell spread). A cell-surface gD receptor such as nectin-1 is required for all three forms of spread. The long term objective of these studies is to characterize themechanisms of all three forms of nectin-1-dependent viral spread. We hypothesize that the structural features of nectin-1 that are critical for these three activities (and therefore the mechanisms) may differ particularly for cell-cell spread. To test this hypothesis we will identify domains of nectin-1 that are important for cell fusion and cell-cell spread. We willfurther characterize the mechanism of cell-cell spread by examining the functional requirements of adherens-junction proteins for efficient cell-cell spread in epithelial cells. The results of these studies when compared and contrasted with previous work in viral entry will elucidate nectin-1-mediated events at the cell membrane during viral spread. These results are importantfor the characterization of viral spread in an epithelium and may also be important for the characterization of spread of virus to neurons and interneuronal spread. Results from these studies will contribute to the understanding of viral spread in human and animal herpesviruses.

project_terms:
cadherins;cell cell interaction;cell fusion;epithelium;gene mutation;herpes simplex virus 1;membrane proteins;protein sequence;tissue /cell culture;transfection;virus infection mechanism;virus receptors


application_id: 7031475
project_number: 2R01HL055477-10A1
project_title: Toxicity and Detoxification of 4Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2005-12-31
application_type: 2
activity_code: R01
ic: HL
serial_number: 055477
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2010-12-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although several studies suggest that myocardial injury during ischemia/reperfusion is in part due to reactive oxygen species the mechanisms by which these oxidants injure the heart and those by which the heart protects itself from their effects are not known. We propose that the myocardial effects of oxidative stress are mediated in part by 4-hydroxyalkenals such as 4-hydroxy-trans-2-nonenal (HNE) which are derived from oxidation of lipoproteins and membrane lipids. Our previous work has led to the identification of the major biochemical pathways of HNE detoxification in cardiovascular tissues. These results suggest that aldose reductase (AR)-catalyzed reduction of HNE and its glutathione conjugate is a particularly critical step in this metabolism because inhibition of AR increases HNE accumulation in the ischemic heart and abolishes the cardioprotective effects associated with the late phase of ischemic preconditioning (PC). Based on these observations and our preliminary data we now plan to test how the ischemic heart metabolizes HNE and whether this is facilitated by the activation of AR due to nitric oxide (NO) generated during ischemia. Using both ex vivo and in situ murine models of myocardial ischemia-reperfusion injury we will identify ischemic changes in AR and HNE metabolism and identify the chemical nature of AR modification and the oxidants and triggers that induce it (Aim 1). In addition we will determine the role of endothelial and inducible NO synthases (NOS) in activating AR and increasing HNE detoxification in the ischemic heart using mice deficient in individual NOS isoforms or overexpressing inducible NO synthase in the heart (Aim 2). To understand the mechanisms of AR-mediated cardioprotection we will examine changes in the mitochondria and myocardial survival signaling (Aim 3) and elucidate how pharmacologic inhibition of AR or cardiospecific overexpression of AR (or its murine homolog FR-1) affects ischemia-reperfusion-induced mitochondrial permeability transition and NF-kappaB activation (Aim 3). Successful completion of this project will lead to a better understanding of mechanisms of cardioprotection due to ischemic PC and NO and could form the basis of new clinical approaches to limit myocardial infarction. Delineation of the contribution of specific enzymes to HNE metabolism in the ischemic heart will be useful in identifying population subgroups that may be highly susceptible to oxidative stress caused by cardiovascular disease.

project_terms:
adduct;aldehyde dehydrogenases;aldehyde reductase;aldehydes;biological signal transduction;cardiac myocytes;cardiotoxin;cytotoxicity;detoxification;electrospray ionization mass spectrometry;gene expression;high performance liquid chromatography;immunoprecipitation;ischemic preconditioning;laboratory mouse;matrix assisted laser desorption ionization;molecular pathology;myocardial ischemia /hypoxia;nitric oxide;oxidative stress;peroxidation;protein kinase C;protein localization;protein purification;proteomics;reperfusion


application_id: 7030979
project_number: 5R37AG004542-20
project_title: HIPPOCAMPAL SYNAPTIC STRUCTURE--PHYSIOLOGY DURING AGING
administering_ic: NIA
award_notice_date: 2006-03-14
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1998-01-01
project_end_date: 2008-02-28
study_section: NSS
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-15
project_terms:
aging;brain electrical activity;calcium channel;calcium ion;cell death;confocal scanning microscopy;electrophysiology;hippocampus;laboratory rat;membrane potentials;membrane structure;neural degeneration;neural plasticity;neurons;neurophysiology;neurotoxins;synapses;synaptic vesicles;tissue /cell culture;voltage /patch clamp


application_id: 7029002
project_number: 5R01HD042451-04
project_title: Development of Perceptual Organization in Infancy
administering_ic: NICHD
award_notice_date: 2006-02-27
application_type: 5
activity_code: R01
ic: HD
serial_number: 042451
program_official: FREUND, LISA S
project_start_date: 2003-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-6(03)M]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Pattern perception and organization provide the representations that form the basic processing units in the visual cognition system of adults. The overall aim of the proposed research is to investigate the origins and development of such perceptual organization abilities in infants. Specifically we are concerned with the very beginnings of perceptual unit formation and the operation of a variety of organizational principles during the first months of life. The research proposal describes a number of experiments that rely on visual preference procedures to study the organization of arrays of visual elements by young infants. The experiments seek to determine: (1) Which grouping principles lead to organized representations of visual pattern information? (2) Do some principles consistently take precedence over others thereby suggesting a hierarchy of rule use in the development of perceptual organization? (3) Can the principles work in an additive fashion thus suggesting a kind of threshold model for perceptual unit formation? (4) What is the time course of development for each of the various principles? Are the individual principles yoked or do they have independent developmental trajectories? And (5) What are the developmental factors (i.e. maturation experience) that affect the emergence of the different grouping principles? The significance of the proposed research is that it will provide knowledge about how perceptual units are formed their nature and their ontogenesis as well as how representations of visual pattern information by adults arise from the perceptual units of infants. In short this research will inform us about the formation of the coherent representations of visual patterns that form the basic functional units of human cognition. Knowledge about the development of this fundamental mental ability will also provide insights into understanding deviations from the normal course of perceptual-cognitive development.

project_terms:
behavioral /social science research tag;brightness discrimination;clinical research;cognition;cues;form /pattern perception;human subject;infant human (0-1 year);mathematical model;neural information processing;vision tests;visual feedback;visual perception;visual stimulus


application_id: 7027938
project_number: 1R01DK073586-01
project_title: Prolonged Diabetic Damage to Cardiac Mitochondria
administering_ic: NIDDK
award_notice_date: 2006-01-02
opportunity_number: RFA-DK-05-001
application_type: 1
activity_code: R01
ic: DK
serial_number: 073586
program_official: JONES, TERESA L Z
project_start_date: 2006-01-15
project_end_date: 2009-12-31
study_section: Special Emphasis Panel[ZDK1 GRB-N (O1)]
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):   In diabetic patients complications such as cardiomyopathy develop over many years of hyperglycemia. We are proposing that the prolonged time course stems from the gradual accumulation of damage to mitochondrial DNA caused by increased mitochondrial generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). For several reasons mitochondrial DNA is especially vulnerable to damage and some types of damage are poorly repaired. We hypothesize that mitochondrial DNA damage is causal for cellular and organ dysfunction in the diabetic state. Our laboratory developed the OVE26 mouse model of Type I diabetes optimal for following chronic development of complications. Cardiac mitochondria from long-term diabetic OVE26 mice exhibit morphological degeneration decreased glutathione content and increased DNA damage. Transgenic mice with increased activity of the mitochondrial antioxidant MnSOD targeted to the heart when crossed onto the OVE26 background show less contractile dysfunction improved mitochondrial morphology and a significant improvement in mitochondrial respiration. We propose that MnSOD overexpression suppresses damage to the mitochondrial genome and that this accounts for improved cardiomyocyte function. To test the hypothesis that progressive mitochondrial DNA damage by ROS or RNS contributes to the development of diabetic cardiomyopathy we will carry out the following Specific Aims: Aim 1: Evaluate mutations and deletions in mitochondrial DNA and correlate these changes with mitochondrial respiratory function electron  ROS generation and cardiomyocyte contractility. Aim 2: Determine if there is a cause and effect relationship between mitochondrial DNA damage and diabetic cardiomyopathy. On the OVE26 diabetic background mitochondrial DNA will be protected by cardiac overexpression of MnSOD and mitochondrial targeted OGG1. We will also determine whether both DNA damage and diabetic cardiomyopathy are exacerbated by crossing existing OGG1 knockout animals to our diabetic mice. Aim 3: Assess whether systemic therapy with agents that bind free transition metals can prevent superoxide from forming more reactive species that damage mitochondrial DNA. Results of these investigations may be directly applicable to the development of new therapies which minimize or absolutely prevent certain diabetic complications.

project_terms:
DNA damage;cardiac myocytes;cardiovascular disorder prevention;cell morphology;chemical binding;chemoprevention;chronic disease /disorder;diabetic cardiomyopathy;electron transport;free radical oxygen;gene deletion mutation;gene expression;gene mutation;genetically modified animals;heart contraction;heart disorder chemotherapy;laboratory mouse;metal oxide;mitochondrial DNA;mitochondrial disease /disorder;muscle contraction;nitrogen oxides;nonhuman therapy evaluation;oxidative stress;respiratory function;superoxides


application_id: 7027052
project_number: 5R01NR008567-03
project_title: Biobehavioral Intervention in Heart Failure
administering_ic: NINR
award_notice_date: 2006-02-15
application_type: 5
activity_code: R01
ic: NR
serial_number: 008567
program_official: HUSS, KAREN
project_start_date: 2004-06-01
project_end_date: 2009-02-28
study_section: Nursing Science: Adults and Older Adults Study Section[NSAA]
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Heart failure has been called the most important public health problem facing cardiovascular clinicians and researchers because of its high and increasing incidence prevalence morbidity and mortality.  Despite substantial advances in pharmacologic therapy made in recent years clinical improvements seen among patients are relatively modest and quality of life often remains poor.  Nonpharmacologic therapy has received relatively little attention yet has potential to serve as an important adjunct to pharmacologic therapy.  Biofeedback-relaxation a cognitive biobehavioral nonpharmacologic intervention has been demonstrated to be effective in conditions with pathophysiological and psychological manifestations of heart failure.  Accordingly specific aims of this project are to determine the impact of biofeedback-relaxation training on 1) the combined primary end-point of heart failure rehospitalizations or cardiac mortality 2) quality of life; 3) intermediate (mediating) patient outcomes of perceived control anxiety and depression and 4) intermediate (mediating) physiologic outcomes of finger and foot skin temperature heart rate variability and plasma norepinephrine.  We hypothesize that biofeedback-relaxation training will result in decreased heart failure rehospitalizations or cardiac death improved quality of life increased perceived control decreased anxiety and depression increased finger and foot temperature improved heart rate variability and decreased plasma norepinephrine.  To test these hypotheses 420 patients with advanced heart failure will be randomized to one of three groups: 1) biofeedback-relaxation (intervention); 2) sham biofeedback-relaxation (placebo-control); or 3) usual care control.  Within these groups patients will be stratified such that each group will include 50% taking and 50% not taking angiotensin converting enzyme inhibitors.  Data will be collected at baseline 3 and 12 months and will be analyzed using survival analyses and repeated measure ANOVA.  Biofeedback-relaxation training for patients with heart failure may have potential long-term clinical benefits and may serve as an important adjunct to pharmacologic therapy.

project_terms:
ACE inhibitors;anxiety;autogenic training;behavioral /social science research tag;biofeedback;clinical research;cognitive behavior therapy;depression;heart failure;heart rate;hospital length of stay;hospital utilization;human subject;human therapy evaluation;locus of control;norepinephrine;patient oriented research;quality of life;relaxation;temperature


application_id: 7027022
project_number: 5R01HL036597-19
project_title: Pleural Liquid Exchange and Lung Mechanics
administering_ic: NHLBI
award_notice_date: 2006-03-09
application_type: 5
activity_code: R01
ic: HL
serial_number: 036597
program_official: DENHOLM, ELIZABETH M
project_start_date: 1995-07-01
project_end_date: 2008-03-31
study_section: Respiratory Physiology Study Section[RESP]
contact_pi_person_id: 1862938
contact_pi: LAI-FOOK, STEPHEN J
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
budget_start_date: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this research is to study some factors that contribute to the formation of pleural liquid. The primary function of pleural liquid is lubrication of the pleural surfaces during breathing. Thus the mechanisms by which pleural liquid is formed in and cleared from the pleural space are important to understanding the pathogenesis of diseases such as pleural effusions and pleural adhesions. Our recent studies in the excised rat diaphragm showed transport properties similar to those of pleural and other interstitial membranes and suggested that part of the pleural liquid might be derived from the peritoneal cavity via the diaphragm. Studies by other investigators have suggested a role for active mesothelial transport of liquid and protein. This proposal focuses on two areas. One is the contribution to pleural liquid and protein from the peritoneal cavity via the diaphragm relative to the contribution from the microcirculation. The transport of radioactive tracer albumin from the circulation into the pleural space diaphragm and peritoneal cavity will be measured in conscious rats. Other experiments will study transport from the peritoneal cavity into the diaphragm circulation and pleural space. The effect of hypertension on transport will be studied using spontaneously hypertensive rats and its genetic normotensive control the Wistar-Kyoto rat. The second area of research deals with the contribution of active transport of liquid and protein across pleural membrane relative to passive transport by diffusion and bulk flow. The pericardial membrane and diaphragm will be studied because these tissues are free standing unlike the visceral and parietal pleurae that need to be stripped for in vitro studies. A specific objective is to develop a method to separate passive from active transport properties of pericardium and diaphragm tissues that have both mesothelium and interstitium.

project_terms:
active transport;albumins;biological transport;biomechanics;diaphragm;electron microscopy;fluid flow;ion transport;laboratory rabbit;laboratory rat;lung;mathematics;passive transport;pericardium;peritoneal cavity;peritoneal fluid;protein transport;radiotracer;respiratory circulation;scintillation counter;transcytosis


application_id: 7025749
project_number: 5R01CA104333-02
project_title: DNA Mismatch Repair Deficiency and Leukemia Relapse
administering_ic: NCI
award_notice_date: 2006-03-02
application_type: 5
activity_code: R01
ic: CA
serial_number: 104333
program_official: OKANO, PAUL
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7956619
contact_pi: GU, LIYA
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: 2006-04-01
project_terms:
DNA repair;acute myelogenous leukemia;chemical stability;clinical research;drug adverse effect;human tissue;molecular oncology;neoplasm /cancer chemotherapy;neoplasm /cancer genetics;neoplasm /cancer relapse /recurrence;neoplasm /cancer remission /regression;neoplastic cell;nucleic acid sequence;point mutation;polymerase chain reaction;recombinant proteins;single strand conformation polymorphism;site directed mutagenesis;transfection /expression vector


application_id: 7025002
project_number: 5R01AG009862-15
project_title: Independent and Dependent Life in the Elderly
administering_ic: NIA
award_notice_date: 2006-02-23
application_type: 5
activity_code: R01
ic: AG
serial_number: 009862
program_official: ANDERSON, DALLAS
project_start_date: 1990-09-01
project_end_date: 2009-02-28
study_section: Special Emphasis Panel[ZRG1-EDC-3(01)S]
contact_pi_person_id: 1894348
contact_pi: SNOWDON, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): This grant application is a continuation       of a longitudinal study of aging and Alzheimer's disease in a defined               population of 678 Catholic sisters who were 75 to 102 years old when the study      began in 1991. By the end of 2001 approximately 250 survivors will range in        age from 85 to as old as 107 years. The continuation of the Nun Study will          provide valuable data on the oldest old (85+) the fastest growing segment of       the American population.                                                                                                                                                Early and late life risk factors documented in convent archives annual             assessments of cognitive and physical function and brain donation by all           participants make the Nun Study a unique resource. Because of the high level of     homogeneity of adult lifestyles many factors that confound other epidemiologic     studies will be eliminated or minimized such as smoking occupation               reproductive history and access to health care. More than ten years of             extensive data collection provide us with the opportunity to describe the           natural history of cognitive dysfunction from intact cognitive status to mild      cognitive impairment to early and late stages of dementia. At the other            extreme our data allow us to investigate the determinants of survival and          successful aging in the very old. Our study also is enhanced by combining the       gross and microscopic findings from autopsies with data from postmortem MR          images.                                                                                                                                                                 Aim I. Mild cognitive impairment: Identify risk factors for both the                development of mild cognitive impairment and its conversion to dementia.            Determine if the risk factors for the development of mild cognitive impairment      are different from those for the conversion to dementia.                                                                                                                Aim II. Alzheimer's disease and dementia: Determine why some individuals with       relatively little neuropathology succumb to the clinical manifestations of          dementia while others with severe neuropathology do not develop dementia.          Furthermore describe how this difference in the clinical expression of             neuropathology is due in part to early life factors as well as increasing age.                                                                                          Aim Ill. Successful aging and longevity: Describe the relationship of               Alzheimer's and cerebrovascular pathology to successful aging and longevity        and the role early life factors play in this relationship.

project_terms:
Alzheimer&apos;s disease;aging;apolipoprotein E;cerebrovascular disorders;clinical research;cognition disorders;dementia;disease /disorder proneness /risk;education;functional ability;hippocampus;human old age (65+);human subject;human very old age (85+);language;lifestyle;longevity;longitudinal human study;magnetic resonance imaging;memory;neuritic plaques;neuroanatomy;neurofibrillary tangles;postmortem;prognosis;synaptophysin


application_id: 7024607
project_number: 5R01AA013853-04
project_title: Transdermal Codrugs for Treatment of Alcoholism
administering_ic: NIAAA
award_notice_date: 2006-02-09
opportunity_number: RFA-AA-02-004
application_type: 5
activity_code: R01
ic: AA
serial_number: 013853
program_official: GENTRY, THOMAS
project_start_date: 2003-03-01
project_end_date: 2008-02-28
study_section: ZAA1-CC(15)
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Naltrexone is currently used in oral tablet form as an adjunct in the treatment of alcohol dependence as well as to help maintain opioid addicts in a drug-free state. Transdermal delivery of naltrexone is desirable in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. This problem may be solved by designing and synthesizing derivatives (co-drugs) which are more skin permeable than naltrexone. A co-drug or mutual pro-drug consists of two synergistic drugs chemically linked together in order to improve the drug delivery properties of one or both drugs. Bupropion a successful smoking cessation treatment is the drug chosen for linkage to naltrexone. Simultaneous treatment of alcohol and tobacco addiction is vital because of the biochemical and behavioral causal links in this common co-morbidity as well as alcoholics' high death rate from tobacco-related diseases. Opioid addicts may also benefit from this treatment combination because of their high prevalence of smoking and co-abuse. The hypothesis is that chemical combinations of naltrexone and bupropion in a co-drug form will improve the transderrnal delivery rate of the drugs. The specific aims of this project are: (1) to synthesize a series of naltrexone 6-beta-naltrexol bupropion and hydroxybupropion codrugs designed to elucidate quantitative structure-activity relationships (QSARS) for transdermal flux and subsequent bioconversion rates (2) to characterize the physicochemical properties of the co-drugs including molecular volume lipophilicity hydrogen-bonding potentials melting points heats of fusion hydrolysis kinetics and solubilities in select solvents (3) to measure the co-drugs' penetration and bioconversion rates in human skin in vitro and (4) to characterize the pharmacokinetics of the co-drugs in guinea pigs in vivo. These objectives will help to identify the critical parameters involved in the optimization of transdermal co-drug designs. Correlation of the in vitro data with the in vivo model will aid in the creation of a reliable QSAR database that is necessary to help identify the best co-drugs for clinical use.

project_terms:
alcoholism /alcohol abuse chemotherapy;bupropion;drug addiction;drug administration rate /duration;drug design /synthesis /production;drug interactions;guinea pigs;high performance liquid chromatography;human tissue;infrared spectrometry;naltrexone;nonhuman therapy evaluation;nuclear magnetic resonance spectroscopy;pharmacokinetics;skin;thin layer chromatography;transdermal drug delivery


application_id: 7023886
project_number: 5R01HL056910-08
project_title: Ionic Homeostasis in Anoxic Cardiac Muscle Cells
administering_ic: NHLBI
award_notice_date: 2006-02-22
application_type: 5
activity_code: R01
ic: HL
serial_number: 056910
program_official: PRZYWARA, DENNIS
project_start_date: 1996-08-01
project_end_date: 2009-02-28
study_section: Cardiovascular and Pulmonary Research A Study Section[CVA]
contact_pi_person_id: 7875379
contact_pi: HADLEY, ROBERT W
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): This project's long-term goal is to define the mechanisms by which altered Ca2+ homeostasis contributes to hypoxic injury in cardiac muscle and to identify beneficial pharmacological mechanisms that can target these mechanisms. Therefore these studies are aimed at obtaining basic information that will also be relevant to myocardial ischemia/reperfusion. The project will test a new hypothesis focused on the cytoprotective mechanisms of diazoxide an activator of mitochondrial ATP-dependent K+ channels (KATP). Specifically it is proposed that diazoxide inhibits the reactivation of the sarcolemmal Na+/Ca2+ exchanger (NCX) during reoxygenation and that this protects against Ca2+ overload and many types of Ca2+-induced injury in cardiac myocytes.   
This central hypothesis will be tested through four specific aims. 1) Determine the mechanism by which the reactive oxygen species (ROS) generated during hypoxia/reoxygenation stimulate NCX activity. 2) Determine whether diazoxide inhibits NCX activity during reoxygenation by decreasing the generation of ROS. 3) Determine whether diazoxide exerts its cytoprotective effects during hypoxia by modulating cytosolic and intra-mitochondrial [Ca2+]. 4) Test the hypothesis that diazoxide can selectively inhibit arrhythmogenic transient inward currents when they are induced by Ca2+ overload and NCX activation during hypoxia/reoxygenation.   
These aims will be investigated in hypoxic guinea-pig and rat cardiac myocytes. Ca2+ homeostasis and NCX activity will be studied using cell imaging immunocytochemical and electrophysiological methods. The role of mitochondrial KATP channels will be studied using pharmacological methods and confocal imaging. Two particular strengths of the proposal are that it hypothesizes a novel link between activation of mitochondrial KATP and Ca2+ signaling based on this lab's previous studies and that our extensive experience studying the NCX should facilitate a definitive test of the hypothesis.

project_terms:
calcium flux;calcium ion;cardiac myocytes;cell death;confocal scanning microscopy;cytoprotection;diazoxide;free radical oxygen;guinea pigs;ion transport;laboratory rat;membrane transport proteins;myocardial ischemia /hypoxia;potassium channel;reperfusion;sarcolemma;sodium ion;tissue /cell culture


application_id: 7022175
project_number: 5R01CA092528-05
project_title: Mechanisms of DNA Lesion Bypass in Eukaryotes
administering_ic: NCI
award_notice_date: 2006-02-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 092528
program_official: OKANO, PAUL
project_start_date: 2002-04-01
project_end_date: 2007-03-31
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: 2006-04-01
project_abstract:
Our long-term objective is to understand mechanisms of lesion bypass in eukaryotes. Lesion bypass is an important cellular response to unrepaired DNA damage during replication. Error-prone lesion bypass is the major mechanism of DNA damage-induced mutagenesis and represents a major factor in carcinogenesis. In eukaryotes mechanisms of lesion bypass are poorly understood. Lesion bypass requires a specialized DNA polymerase (Pol). However it is not clear which polymerases are involved in lesion bypass in cells. We hypothesize that (a) Polzeta Poln Polkappa and Rev1 are involved in DNA synthesis opposite the lesion in vivo; and (b) efficient bypass of some lesions in cells requires nucleotide incorporation opposite the lesion by one polymerase and subsequent extension DNA synthesis by Polzeta. Polzeta  Poln Polkappa and Rev1 are able to incorporate nucleotides opposite several DNA lesions in vitro. In this proposal the role of these polymerases in lesion bypass in vivo and their relationships to damage-induced mutagenesis will be studied. Our specific aims are: (1) to study the function of Polzeta in DNA lesion bypass; (2) to determine the role of Rev1 in DNA lesion bypass; (3) to investigate cellular function of Poln in response to chemical induced DNA lesions; and (4) to examine the in vivo role of Polkappa in DNA lesion bypass and its relationship to damage-induced metagenesis. To accomplish the aims in vivo genetic experiments will be performed using the yeasts S. cerevisiae and S. pombe as eukaryotic model organisms. In vivo mutagenesis experiments will be performed in yeast strains proficient or deficient in polzeta Poln Po1kappa and Rev1 activities using-stranded plasmid vector containing a site-specific DNA damage including abasic site and four stereoiomeric anti-benzo[a]pyrene-N2-dG adducts in several sequence contexts. Genetic results will be interpreted with the help of in vitro biochemical experiments. The proposed studies should significantly advance our understanding of mechanisms of lesion bypass and damage-induced mutagenesis in eukaryotic cells.

project_terms:
DNA damage;DNA directed DNA polymerase;DNA repair;Saccharomyces cerevisiae;Schizosaccharomyces pombe;enzyme activity;enzyme deficiency;enzyme mechanism;site directed mutagenesis


application_id: 7021361
project_number: 5R01AI025098-18
project_title: Characterization of the Hms phenotype of Yersinia pestis
administering_ic: NIAID
award_notice_date: 2005-12-30
opportunity_number: PA-03-080
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-09-30
project_end_date: 2008-01-31
study_section: Bacteriology and Mycology Subcommittee 2[BM-2]
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
project_abstract:
DESCRIPTION (provided by applicant):  Yersinia pestis primarily causes a zoonotic disease - plague. Although humans are an accidental dead-end host bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2000 human plague cases occur yearly and small epidemics in South America and Southeast Asia are common. In addition Y. pestis has great potential for use as a bioterrorism agent. In nature the bacterium has an obligate flea-mammal (primarily rodent) life cycle.  Survival of plague in nature is dependent upon its ability to propagate in fleas and upon its transmission from fleas to mammals. In this proposal we will focus on determinants of the hemin-storage (Hms) phenotype of Y. pestis that are involved in the flea portion of the bacterial life cycle. The Hms+ phenotype is required for Y. pestis to cause blockage of the proventricular valve of fleas. Blockage of this valve between the esophagus and stomach of the flea is required for transmission of the disease from fleas to mammals. In vitro the Hms+ phenotype is characterized by binding of enormous quantities of exogenous hemin or Congo red (CR) dye to the outer membrane fraction of cells grown at 26-34 degrees Celcius but not at higher temperatures. Thus Hms+ cells of Y. pestis incubated at 26 degrees Celcius on CR agar form red colonies. We now hypothesize that the Hms phenotype of Y. pestis is the result of an extracellular matrix or biofilm produced by the Hms system. The mechanisms of proventricular blockage roles of Hms proteins in biofilm formation and mechanisms of temperature regulation of the phenotype remain to be elucidated. We propose to continue studies on identifying essential hms genes analyzing the regulation of expression of the Hms+ phenotype as well as characterizing the biochemical properties and physiological role(s) of the Hms system. The specific aims of this proposal are - 1) genetic analysis of essential hms genes; 2) analysis of the regulation of Hms expression; 3) biochemical analysis of the Hms system; and 4) analysis of the physiological role(s) of the Hms system. These studies will enhance our understanding of bacterial features that are required for Y. pestis to block the flea which is essential for the transmission of plague from fleas to mammals. This will facilitate measures to control or eliminate natural reservoirs of plague and control disease transmission. In addition elucidation of the enzymatic activities of Hms proteins and regulatory mechanisms controlling the synthesis of the extracellular matrix likely produced by the Hms system may have relevance for biofilm formation by other pathogenic bacteria.


application_id: 7020737
project_number: 5R01AG022944-03
project_title: The Sexual Abuse of Vulnerable Adults in Institutions
administering_ic: NIA
award_notice_date: 2006-03-20
opportunity_number: PA-02-162
application_type: 5
activity_code: R01
ic: AG
serial_number: 022944
program_official: BHATTACHARYYA, PARTHA
project_start_date: 2004-04-15
project_end_date: 2008-03-31
study_section: Social Sciences, Nursing, Epidemiology and Methods 4[SNEM-4]
contact_pi_person_id: 7598507
contact_pi: TEASTER, PAMELA B
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In 2000 Adult Protective Services (APS) typically the state agency of first contact in cases of abuse neglect or exploitation received 473095 domestic (in the community) and institutional (nursing homes assisted living group homes) reports concerning vulnerable adults. Included in that number were 4150 reports of sexual abuse a number highly under-reported due to differing reporting categories and its taboo nature. Sexual abuse runs the gamut from kissing and fondling to forcible rape and validated by earlier studies results in a diminished quality of life and often premature death. Because sexual abuse poses a significant public health and public safety problem requiring government intervention this study is grounded in democratic governance theory which emphasizes responsively representative ness and responsibility through government intervention. The specific aims are: (1.) to investigate patterns of the sexual abuse of vulnerable older and younger adults living in long-term care institutions; (2.) to test a web-based system for obtaining sensitive and confidential information on the sexual abuse of vulnerable adults; and (3.) to refine an emergent theory of the mistreatment of vulnerable adults derived from democratic governance theory. This multi-state study focused on four states (New Hampshire Oregon Tennessee and Texas) will utilize survey data provided by APS staff regarding all reports reports investigated and reports that were substantiated. Data collection will be undertaken using a web-based protocol. To check for reliability of survey data the Principal Investigator's and APS supervisors will conduct a clustered randomized review of 20% of APS files. A randomized sample of 15% of APS staff will complete in-depth telephone interviews regarding reports that were investigated only and reports substantiated. For nursing home residents only data from resident's Minimum Data Set (MDS) will be collected six months prior to the report and six months after to provide a before and after picture of the resident who was sexually abused. To make comparisons about the types of facilities in which sexual abuse is occurring the research team will use Nursing Home Compare a Medicare website that provides public and facility specific information on all nursing homes receiving Medicare or Medicaid funds. We will analyze the data using descriptive statistics Chi Squares and logistic regression. This is the first systematic multi-state theoretically grounded study to address the sexual abuse of vulnerable adults living in institutional settings. It will lay the foundation for APS law enforcement health-related regulatory agencies and the medical community for establishing investigator protocols and intervention strategies as well as a for a model of prevention to address sexual abuse at local state and national levels.

project_terms:
behavioral /social science research tag;clinical research;data collection;extended care facility;human data;human subject;interview;mental health epidemiology;sex abuse;social model


application_id: 7020714
project_number: 7R01GM060731-07
project_title: An Evolutionary Analysis of Fimbriae in Enterobacteria
administering_ic: NIGMS
award_notice_date: 2006-04-11
opportunity_number: PA-02-113
application_type: 7
activity_code: R01
ic: GM
serial_number: 060731
program_official: ECKSTRAND, IRENE A
project_start_date: 2000-02-01
project_end_date: 2008-02-29
study_section: Genetics Study Section[GEN]
contact_pi_person_id: 1964324
contact_pi: DYKHUIZEN, DANIEL E.
other_pis: Not Applicable
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The major emphasis of this proposal which continues the work of the previous proposal is to devise ways to determine which mutations are involved in adaptive evolution of bacteria as human pathogens. The model system used here is the adaptation of adhesins and other genes of Escherichia coli to extra intestinal infections particularly urinary tract infections (UTI). The within-clonal genetic diversity of the major uropathogenic serotypes will be used to determine gene loci targeted by pathoadaptive mutations i.e. gene changes that are selected in the environment when the organism is a pathogen. We will study in detail strains belonging to O18:K1 :H7 serotype - a major uropathogenic clone. Nucleotide polymorphisms within the gene clusters encoding various adhesive fimbria will be determined and used to characterize ancestral/descendent relationships within the clone. Then two ancestral and two descendant strains will be surveyed for additional mutational changes in up to one megabase of genome by using the newly developed technique GIRAFF. In GIRAFF sized fragments from two strains are melted rehybridized and treated with the mismatch-specific endonuclease CEL 1 that is capable of cutting mismatched DNA regions with high specificity and sensitivity. The CEL I-specific bands are then identified by Southern blot hybridization using multi-kb DNA probes. Within the 20% of the E. coli genome to be surveyed about two-dozen synonymous mutations are expected and will be used to date the clone. All other mutations will be analyzed as potential pathoadaptative changes. The genes in which the nonsynonymous mutations are found and the intervening regions where mutations are found will be tested to see if similar mutations are found in the same regions of DNA in six other uropathogenic clones. Those regions commonly found with mutations within each of these other clones will be assumed to important in pathogenesis. The functional effects of these mutations will be investigated. A subset of these pathoadaptive loci will be sequenced in our collection of 125 E. coli strains which includes both commensal and pathogenic strains to see if our new analytic technique zonal analysis will confirm that these changes are pathoadaptive. If so this approach can be used to discover pathoadaptive loci from the many expected to be sequenced genomes of E. coli.

project_terms:
Escherichia coli;adhesin;alleles;bacteria infection mechanism;bacterial cytopathogenic effect;bacterial genetics;biochemical evolution;endonuclease;evolution;gene expression;gene mutation;genetic strain;laboratory mouse;microorganism culture;nucleic acid probes;pathologic process;pilus;polymerase chain reaction;single strand conformation polymorphism;southern blotting;urinary tract infection;virulence


application_id: 7020079
project_number: 5K23DE015760-02
project_title: Chlorhexidine and Pneumonia in Nursing Home Residents
administering_ic: NIDCR
award_notice_date: 2006-02-23
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015760
program_official: HARDWICK, KEVIN S
project_start_date: 2005-03-01
project_end_date: 2009-02-28
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
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:
The immediate goal of this four-year research career award is to further the candidate's development as a patient-oriented researcher with a focus on oral health and systemic disease. The career development plan will build on her clinical experience as a General Practice Residency Program director and on her research training in Epidemiology. The long-term goal of the career development plan is to enable the candidate to become an independent investigator in oral and systemic health research and to serve as a mentor for junior patient-oriented researchers. The specific training targets are as follows: 1) Attainment of a solid knowledge base in the design and conduct of clinical trials; 2) coursework and consultation in clinical trial and data analytic methods; 3) understanding of procedural philosophical and ethical issues arising in the design and conduct of clinical trials; 4) development based on results and questions raised by the proposed study of a multi-site clinical effectiveness trial to improve the oral and systemic health of dependent nursing home patients and 6) dissemination of research findings to investigators in dentistry and other biomedical fields. Under the mentorship of Dr. Dan Sessler a senior investigator in clinical trials and Director of the Outcomes Research Institute Dr. Denis Kinane a senior research scientist and Director of the Center for Oral Health and Systemic Disease and Dr. Christine Ritchie a Geriatric Medicine physician at the Center for Oral Health and Systemic Disease the candidate will pursue a focused clinical research project and will receive formal and practical instruction in all aspects of clinical investigation. The proposed clinical research is needed to add to the knowledge concerning the role of oral health and systemic disease in a population with health disparities. The candidate's firsthand research training will involve the implementation of a pilot randomized placebo controlled clinical trial of the effects of chlorhexidine oral spray in reducing pneumonia in dependent nursing home patients. The results of the proposed research will serve as the basis for the design and submission of an investigator-initiated research proposal before the end of the award.

project_terms:
aging;antibiotics;chemoprevention;chlorhexidine;clinical research;clinical trials;communicable disease control;disease /disorder onset;geriatrics;human old age (65+);human subject;human therapy evaluation;local antiinfective agents;nosocomial infections;nursing homes;oral bacteria;oral health;patient oriented research;pneumonia;topical drug application


application_id: 7019125
project_number: 5R44HL073578-03
project_title: Development of a Direct Cellular Energy Delivery System
administering_ic: NHLBI
award_notice_date: 2006-02-06
opportunity_number: PA-04-059
application_type: 5
activity_code: R44
ic: HL
serial_number: 073578
program_official: ADHIKARI, BISHOW B
project_start_date: 2003-05-15
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-SBTS(10)B]
contact_pi_person_id: 3148961
contact_pi: EHRINGER, WILLIAM D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 130225076
duns_number: 130225076
fips: US
organization_id: 10000187
organization_name: VITATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021250
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
budget_end_date: 2008-01-31
project_abstract:
DESCRIPTION (provided by applicant):   Adenosine triphosphate (ATP) is the universal energy currency of the body and is made in large amounts by cells using substrate and oxygen. In the absence of oxygen such as in disease states or surgical procedures that affect oxygen delivery sufficient amounts of ATP cannot be produced and life ceases. We have developed a solution which can deliver large and controlled amounts of ATP to cells and tissues using highly fusogenic lipid vesicles containing Mg-ATP (VitaSol) and thus significantly reduce the effects of ischemia. During knee surgeries and many extremity procedures tourniquets are used to create a blood-free operation field. However the use of tourniquets for periods in excess of 2 hrs significantly increases morbidity. The long-term goal of this project is to develop a safe and effective solution which can deliver ATP to tissues during tourniquet-induced ischemia and significantly decrease morbidity from reperfusion injury. This is a first step in eventually using VitaSol in many surgical procedures were ischemia or hypoxia are problematic. The ultimate goal is to be able to use VitaSol to decrease the effects of whole-body hypoxia.    In Phase I VitaSol was optimized and stabilized (as a freeze-dried powder) and we have proven its efficacy in maintaining animal viability and function in the absence of oxygen. We have maintained cells tissues organs and organisms under hypoxia or chemical hypoxia (KCN) for periods of time that exceed any known method of preserving tissue. Composite tissues can be maintained viable for up to 21 hrs at room temperature with little or no loss in viability or function when perfused with VitaSol. In addition we can currently maintain rats for up to 1 hr without oxygen at normothermia or completely abolish the effects of an 8x lethal dose of IV injected KCN (2.5 mM). These and other exciting results clearly demonstrate the efficacy of this technique and given that VitaSol(tm) has a shelf-life in excess of 12 months will allow VitaSol to be tested to prevent the effects of tourniquet-induced ischemia.    In Phase II of this proposal we will optimize the delivery of VitaSol for tourniquet-induced ischemia test VitaSol in a large vertebrate animal model of tourniquet-induced ischemia and ready VitaSol for a Phase I clinical trial by running pre-clinical toxicity studies preparing a pre-lND meeting and producing VitaSol under cGMP. If the Phase II study is successful VitaSol will be readied for a Phase I clinical trial. Once approved VitaSol could be indicated for many other ischemic tissue procedures such as free-flap surgery limb replantation resection of invasive tumors or lesions repair of congenital anomalies and bilateral extremity surgery. If these trials are successful and once we better understand its toxicity and efficacy we will reenter VitaSol in trials for whole-body hypoxia.

project_terms:
adenosine triphosphate;apoptosis;bioenergetics;biological transport;cell biology;energy source;hypoxia;immunocytochemistry;intracellular transport;ischemia;laboratory rat;swine;technology /technique development;tissue /organ preservation


application_id: 7018011
project_number: 1R03HD051727-01
project_title: The function of Runx1 in the ovary
administering_ic: NICHD
award_notice_date: 2006-02-24
opportunity_number: PA-03-108
application_type: 1
activity_code: R03
ic: HD
serial_number: 051727
program_official: TAYMANS, SUSAN
project_start_date: 2006-03-01
project_end_date: 2008-02-29
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The goal of the present proposal is to elucidate the role of Runx1 a nuclear transcription factor in the ovary. We have recently identified that this transcription factor is dramatically and transiently induced in granulosa cells of periovulatory follicles after the LH [luteinizing hormone] surge. The periovulatory follicle undergoes rapid changes in the expression patterns of a myriad of genes to bring about ovulation and luteinization. Therefore transcriptional regulators induced by the LH surge are believed to play an essential role in the ovulatory process and luteinization. We have preliminary data showing that knockdown of the LH-induced Runx1 expression in periovulatory granulosa cells resulted in a decrease in progesterone production implicating the involvement of Runx1 in luteinization. We also found that Runx1 expression is regulated by the activation of the progesterone receptor and EGF [epidermal growth factor]-receptor two known key mediators for the ovulatory process. Based on these novel findings we hypothesize that Runx1 plays an important role(s) in ovulation and luteinization. The goal of this proposal is to: 1) demonstrate that the induction of Runx1 in periovulatory granulosa cells is essential for successful ovulation and luteinization and 2) determine the specific role(s) of Runx1 in periovulatory granulosa cells. To accomplish this goal we will generate mice lacking functional Runx1 specifically in granulosa cells and then examine the ovarian phenotype of these mutant mice (Specific Aim 1). Using the granulosa cell-specific Runx1 null mice we will identify the genes down-stream of Runx1 action in periovulatory granulosa cells (Specific Aim 2). Information derived from this proposal will provide new insight into the mechanism(s) involved in ovulation and corpus luteum formation. Such knowledge can be applied for promoting or inhibiting these critical facets of ovarian physiology thereby allowing us to better manage fertility infertility and ovarian-based disorders.

project_terms:
corpus luteum;developmental genetics;fertility;gene expression profiling;gene induction /repression;genetically modified animals;graafian follicles;granulosa cell;hormone regulation /control mechanism;laboratory mouse;luteinizing hormone;ovary;ovulation;protein structure function;recombinase;transcription factor


application_id: 7017110
project_number: 5R21DK066232-02
project_title: Redox Signaling in Skeletal Muscle Biology
administering_ic: NIDDK
award_notice_date: 2006-03-30
opportunity_number: PA-02-008
application_type: 5
activity_code: R21
ic: DK
serial_number: 066232
program_official: LAUGHLIN, MAREN R
project_start_date: 2005-02-15
project_end_date: 2007-01-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
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): Skeletal muscle continually takes up glucose a process critical for regulation of blood sugar levels and for energy delivery to working muscle. Mechanical loading causes glucose uptake to increase. Skeletal muscles produce ROS at higher rates during exercise and exposure to hydrogen peroxide stimulates glucose uptake. Preliminary data show that antioxidant pretreatment decreases glucose uptake by exercising muscle. Taken together these data suggest muscle-derived ROS might function as second messengers to promote glucose uptake during mechanical loading. The current project addresses this model. Aim 1. To evaluate muscle-derived ROS as mediators of glucose uptake during mechanical loading. Skeletal muscle continually generates hydrogen peroxide and related ROS molecules a process that increases during contractile activity. Hydrogen peroxide has been used as a tool to stimulate glucose uptake but the physiological effects of muscle-derived ROS have not been determined. We will do so by testing two hypotheses: A.) ROS levels in skeletal muscle fibers are increased by external mechanical loading. B.) Muscle-derived ROS mediate the increase in glucose uptake induced by mechanical loading. Aim 2. To determine if influx of extracellular calcium stimulates ROS-dependent glucose transport. During contractile activity extracellular calcium appears to enter muscle fibers and stimulate intracellular ROS production. We postulate this is a localized response that occurs near the cell membrane is induced by mechanical loading and stimulates glucose uptake. Our model will be evaluated by testing two hypotheses: A.) Mechanical loading increases subsarcolemmal calcium concentration. B. Extracellular calcium stimulates ROS production and glucose uptake in response to loading.

project_terms:
biological signal transduction;biomechanics;calcium flux;electrodes;exercise;fluorescence microscopy;free radical oxygen;glucose metabolism;glucose transport;hydrogen peroxide;laboratory mouse;mathematical model;microelectrodes;muscle contraction;muscle function;oxidation reduction reaction;second messengers;striated muscles


application_id: 7016696
project_number: 4R37AA010762-12
project_title: TNF and Mitochondrial Dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2006-08-24
application_type: 4
activity_code: R37
ic: AA
serial_number: 010762
program_official: GENTRY, THOMAS
project_start_date: 1996-03-01
project_end_date: 2011-08-31
study_section: NSS
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-09-01
project_abstract:
EXCEED THESPACEPROVIDED. Alcoholic liver disease (ALD)is an importanthealthproblem in the United States. The major difficultyin devising specific therapies for ALD has been our limited understanding of the mechanisms of this liver injuryand its systemic complications. This proposal will evaluate the interactionsof cytokines andnutritional/metabolic abnormalities in the development of ALDusing novel animal and in vitro models. Cytokines are low molecular weight mediators of cellular communication that are produced andreleased by numerous cell types such as monocytes macrophages andof particular relevance to liverdisease Kupffer cells and hepatocytes. Pro-inflammatorycytokines such as tumor necrosisfactor-alpha (TNF) and interleukin-18 (IL-18) and chemokines such as interleukin-8 (IL-8) have been postulated to play a role in mediating manyof the systemic manifestations of ALDand the hepatotoxicity in ALD. Itis our working hypothesis that cytokines such as TNF in conjunction with certain metabolic abnormalities observed in ALDsuch as altered proteasome function and cAMP metabolism play an etiologic role inthe development and progression of liver injury in ALD. We postulate that chronic alcohol abusecauses increased gut permeability and endotoxemia(increased LPS) depletionof critical antioxidants (e.g. GSH and Vitamin E)generation of reactive oxygen intermediates altered methionine metabolism decreased cAMP activation of Kupffer cell NFtcB with increased TNFproduction mitochondrial dysfunction with mitochondrial GSH depletion proteasome dysfunction alterations in liver membrane lipid raft composition increased susceptibility to hepatic TNF cytotoxicity and liver injury.With decreased proteasome function and hepatocyte injury/death there is increased IL-8 productionwith neutrophil infiltration and increasedIL-18 production that sustainsthis inflammatorycytokine response. The focus of our research group has been the interactions of cytokines oxidative stress and factors that sensitize to TNF mediated hepatocyte deathsuch as proteasome dysfunction in the inductionof ALD. The long-termgoals of our laboratoryare to further define the mechanism(s) involved in the development/evolution of ALDand to develop specific therapies based on this knowledge. The specific objectives of this proposal are: 1. Evaluate the role of cAMP and phosphodiesterase inhibitors on LPS-stimulated TNFproduction in ALD;2: Evaluate monocyte/Kupffer cell Toll-like receptor signaling in ALD;3: Evaluate the effects of hepatocyte lipid rafts on TNF-inducedapoptosis and NFicB activation; and 4: Determinethe effects of proteasome inhibition on "sensitization" to TNF hepatotoxicity and to hepatocyte production of proinflammatory cytokines/chemokines.


application_id: 7016199
project_number: 1R03OH008651-01
project_title: A Model-Based Estimate of Carbon Monoxide Uptake by Heart Muscle During Exercise
administering_ic: NIOSH
award_notice_date: 2006-06-27
opportunity_number: PA-04-021
application_type: 1
activity_code: R03
ic: OH
serial_number: 008651
program_official: NEWHALL, JIM
project_start_date: 2006-07-01
project_end_date: 2008-06-30
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 1918429
contact_pi: BRUCE, EUGENE N
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Intermittent exposures to carbon monoxide (CO) concentrations that exceed permissible levels are thought to contribute to the increased incidence of cardiovascular disease in exposed workers. A valid assessment of the cardiac risk associated with these exposures has proved difficult in part because of limited information regarding the degree of hypoxia that occurs in heart tissue during these exposures. Although the Coburn-Forster-Kane Equation (CFKE) is often used to predict CO uptake by and removal from hemoglobin (Hb) it can not estimate CO uptake by extravascular tissues such as muscle a potentially large storage site for CO as muscle accounts for approximately 41% of body weight in young adult males. Therefore we developed and validated with human data a mathematical model of CO uptake and washout that unlike the CFKE includes a muscle compartment. Our model predicts that the CO concentration in muscle increases soon after the onset of the exposure and rises steadily as carboxyhemoblobin (COHb) increases. When used to assess CO washout under hyperoxia the common treatment strategy for toxic CO exposures our model predicts a further rise in CO uptake by muscle myoglobin (Mb) even as COHb levels fall suggesting an increased risk for hypoxic injury to the myocardium. Based on these results we hypothesize that a mathematical model that could predict COMb levels in cardiac muscle would provide a more accurate estimate of risk for cardiac hypoxia than COHb alone. Accordingly the objectives of this proposal are to use data sets obtained from two human CO exposure experiments to: 1) enhance our model to enable it to predict COHb and COMb during exercise and washout under hyperoxia and 2) evaluate the correlation between the predicted CO dose to the heart and subtle ECG changes during exercise and washout under hyperoxia. To accomplish these objectives we will expand the model to include a separate myocardial compartment optimize our method for fitting the model and estimating myocardial COMb at rest and during exercise in each subject and correlate model estimates of myocardial COMb levels with degree of cardiac electrical instability. Relevance: To understand the increased risk for heart disease in workers exposed to carbon monoxide we will use our mathematical model to analyze existing data from exposed humans to determine the exposure conditions likely to damage the heart. We will also determine whether treatment with 100% oxygen may be harmful in some cases.

project_terms:
carbon monoxide;carboxyhemoglobin;environmental exposure;exercise;human data;mathematical model;model design /development;myocardium;myoglobin;occupational hazard


application_id: 7014578
project_number: 5R01NS046566-03
project_title: Peroxynitrite-Induced Oxidative Damage in TBI
administering_ic: NINDS
award_notice_date: 2006-03-16
application_type: 5
activity_code: R01
ic: NS
serial_number: 046566
program_official: HICKS, RAMONA R
project_start_date: 2004-02-01
project_end_date: 2008-01-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Extensive evidence now supports the concept that the reactive oxygen species (ROS)-mediated oxidative damage to lipids proteins and nucleic acids plays a major role in the acute pathophysiology of traumatic brain injury (TBI) and that antioxidant drugs which inhibit this damage will reduce secondary brain injury and improve neurological recovery. However the optimal design of antioxidant treatment for TBI requires a more complete understanding of the source and characteristics of ROS formation. Recent work indicates that mitochondria can become an important source of ROS when they become dysfunctional as a result of the massive TBI-induced rise in intracellular calcium (Ca++). Other work suggests that a key ROS formed by mitochondria is peroxynitrite (PON). PON-derived nitrogen dioxide (NO2) carbonate (CO3) and hydroxyl (OH) radicals can cause oxidative damage to mitochondrial lipids (lipid peroxidation) and proteins (carbonylation nitration) exacerbating intracellular Ca++ overload and triggering calpain-mediated cytoskeletal degradation and neurodegeneration. The specific aims of this proposal are to test the following hypotheses: 1) that post-traumatic oxidative damage in both diffuse and focal TBI is mediated by PON and that the time course of PON-mediated damage to lipids and proteins precedes calpain-mediated cytoskeletai damage and neurodegeneration 2) that mitochondrial dysfunction is a major source of PON and that mitochondria are an initial site of lipid and protein oxidative damage 3) that pharmacological scavengers of PON or PON-derived oxygen radicals can protect isolated brain mitochondria from oxidative damage and dysfunction and 4) that pharmacological scavenging of PON or PON-dedved oxygen radicals will effectively inhibit post-TBI oxidative damage and dysfunction in brain mitochondria and attenuate downsteam cytoskeletal degradation and neurodegeneration. Experiments will be carried out in models of moderate and severe diffuse and focal TBI. A systematic investigation of the role of PON in acute TBI and a careful examination of the neuroprotective efficacy of compounds which scavenge it after it is formed or that block PON-induced oxidative damage is expected to lead to a clinically effective and practical antioxidant neuroprotective strategy for acute TBI.

project_terms:
adenine nucleoside;antioxidants;behavior test;brain disorder chemotherapy;brain injury;calcium channel blockers;calcium flux;carboxylation;cytoskeleton;free radical oxygen;free radical scavengers;high performance liquid chromatography;hydroxylation;immunocytochemistry;laboratory mouse;mitochondrial disease /disorder;nerve injury;neural degeneration;neuroprotectants;nitration;oxidative stress;penicillamine;peroxidation;peroxynitrites;western blottings


application_id: 7014543
project_number: 5R01AG020251-05
project_title: Estrogen CA2+ Channels and (ca2+) in Hippocampal Aging
administering_ic: NIA
award_notice_date: 2006-03-24
application_type: 5
activity_code: R01
ic: AG
serial_number: 020251
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2002-02-01
project_end_date: 2008-01-31
study_section: Integrative, Functional and Cognitive Neuroscience 7[IFCN-7]
contact_pi_person_id: 7875396
contact_pi: PORTER, NADA MICOVIC
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: 2006-04-01
project_abstract:
DESCRIPTION (provided by applicant): Very little is known about cellular            patterns of brain aging in female mammals or about how brain aging in male or       female rodents depends on hormonal status. An increase in L-type voltage-gated      Ca2+ channels (LIGCCs)/currents and expression of the L-VGCC alpha1 subunit in      hippocampal CA1 neurons and altered recover of [Ca2+]i responses have been          found to be among the most consistent cellular/molecular biomarkers of brain        aging in male rats and female rabbits. These age changes in Ca2+ homeostasis        also appear to contribute directly to impaired plasticity and learning.             Estradiol (E2) has been found to be neuroprotective and to counteract a number      of aging-related alterations in long-term potentiation/depression (LTP/LTD) and     cognitive function and may retard Alzheimer's disease (AD). However the           molecular/cellular mechanisms that mediate these actions are not understood.        Recently we found a potential link between this cellular aging biomarker           (L-VGCCs) and E2 actions in that E2 downregulated L-VGCCs in hippocampal           "zipper" slices f ovariectomized (OVX) aged female rats and in hippocampal        cultures. E2 decreases in an ageiependent manner and it has been suggested that     this contributes to brain aging and declining function in Females and possibly      males. This application proposes to test the hypothesis that declining E2           levels with age are a stimulus for altered Ca2+ homeostasis and increased           L-VGCCs in hippocampal neurons whereas chronic E2 retards development of these     cellular and behavioral biomarkers of brain aging. In addition we will             identify cellular/genomic pathways through which E2 regulates L-VGCCs and other     aging markers. To carr out these studies we will combine two highly                 advantageous preparations the hippocampal "zipper" slice and an age-dependent     hippocampal cell culture model with single channel electrophysiology Ca2          imaging in single cells and gene expression analyses by real-time PCR and          Affymetrix gene chip microarray technology. Recently we adapted the                hippocampal "zipper" slice for single cell gene expression/function studies        and therefore will be able to test correlations between L-VGCC activity and        expression of multiple genes in the same cells. Together these studies will        systematically determine whether the development of some biomarkers of brain        aging is modulated by E2 in female and male rats and will elucidate linkage of     functional biomarkers to specific genomic pathways.

project_terms:
behavior test;biological signal transduction;biomarker;calcium channel;cell age;cognition;confocal scanning microscopy;electrophysiology;estradiol;estrogen inhibitor;estrogen receptors;gene expression;hippocampus;laboratory rat;messenger RNA;microarray technology;neurons;neuroprotectants;polymerase chain reaction;single cell analysis;tissue /cell culture;voltage /patch clamp;voltage gated channel


application_id: 7013999
project_number: 5R01EY014701-03
project_title: GABAc Receptors & Mouse Retinal Ganglion Cell Responses
administering_ic: NEI
award_notice_date: 2006-02-03
application_type: 5
activity_code: R01
ic: EY
serial_number: 014701
program_official: HUNTER, CHYREN
project_start_date: 2004-02-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): Vision requires the integration of many aspects of the visual field into a cohesive whole that is used by the organism to navigate its environment. The mammalian retina is a laminar structure and each layer is populated by several cell types that combine to define the response properties of the retinal ganglion cells (RGCs) which transmit the signal to the brain. The many aspects of the visual scene are encoded by two parallel pathways within the retina that either detect increases or decreases in light intensity. There are many types of RGCs and their responses are defined by the inputs they receive. One key element in shaping their response properties is inhibition which like other regions of the brain is mediated by glycine and gamma amino butyric acid (GABA). GABA inhibition is mediated by three receptors GABAA GABAB and GABAC all of which are present in the retina. One challenge then is to determine how each of these inhibitory and excitatory inputs shapes the responses of the RGCs. A new tool towards attaining this goal is the ability to manipulate the mouse genome and selectively remove specific inputs the effect of which then can be assessed on the RGCs. However unlike the extensive literature for cat rabbit and primate relatively little is known about the fundamental properties of murine RGCs. The goal of this proposal is to characterize the response properties of mouse RGCs both in vivo and in vitro and in particular determine the role that GABACR-mediated input plays in shaping the responses. The specific aims are (1) to determine the effect of eliminating genetically GABACR-mediated inhibition on a subset of RGC response properties recorded in vivo and (2) correlate structure and function of a diverse set of RGCs and determine the impact of eliminating GABACR-mediated input on the response properties of each of these cell types. These data will enhance our understanding of the role of inhibition in shaping the response of the output cells of the retina and therefore important aspects of integration of information in the visual field.

project_terms:
GABA receptor;behavioral /social science research tag;cell population study;gene mutation;laboratory mouse;neural information processing;neural inhibition;neural transmission;retinal ganglion;visual perception;visual phototransduction


application_id: 7013660
project_number: 5R01DK053220-09
project_title: DNA sequences impact estrogen and antiestrogen activity
administering_ic: NIDDK
award_notice_date: 2006-02-22
application_type: 5
activity_code: R01
ic: DK
serial_number: 053220
program_official: MARGOLIS, RONALD N
project_start_date: 1998-04-01
project_end_date: 2008-09-24
study_section: Reproductive Endocrinology Study Section[REN]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_abstract:
DESCRIPTION (provided by applicant): Estrogen receptors (ER) alpha and beta are members of the nuclear receptor superfamily of proteins that regulate target gene transcription in response to hormones. Although co-expressed in certain tissues the properties of ERalpha-ERbeta heterodimers are unknown. A number of studies indicate that ERbeta is a dominant negative inhibitor of ERalpha action but these studies used an N-terminal truncated version of ERbeta and therefore further experiments are needed to address differences between the long and short forms of ERbeta. Tamoxifen (TAM) binds ER and is used to prevent recurrence of estrogen-dependent breast tumors and has mixed agonist-antagonist effects in other estrogen target tissues. The precise molecular mechanisms allowing estrogen response element (ERE) - containing genes to be selectively responsive to TAM versus estradiol are not well understood and may play a role in TAM resistant breast cancer. Several classes of nuclear accessory proteins are recruited to ERalpha and act as coactivator or corepressor complexes to activate or suppress transcription from EREs to which ERalpha is bound usually in the promoter region. We reported significant differences in the ligand and ERE binding characteristics and transcriptional responsiveness of ERalpha and ERbeta revealed by the use of natural and synthetic EREs that varied in sequence and spacing. Of note was our finding that the conformation of ERalpha changes when bound to different EREs confirming our central hypothesis that DNA is an allosteric modulator of ER action. We hypothesize that these DNA-induced alterations in ER conformation will impact ER interaction with and activation by coactivator proteins. Comparatively little is known about ERbeta interaction with coactivators or corepressors. Using purified ERalpha and ERbeta for FRET and human normal and neoplastic mammary cells for transfection assays and ChIP we will test the hypotheses that: ERalpha/ERbeta heterodimer differs in ERE and coactivator interaction from either ERalpha or ERbeta homodimers; alterations in ERalpha or ERbeta conformation induced by binding to different ERE sequences modulates ER interaction with coactivators SRC-1 SRC-2 (GRIP1) SRC-3 (AIB1) PRMT and SRA; ERE regulated ER-coactivator interaction in turn modulates acetylation of histones H3 and H4 and the assembly of the coactivator/RNA polymerase II transcription initiation complex. Results will define the molecular mechanisms of ERalpha ERbeta and ERalpha/beta heterodimers as transcriptional regulators with emphasis on the action of antiestrogens.

project_terms:
Baculoviridae;CHO cells;DNA directed RNA polymerase;MCF7 cell;acetylation;affinity chromatography;biological signal transduction;cathepsin D;chromatin;conformation;dimer;estrogen receptors;estrogens;fluorescence resonance energy transfer;gel mobility shift assay;genetic regulatory element;genetic transcription;histones;immunoprecipitation;nucleic acid sequence;protein protein interaction;receptor expression;tamoxifen;transfection /expression vector;vascular endothelial growth factors


application_id: 7013404
project_number: 1R01DE017138-01
project_title: Oral Immunity and Adjuvant Receptors
administering_ic: NIDCR
award_notice_date: 2006-01-17
application_type: 1
activity_code: R01
ic: DE
serial_number: 017138
program_official: LUNSFORD, DWAYNE
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): The need to develop new vaccines against mucosal pathogens has compelled a search for adjuvants that can effectively stimulate mucosal immunity to vaccine proteins most of which are poor immunogens. Toll- like receptors (TLRs) and gangliosides are considered "adjuvant receptors" because their interaction with certain classes of noxious microbial molecules generates potent immunomodulatory signals in antigen-presenting cells (APCs) that mobilize adaptive immunity. An ideal adjuvant should thus stimulate adjuvant receptors without however inducing toxic effects. This application will investigate the adjuvant activities of a novel ganglioside-binding TLR2 agonist recently identified by our group. The molecule under investigation is the pentameric B subunit of a unique E. coli enterotoxin designated Type Mb (LT-llb) and quite different from Type I enterotoxins such as cholera toxin. In contrast to the intact toxin the B subunit (designated LT- llb-B) induces TLR2-dependent activation of transcription factor NF-KB which plays a central role in the induction of immunoregulatory cytokines and costimulatory molecules on APCs such as dendritic cells. The overall hypothesis is that LT-llb-B exhibits immunomodulatory activity which requires the cooperation of GD1a ganglioside and TLR2 promotes antigen-presenting cell function and induces mucosal immunity. We thus Aim to elucidate the immunomodulatory mechanisms of LT-llb-B and demonstrate its mucosal adjuvanticity. Specifically using immunological biophysical and cell imaging techniques we will determine cooperative interactions between gangliosides and TLR2 in response to LT-llb-B and the importance of these interactions in up-regulating dendritic cell-mediated functional costimulation to CD4+T cells. Moreover it will be determined if these adjuvant mechanisms of LT-llb-B correlate with induction of mucosal adjuvant activity in vivo. The proposed studies are supported by a plethora of preliminary findings and are facilitated by the availability of (a) engineered wild-type and single point substitution mutants of LT-II molecules (b) model cell systems where expression of receptors of interest is manipulated and (c) a well-established mouse mucosal immunization model. Using these models and state-of-the-art interdisciplinary techniques the generated data will form the basis for our ultimate objective which is to establish LT-llb-B as a safe and effective adjuvant in vaccine formulations against oral or other mucosal pathogens.

project_terms:
adhesin;antigen presentation;antigen receptors;cholera toxin;clinical research;dendritic cells;enterotoxins;fluorescence resonance energy transfer;gangliosides;human subject;immunomodulators;laboratory mouse;leukocyte activation /transformation;lipid raft;molecular /cellular imaging;mucosal immunity;nuclear factor kappa beta;point mutation;tissue /cell culture;toll like receptor;transfection


application_id: 7013236
project_number: 5R01DA015097-04
project_title: Opioids Modulate Oligodendrocyte Development & Function
administering_ic: NIDA
award_notice_date: 2006-02-15
application_type: 5
activity_code: R01
ic: DA
serial_number: 015097
program_official: POLLOCK, JONATHAN D
project_start_date: 2003-05-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-SSS-P(01)M]
contact_pi_person_id: 1958914
contact_pi: KNAPP, PAMELA 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: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Pre- and postnatal exposure to opioids can profoundly affect CNS development and function. Since the fastest growing population of opiate (heroin) abusers are young women of childbearing years there is a public health interest in understanding how opioid signaling affects CNS development. Opioids given experimentally in vivo or to slice cultures during pre- or perinatal periods can alter survival and proliferation of neurons and astroglia cause permanent changes in CNS structure and adversely affect learning and memory. Opiate exposure also reduces neurogenesis in adult hippocampus by 40 percent. Opioid effects are complex. Depending on the cell type or receptor (mu delta or kappa) targeted opioids can be toxic or protective and can have distinct effects on cell maturation. The survival of oligodendrocytes (OLs) and formation of myelin is critical for CNS function. Although opiate abuse can result in myelin pathology essentially nothing is known about opioid effects on OLs either during neonatal or perinatal periods or in the adult. Our work has defined the existence of opioid signaling pathways in cultured OLs by showing that: (a) OLs express mu- and kappa-opioid receptors in a temporally specific pattern; (b) OLs have physiologic responses (survival proliferation myelin production) to selective manipulation of receptors; (c) OLs synthesize process and probably secrete 2 classes of endogenous opioids (dynorphins enkephalins). The central goals of this proposal are to determine the spatiotemporal expression patterns of opioid receptors and peptides within the developing and mature CNS and to determine the role that opioids play in modulating the survival and function of OLs. Functional studies center on the role of dynorphin peptides since our findings show dynorphin mediates effects on the survival of OLs and neurons. A secondary goal is to determine whether manipulation of opioid signaling pathways can promote OL survival and myelination in clinical conditions with myelin pathology. Proposed studies use complementary in vivo and in vitro approaches employing mice deficient in opioid receptors and dynorphin to: (1) Identify spatiotemporal patterns of opioid receptor expression on OLs in the CNS; (2) Identify spatiotemporal patterns of dynorphin expression on OLs in the CNS and determine if dynorphin peptides are secreted; (3) Test the hypothesis that signaling through kappa-opioid receptors promotes OL survival and activates the PI3-kinase/Aktl pathway; (4) Test the hypothesis that some dynorphin peptides have glutamatergic effects on OLs. Techniques used include cell culture immunostaining in situ hybridization immunoblot confocal microscopy and adenoviral transfection.

project_terms:
biological signal transduction;cell growth regulation;central nervous system;developmental neurobiology;drug abuse;dynorphins;embryo /fetus toxicology;enzyme activity;gene expression;genetically modified animals;glutamates;immature animal;intracellular;laboratory mouse;mature animal;myelin;neuropharmacology;oligodendroglia;opiate alkaloid;opioid receptor;phosphatidylinositol 3 kinase;protein structure function;receptor expression;tissue /cell culture


application_id: 7012223
project_number: 5R01NS035102-12
project_title: Genotype/Phenotype Correlations in Williams Syndrome
administering_ic: NINDS
award_notice_date: 2006-04-06
application_type: 5
activity_code: R01
ic: NS
serial_number: 035102
program_official: MAMOUNAS, LAURA
project_start_date: 1996-05-17
project_end_date: 2010-03-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
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: 2006-04-01
project_terms:
Williams syndrome;clinical research;cognition;echocardiography;family genetics;gene deletion mutation;gene expression;genetic disorder;genetic mapping;genetic markers;genetic screening;genotype;human subject;hypercalcemia;hypertension;in situ hybridization;intelligence;language;medical records;memory;neuropsychological tests;personality;phenotype;psychological adaptation;space perception


application_id: 7011206
project_number: 5R01NS047395-03
project_title: Focal Brain Ischemia in the TNF-alpha-Transgenic Rat
administering_ic: NINDS
award_notice_date: 2006-03-22
application_type: 5
activity_code: R01
ic: NS
serial_number: 047395
program_official: JACOBS, TOM P
project_start_date: 2004-02-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-3(01)Q]
contact_pi_person_id: 1859648
contact_pi: PETTIGREW, L. CREED
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): Tumor necrosis factor-alpha (TNFalpha) is a pleotrophic cytokine secreted by astroglia macrophages and other cells participating in the inflammatory reaction initiated by cerebral infarction. Levels of TNFalpha rise sequentially in the infarct core the ischemic penumbra and in unaffected tissue in human brain damaged by stroke and may persist up to 40 days afterward. The Overall Goal of this R01 proposal is to establish the TNFalpha-transgenic rat as a new model for investigation of TNF receptor (TNFR)-mediated signal transduction and cell death pathways activated during brain infarction in man. This animal was constructed to overexpress the murine TNFalpha gene with its own promoter and has never been used to investigate the pathophysiology of any brain disorder. Cerebral tissue obtained from the transgenic rat shows elevated levels of TNFalpha mRNA and protein. When subjected to middle cerebral artery occlusion transgenic animals have larger mean percent infarct volume than wild type controls. We will employ this unique animal to test our principal Hypothesis: Upregulated synthesis of TNFalpha in ischemic brain augments neuronal apoptosis by receptor-mediated activation of signal transduction cascades. We propose to accomplish the following Specific Aims: 1) to characterize the neurochemical and cerebrovascular anatomy physiology and cognitive function of the TNFalpha-transgenic rat under normal conditions and in response to ischemic brain injury 2) to identify the cellular origin of TNFalpha and define the immune response to cerebral ischemic injury in the TNFalpha-transgenic rat 3) to use the transgenic animal to simulate how elevated TNFalpha levels affect TNFR number or distribution and modulate signal transduction cascades in ischemic human brain 4) to use the transgenic animal to simulate how elevated TNFalpha levels influence apoptotic neuronal degeneration in ischemic human brain and 5) to assess the research utility of the TNFalpha-transgenic rat as a model for therapeutic intervention by determining if pre- or post-ischemic inhibition of TNFalpha synthesis attenuates ischemic injury.

project_terms:
apoptosis;behavior test;biological signal transduction;brain circulation;cerebral ischemia /hypoxia;cognition;cytokine receptors;disease /disorder model;gel mobility shift assay;genetically modified animals;immune response;immunocytochemistry;laboratory rat;model design /development;neural degeneration;neurochemistry;polymerase chain reaction;tumor necrosis factor alpha


application_id: 7010882
project_number: 5R01AA013561-03
project_title: Ethanol withdrawal and HIV-1 neurotoxicity
administering_ic: NIAAA
award_notice_date: 2006-01-27
opportunity_number: PA-02-039
application_type: 5
activity_code: R01
ic: AA
serial_number: 013561
program_official: SORENSEN, ROGER
project_start_date: 2004-02-10
project_end_date: 2009-01-31
study_section: AIDS Clinical Studies and Epidemiology Study Section[ACE]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol dependence or abuse is often observed in some populations of patients infected with human immunodeficiency virus type-1 (HIV-1). However the consequences of alcohol intake in those who are HIV- 1 infected with regard to function of the brain have been little studied. This is significant in that HIV-1 infection often results in motor and cognitive impairments collectively termed HIV-associated dementia (HAD). Long-term ethanol intake produces increased expression or sensitivity of N-methyl-D-aspartate type glutamate receptors (NMDAr). This effect may sensitize the brain to insult caused by excitotoxins such as the HIV-1 protein Tat a viral transcription factor thought to contribute to the development of HAD. In vitro and in vivo studies using Tat have shown that it causes NMDAr-mediated excitation Ca 2+ influx into neurons and neurotoxicity. Thus it was hypothesized that chronic ethanol exposure would sensitize the brain to the neurotoxic effects of Tat. The aims of these studies are to: 1. Determine if chronic ethanol ingestion sensitizes the NMDAr system to the detrimental effects of intra-hippocampal Tat injection on behavior and neuronal viability in rats; 2. Determine if Tat (1-72 and 1-86 amino acid forms) may directly interact with specific sites on the NMDAr using radioligand binding studies of rat hippocampus; 3. Determine the role of NMDAR polyamine-site over-activity and Ca 2v influx into neurons in the ability of chronic ethanol exposure to sensitize the hippocampus to Tat toxicity. These studies will employ fluorescent microscopy and immunohistoehemical methods in an organotypic slice-culture model derived from male rats; and 4. Evaluate the ability of novel synthetic NMDAr polyamine-site antagonists to attenuate the neurodegenerative and behavioral effects of ethanol and Tat exposure. In sum these studies are designed to elucidate the means by which ethanol intake sensitizes the brain to Tat toxicity and to identify potential therapeutic strategies that may be useful in reducing the incidence of neurological problems caused by HIV-1 infection in those who abuse alcohol or are alcohol-dependent.

project_terms:
AIDS dementia complex;HIV infections;NMDA receptors;alcoholism /alcohol abuse;calcium flux;drug withdrawal;ethanol;fluorescence microscopy;hippocampus;human immunodeficiency virus 1;immunocytochemistry;laboratory rat;learning;male;neural degeneration;neuropharmacology;neurotoxicology;radiotracer;receptor sensitivity;tissue /cell culture;transcription factor;virus protein


application_id: 7010056
project_number: 5R01GM070559-02
project_title: Molecular Analysis of Juvenile Hormone Action
administering_ic: NIGMS
award_notice_date: 2006-01-24
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-TMP(99)]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: 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
budget_start_date: 2006-02-01
project_terms:
Drosophilidae;RNA interference;biological signal transduction;ecdysone;gene induction /repression;genetic regulation;genetic regulatory element;hormone receptor;hormone regulation /control mechanism;juvenile hormones;messenger RNA;metamorphosis;protein binding;protein localization


application_id: 7009944
project_number: 5R01MH056536-09
project_title: Exerting Control Over Prejudiced Responses
administering_ic: NIMH
award_notice_date: 2006-01-26
application_type: 5
activity_code: R01
ic: MH
serial_number: 056536
program_official: OTEY, EMELINE M
project_start_date: 1997-01-01
project_end_date: 2006-06-30
study_section: Special Emphasis Panel[ZRG1-RPHB-4(01)S]
contact_pi_person_id: 1960285
contact_pi: MONTEITH, MARGO J.
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: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): The fact that stereotypes prejudice operate automatically or implicitly (unconsciously) adverse and often has consequences for people who must continually endure discriminatory outcomes and also for people who feel guilty about their unintended biases. The PI previously advanced a model of self-regulation to explain how control over automatically activated prejudices might be achieved. The model posits that the neurophysiological behavioral inhibition system (BIS) mediates the processes involved in bringing behavior that results from automatically activated biases under control. Theoretically this system enables the development and operation of cues for control which are stimuli that have come to be associated with prejudiced responses and the negative consequences of those responses (e.g. feelings of guilt). Through the development and operation of cues for control implicit biases and their consequences can be changed. Although supported in experiments that maximized conditions for successful self-regulation the model has not been tested in more realistic contexts nor has it addressed actual strategies for replacing prejudiced responses. The current program of research extends the application and theoretical breadth of the self-regulation model. Aim 1 is to examine experimentally the power of cues for control to command attention and facilitate non-prejudiced responding (1) when people have access to limited processing resources; (2) across time; and (3) after an experience that affirms one's non-prejudiced self-image. Thus these experiments test the power of cues to encourage non-prejudiced responding under situations that challenge the potential operation of cues. Aim 2 is to examine the operation of "real world" cues by obtaining a rich source of experiential data using an interview methodology to answer questions about the self-regulation of prejudiced responses in people's everyday lives. The operation of "real world" cues will also be examined experimentally by presenting individuals' idiosyncratic cues (as determined in the interview study) in a priming task to determine whether they do indeed facilitate control over prejudice. Aim 3 is to theoretically extend the self-regulation model by drawing on the de-biasing and correction literatures to provide an account of replacement strategies and to explain how the use of different strategies will depend on a likely moderator (capacity for reflection). Relevant experiments will test this theoretical extension.

project_terms:
behavior test;behavioral /social science research tag;bias;clinical research;cognition;computer human interaction;cues;experience;guilt;human subject;interview;motivation;neurophysiology;prejudice;psychological models;racial /ethnic difference;self concept;social psychology


application_id: 7009612
project_number: 5R01GM061655-04
project_title: Nitrous Oxide and Wound Infections
administering_ic: NIGMS
award_notice_date: 2006-03-06
application_type: 5
activity_code: R01
ic: GM
serial_number: 061655
program_official: IKEDA, RICHARD A
project_start_date: 2003-02-01
project_end_date: 2008-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 7547477
contact_pi: AKCA, OZAN
other_pis: Not Applicable
congressional_district: 03
department: ANESTHESIOLOGY
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: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): Nitrous oxide remains the most commonly used anesthetic and has been given to several billion patients. In vitro even brief exposure to nitrous oxide inactivates methionine synthetase which reduces induction of enzymes required for immune function. Nitrous oxide also reduces chemotactic migration by monocytes. However nitrous oxide improves neutrophil chemotaxis and facilitates oxygen radical formation and may therefore augment the efficacy of oxidative killing by neutrophils - the primary defense against pathogenic bacteria. Preliminary results in 200 patients suggest that the beneficial effects of nitrous oxide on wound healing outweigh its toxicities. We will thus test the hypothesis that the incidence of postoperative wound infection will be less in patients given 60% nitrous oxide than in those given 60% nitrogen during elective colon surgery. We propose to study up to 1000 patients undergoing elective colon resection. Perioperative antibiotic anesthetic fluid and oxygen management will be set by protocol. Patients will be anesthetized with isoflurane in 40% inspired oxygen with the remaining ventilatory mixture randomly assigned as nitrous oxide or nitrogen. Surgical wounds will be evaluated daily by a physician blinded to group assignment. Wounds will be considered infected when they meet CDC criteria or pus is detected and they are culture-positive for pathogenic bacteria. As a secondary outcome incidence of nosocomial pneumonia in the two groups will be determined. Results will be analyzed by Fisher Exact and unpaired two-tailed t-tests; P < 0.05 will be considered statistically significant. We anticipate showing that substituting nitrous oxide for nitrogen reduces the incidence of surgical wound infection. Confirming our hypothesis would thus allow clinicians to make a minor modification in anesthetic practice that might reduce the incidence of a complication responsible for considerable perioperative morbidity and cost.

project_terms:
anesthesia;anesthesia complication;anesthetics;clinical research;disease /disorder proneness /risk;drug adverse effect;drug screening /evaluation;human subject;nitrous oxide;nosocomial infections;outcomes research;pneumonia;postoperative complications;radiosensitizer;wound infection


application_id: 7009582
project_number: 5R01LM008323-02
project_title: Histological Reasoning: Visual Cognition in Microanatomy
administering_ic: NLM
award_notice_date: 2006-03-10
application_type: 5
activity_code: R01
ic: LM
serial_number: 008323
program_official: SIM, HUA-CHUAN
project_start_date: 2005-02-01
project_end_date: 2009-01-31
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 1911606
contact_pi: PANI, JOHN R
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_terms:
anatomy;clinical research;cognition;computer simulation;histology;human subject;information retrieval;microscopy;model design /development;space perception;videotape /videodisc


application_id: 7009207
project_number: 5R01EY014060-04
project_title: Tolerance and autoimmunity in the eye
administering_ic: NEI
award_notice_date: 2006-01-19
application_type: 5
activity_code: R01
ic: EY
serial_number: 014060
program_official: SHEN, GRACE L
project_start_date: 2003-01-01
project_end_date: 2007-12-31
study_section: Visual Sciences A Study Section[VISA]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100000 people per year. Like other autoimmune diseases uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated and the mechanism of autoimmune tissue destruction is poorly understood. In mice experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell yet nothing is known about how this interaction affects EAU in vivo. In the first aim the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated and the nature of the antigen presenting cell within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na?ve mice with IRBP specific T cells has been demonstrated the nature of the T cell that is capable of inducing disease is not known. In the second aim a panel of IRBP specific T cell clones will be characterized for a variety of functional properties as well as their ability to transfer EAU to normal mice. In the third aim T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina rather than being secreted. Together these studies will provide important new information as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis.


application_id: 7008087
project_number: 5R01NS046380-03
project_title: COX-2 Pathophysiology in Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2006-03-02
application_type: 5
activity_code: R01
ic: NS
serial_number: 046380
program_official: KLEITMAN, NAOMI
project_start_date: 2004-02-01
project_end_date: 2008-01-31
study_section: Special Emphasis Panel[ZRG1-CNNT(01)Q]
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Traumatic spinal cord injury (SCI) results in a loss of voluntary motor and sensory function below the site of injury and affects some 300000 individuals in the United States with ~10000 new cases each year. Pathophysiological secondary responses following the initial insult promote additional and extensive damage occurring hours to weeks following injury and therefore are amenable to therapeutic interventions. Current therapies provide at best modest improvement of function and alternative strategies are warranted. The studies proposed in this application are designed to identify and better characterize the pathophysiological consequences of cyclooxygenase (COX) expression in traumatic spinal cord injury (SCI). Despite evidence of a pathological role for COX-2 induction in several models of central nervous system (CNS) injury the role of the two COX isoforms (COX-1 and COX-2) as a mediators of cell death following SCI is unclear. The overall objective of the proposed experiments is to provide evidence that COX functions as an intracellular activator of cytotoxic oxidative damage and a mediator of apoptotic cell death following SCI. Specific Aim 1 will use pharmacological strategies and a number of biochemical assays to examine the contribution of COX-1 and COX-2 to oxidative damage. Studies in Specific Aim 2 will document conclusively that COX expression occurs in cells that are undergoing apoptotic cell death following SCI (Aim 2a) and demonstrate that inhibiting the actions of either COX isoform reduces the appearance of apoptotic markers (Aim 2b). Studies proposed in Specific Aim 2 are a logical extension of Aim 1 as several studies have demonstrated that oxidative damage contributes to apoptotic cell death. Finally Specific Aim 3 will demonstrate the therapeutic potential of blocking the actions of COX-1 or COX-2 in SCI. This will include a battery of behavioral tests that are highly sensitive to changes in sensorimotor and coordinated locomotor function. In addition histological and morphological studies will be performed to document long term cell survival improved tissue sparing at the injury epicenter and enhanced myelination in fiber tracks distant to the site of injury. The outcome of these studies will document the pathophysiological involvement of COX expression in cell death following SCI which has clear clinical implications for developing therapies in the treatment of SCI in humans.

project_terms:
apoptosis;behavior test;bioassay;biomechanics;enzyme activity;enzyme induction /repression;enzyme inhibitors;field study;laboratory rat;myelinopathy;nervous system regeneration;oligodendroglia;oxidative stress;pathologic process;prostaglandin endoperoxide synthase;protein isoforms;sensorimotor system;spinal cord injury


application_id: 7007624
project_number: 5R01CA105453-03
project_title: Novel Mechanisms of PTEN Gene Regulation
administering_ic: NCI
award_notice_date: 2006-01-31
application_type: 5
activity_code: R01
ic: CA
serial_number: 105453
program_official: YASSIN, RIHAB R
project_start_date: 2004-02-05
project_end_date: 2009-01-31
study_section: Special Emphasis Panel[ZRG1-CPA(05)M]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
DESCRIPTION (provided by applicant): The pro-apoptotic tumor suppressor gene PTEN (Phospatase and Tensin Homologue deleted from Chromosome 10) is a negative regulator of the PI-3 kinase/Akt dependent cell survival pathway. PTEN is located on chromosome 10q23 within a region that shows loss of heterozygosity in many human cancers and PTEN gene function is lost in diverse cancers either by mutation of PTEN or deletion of chromosome 10q23. However in several cancers such as non-small cell lung cancer and thyroid cancer the PTEN gene is intact and wild type but its expression is diminished. As haplo-insufficiency of PTEN is associated with tumorigenesis understanding the mechanism(s) involved in epigenetic down-regulation of PTEN is of both clinical and fundamental significance. Recent studies have shown that the PTEN pseudo-gene but not wild type PTEN gene is methylated indicating that DNA methylation is not a potential mechanism for silencing of the PTEN promoter leading to diminished PTEN gene expression. Our preliminary studies indicated that the anti-apoptotic transcriptional regulator NF-kappaB and oncogenic Ras which are over-expressed and activated in lung cancer down-regulate the expression of PTEN. Interestingly oncogenic Ras up-regulates the expression of the transcription factor Egr-1 which by itself suppresses PTEN gene expression.  The studies proposed here will address the mechanisms for down-regulation of PTEN gene expression that are functionally relevant; i.e. they result in elevated phospho-Akt levels and anti-apoptosis. We will determine the mechanisms of suppression of PTEN gene expression by NF-kappaB (Aim 1) and by oncogenic Ras (Aim 2) that confer apoptosis inhibition tumor progression and chemo- or radiation-resistance. Because these studies will elucidate novel mechanisms of PTEN tumor suppressor gene regulation by pro-survival and oncogenic factors most commonly encountered in lung cancer the findings may lead to the development of intervention strategies that can ablate the NF-kappaB or activated Ras-inducible anti-apoptotic pathways and thereby restore expression and the pro-apoptotic potential of PTEN.

project_terms:
apoptosis;athymic mouse;biological signal transduction;chromatin immunoprecipitation;gene expression;gene induction /repression;genetic regulation;guanine nucleotide binding protein;ionizing radiation;lung neoplasms;neoplasm /cancer chemotherapy;neoplastic process;nuclear factor kappa beta;radiation resistance;transfection;tumor suppressor genes;western blottings


application_id: 7007269
project_number: 5R01AI051592-04
project_title: Cis-acting RNA elements in hepatitis C virus replication
administering_ic: NIAID
award_notice_date: 2006-01-27
application_type: 5
activity_code: R01
ic: AI
serial_number: 051592
program_official: KOSHY, RAJEN
project_start_date: 2003-01-01
project_end_date: 2007-12-31
study_section: Experimental Virology Study Section[EVR]
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: 2006-01-01
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 has a positive-stranded RNA genome consisting of a single open reading frame (ORF) flanked by the untranslated regions (UTR) at the 5' and 3' ends. The ORF encodes a large polypeptide that is processed to structural and nonstructural viral proteins. The roles of viral proteins and conserved RNA sequences/structures in HCV replication are poorly understood. The overall goal of this research proposal is to determine the sequence and structural requirements of cis-acting RNA elements in the 5' and 3' UTRs in viral RNA replication. Both the 5' and 3' UTR sequences are highly conserved among various HCV isolates. Genetic studies have demonstrated that both 5' and 3' UTRs are essential for HCV RNA replication. We hypothesize that the conserved 5' and 3' UTRs contain cis-acting RNA elements important for control of HCV RNA replication. The highly conserved 5'UTR harbors two distinct RNA elements a short 5'-proximal RNA element with a stern-loop structure and a longer element of internal ribosomal entry site (IRES). To determine cis-acting RNA elements in the 5'UTR and to define their roles in HCV RNA replication we will perform systematic mutagenesis analyses of the conserved sequences/structures by nucleotide deletions substitutions and replacement with non-HCV IRES. The 3'UTR consists of three distinct regions a highly conserved 98 nucleotides that form three stern-loop structures a poly(U/C) tract of variable length and a variable region at immediate downstream of the ORF. Cis-acting RNA elements in the 3'UTR for HCV RNA replication will be defined by nucleotide deletions and substitutions. The effects of mutations in the 5' and 3' UTRs on HCV RNA replication will be determined by using reverse genetics systems. We have developed a DNA-based HCV replicon replication system. We have also demonstrated that a DNA-based HCV 'minigenome' RNA was replicated when active replicase complex was provided in trans. These reverse genetics systems for HCV RNA replication will be used to determine cis-acting RNA elements in the 5' and 3' UTRs and their roles in HCV RNA replication. Information gained from these studies will immediately contribute to our understanding of the molecular mechanism of HCV RNA replication and provide meaningful insights to the design of effective strategies for controlling HCV infection.


application_id: 7006097
project_number: 5R01DC007176-02
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2006-02-06
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2010-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-03-01
project_terms:
brain derived neurotrophic factor;cell proliferation;cell sorting;developmental neurobiology;genetically modified animals;in situ hybridization;innervation;laboratory mouse;mammalian embryology;neuronal guidance;neurotrophic factors;taste;taste buds


application_id: 7005601
project_number: 1UC6AI066844-01
project_title: Center of Predictive Medicine for Biodefense
administering_ic: NIAID
award_notice_date: 2005-09-01
opportunity_number: RFA-AI-04-032
application_type: 1
activity_code: UC6
ic: AI
serial_number: 066844
program_official: LEWIS, AMBROSE B
project_start_date: 2005-09-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZAI1 JB-M (M2)]
contact_pi_person_id: 10316741
contact_pi: PIERCE, WILLIAM M
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: UNIVERSITY-WIDE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The University of Louisville proposes to establish a Center for Predictive Medicine forBiodefense and Emerging Infectious Diseases (CPMBEID). Our long-term objective is to support the development of gene-based countermeasures and diagnostic approaches based on system changes that occur during host-pathogen interactions. Focusing on host-based bio-threat and emerging infectious disease research should allow the development of broad-spectrum interventions to infectious agents rather than the current paradigm of "one bug/one vaccine" approach so prevalent today. Our specific aims are to 1) meet the expanding needs of current researchers who work with Category A B or C priority pathogens at the University of Louisville; 2) expand facilities so that we can add an additional six faculty investigators who work with these agents; 3) assemble a unique mix of technologies in a free standing BSL3 facility so that the instrumentation and expertise is available on site to manipulate experimental materials and avoid the need for shipping material off site; and 4) to serve as a resource for investigators from other institutions in our region who can benefit from the unique mix of technologies we will assemble in the facility as well as be prepared to bring those technologies to bear in the event of a bioterrorism emergency. The University created a superb team of investigators and administrators to shepherd this project from application to operation. We are committed to working with NIAID and believe our missions can be mutually reinforced by building a RBL in Louisville.

project_terms:
behavioral /social science research tag;biomedical facility;bioterrorism /chemical warfare;building /facility design /renovation;cooperative study;emerging infectious disease;host organism interaction;interdisciplinary collaboration;medicine;proteomics


application_id: 7005425
project_number: 5P01AG005119-19
project_title: OXIDATIVE STRESS IN ALZHEIMER'S DISEASE
administering_ic: NIA
award_notice_date: 2006-01-27
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
program_official: SUNEJA, SANOJ
project_start_date: 1994-12-01
project_end_date: 2008-01-31
study_section: ZAG1-ZIJ-3(O1)
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-02-01
project_abstract:
Alzheimer's disease is a major health problem affecting 4 million persons in the USA. The key to understanding AD is determining the etiology and pathogenesis of neuron degeneration in specific brain regions. This application is for a five year renewal of the Program Project Grant (P01AG05119) at the University of Kentucky (UK) Sanders-Brown Center on Aging. The major goal of this program proje4ct is to gain an understanding of brain oxidation in AD.  The program project is composed of two cores and four closely interrelated projects. Each project has human (AD and control) gene-altered animal and cell culture components. Each project has published and preliminary data relevant to specimens from longitudinally followed AD and control subjects that have short post-mortem interval autopsies. Project by Markesbery examines the hypothesis that oxidation of DNA and RNA oxidation. Project by Butterfield is aimed at defining the molecular mechanisms and sequela of Abeta-associated oxidative stress in AD. Special emphasis will be placed on the action of methionine in Abeta (1- 42) in oxidative stress and neuron toxicity. Project by St. Clair examines the hypothesis that the ability of mitochondria to remove superoxide radicals without inflicting self injury plays a central role in regulating free radical mediated neurodegeneration in AD. This study will investigate the mechanism by which increased expression of manganese superoxide dismutase can be safely achieved in the brain. Project by Kindy is designed to understand the interaction between the receptor for advanced glycation endproducts Abeta and oxidative stress. A coordination and administration Core will provide supervision and coordination of the research projects financial management statistical support internal and external scientific review and procurement of tissue from the Uk ADRC. The Animal Core provides transgenic knockout and knockin mice for all four projects. This program project has the potential of identifying molecular targets for development of therapeutic agents aimed at decreasing neuron injury and improving the outcome of AD.

project_terms:
Alzheimer&apos;s disease;clinical research;gene targeting;genetically modified animals;human tissue;laboratory mouse;oxidative stress;tissue /cell culture


application_id: 7005388
project_number: 5R01ES012062-04
project_title: Vascular Toxicity of Aldehydes
administering_ic: NIEHS
award_notice_date: 2005-12-27
application_type: 5
activity_code: R01
ic: ES
serial_number: 012062
program_official: NADADUR, SRIKANTH
project_start_date: 2003-04-03
project_end_date: 2008-12-31
study_section: Special Emphasis Panel[ZRG1-SSS-3(04)]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant):  Extensive epidemiological data suggest that exposure to aldehydes or aldehyde-generating pollutants increases the risk of cardiovascular disease. However the mechanisms by which aldehydes affect cardiovascular health are not known. We propose that exposure to environmental aldehydes such as acrolein or trans-2-hexenal exacerbates arteriosclerosis. Based on our preliminary results we suggest that aldehyde exposure leads to lipoprotein modification which induces vascular inflammation and dysregulates cell growth thereby resulting in the formation of more extensive unstable and cellular lesions. To test this hypothesis in Specific Aim 1 we will examine how exposure to inhaled acrolein or dietary hexenal or acrolein affects the progression of atherogenesis in wild type apoE and low-density lipoprotein receptor- null mice. We will also determine whether the atherogenecity of aldehydes is modulated by the extent of hypercholestremia. The second aim of the project is to elucidate aldehyde-induced changes in lipoproteins. For this we will examine the severity and the extent of lipoprotein changes in aldehyde-exposed mice and test whether aldehyde exposure causes modification cross-linking or aggregation of lipoproteins and elicits the development of autoantibodies against protein-aldehyde adducts. Our final aim is to delineate the atherogenic consequences of aldehyde-induced lipoprotein modification. We will establish whether modifications due to aldehyde exposure increase the atherogenicity of lipoproteins and whether aldehydes disrupt cholesterol metabolism by preventing the maturation of the HDL (high-density lipoprotein) particle. Finally we will examine whether the aldehyde-induced dyslipidemia is due to the inhibition of lecithin: cholesterol acyl transferase (LCAT) and if the dyslipidemic changes are diminished in LCAT-deficient mice. Together the results of this project will provide new information about the effects of the most toxic and abundant pollutants in the environment on arteriosclerosis and reveal mechanisms by which they contribute to the risk of heart disease - which is the leading cause of death in the industrialized world. Successful completion of these studies will form the basis of future assessment of human risk and susceptibility.

project_terms:
SDS polyacrylamide gel electrophoresis;acrolein;aldehydes;apolipoprotein E;atherosclerosis;autoantibody;biological signal transduction;blood lipoprotein metabolism;blood toxicology;cardiovascular disorder risk;cell adhesion molecules;environmental exposure;enzyme linked immunosorbent assay;genetically modified animals;high density lipoproteins;high performance liquid chromatography;hypercholesterolemia;immunocytochemistry;laboratory mouse;low density lipoprotein;low density lipoprotein receptor;mass spectrometry;phosphatidylcholine sterol acyltransferase;western blottings


application_id: 7004549
project_number: 5U10HD045934-03
project_title: Center for Pediatric Clinical Pharmacology Research
administering_ic: NICHD
award_notice_date: 2006-01-13
opportunity_number: RFA-HD-03-001
application_type: 5
activity_code: U10
ic: HD
serial_number: 045934
program_official: GIACOIA, GEORGE
project_start_date: 2004-03-08
project_end_date: 2008-12-31
study_section: ZHD1-DSR-A(01)
contact_pi_person_id: 2311234
contact_pi: SULLIVAN, JANICE E
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_terms:
biomarker;chemotherapy;clinical research;clinical trials;cooperative study;developmental genetics;diagnosis;human subject;human therapy evaluation;patient oriented research;pediatric pharmacology;pharmacokinetics;prognosis;proteomics


application_id: 7002269
project_number: 5R13AI057800-03
project_title: Autumn Immunology Conference
project_terms: immunology;meeting /conference /symposium;travel
administering_ic: NIAID
award_notice_date: 2005-12-21
application_type: 5
activity_code: R13
ic: AI
serial_number: 057800
program_official: COULTER, NANCY A
project_start_date: 2003-12-15
project_end_date: 2006-11-30
study_section: Allergy, Immunology, and Transplantation Research Committee[AITC]
contact_pi_person_id: 1864845
contact_pi: SNOW, ERNEST CHARLES
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
The Autumn Immunology Conference (AIC) has been held annually since 1971. The 2003 meeting will be held Nov. 22-24 at the Downtown Marriott Hotel in Chicago IL. The AIC has been held at this location and date since 1995 and is committed to this site through the 2004 meeting. The meeting was founded with the intent of providing a forum for the exchange of research and ideas particularly tailored to the needs of graduate students and postdoctoral fellows. Most of the faculty student and fellow attendees are from the Midwest states but the meeting is increasingly attracting more participants from other regions of the country.   
  
The meeting averages 400-450 participants with 225 abstracts presented at the 2002 meeting. The format of the meeting includes three symposia covering current areas of immunological research. Distinguished scientists from throughout the US and abroad speak about their own research with four speakers per symposium. Interspersed among the symposia are poster sessions and workshops in which students present both a poster and brief talk on their research. Faculty from the Midwest chair these workshops which are of special value in providing a forum for students and postdoctoral fellows to share their research receive feedback and gain expertise in presentation skills. Symposium speakers are specifically asked and usually agree to attend the entire meeting; their attendance and participation in the workshops and poster sessions provide additional valuable feedback for trainees. The AIC is organized by the AIC Council which is composed of faculty and industry scientists representing participating Midwest states and institutions. The full Council meets each year at the conference and a subset thereof the Executive Committee holds an additional meeting in the spring to plan specific meeting details. The AIC encourages the participation of underrepresented minority groups through its John Wallace Minority Travel Award program. In addition the AIC offers a workshop on Careers in Immunology to encourage the participation of undergraduate students in the meeting. The AIC is a highly successful regional immunology meeting and has a major impact on the exchange of ideas between established investigators as well as the training of new scientists.


application_id: 7002258
project_number: 5R01AI051533-04
project_title: Vector Population Modification Using Wolbachia Symbionts
administering_ic: NIAID
award_notice_date: 2005-11-28
application_type: 5
activity_code: R01
ic: AI
serial_number: 051533
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2002-12-01
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-TMP(01)]
contact_pi_person_id: 7876895
contact_pi: DOBSON, STEPHEN LEONARD
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: 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
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by the applicant): Intracellular Wolbachia bacteria infect a diverse range of invertebrate hosts including medically important disease vectors. Many Wolbachia infections cause cytoplasmic incompatibility which effectively sterilizes mating between host individuals that harbor differing infection types. We have recently developed a model that defines the relationship between the Wolbachia infection frequency and host population size. Model simulations predict a novel strategy for suppressing insect populations. This strategy is based upon artificially prolonging an unstable coexistence that occurs when two or more incompatible Wolbachia types infect a host population resulting in host population suppression. As Wolbachia occurs naturally within a broad range of invertebrates this strategy is potentially applicable to a variety of medically and economically important systems. In addition to population suppression strategies population replacement strategies propose to employ Wolbachia as a vehicle for spreading desired genotypes (e.g. refractoriness to disease transmission) into vector populations. In the outlined research we will develop test and evaluate population suppression and replacement strategies predicted by model simulations in populations of the vector mosquito Culex pipiens. Cx. pipiens has been selected as the initial target due to its importance as a disease vector and the availability of multiple incompatible Wolbachia infections in naturally occurring Culex populations. Additional experiments will examine strategies for retarding arresting or reversing Wolbachia-based population replacement. The latter strategies represent an appropriate safeguard that may prove necessary if unexpected negative consequences become associated with population replacement. To improve strategy design implementation and evaluation aims will include better defining the infection dynamics of the Culex/Wolbachia symbiosis (e.g. maternal transmission rates and Wolbachia effects on host fitness) simplifying discrimination between Culex infection types and improving methods for field cage evaluation of Wolbachia control strategies.


application_id: 7002185
project_number: 5R01NS036660-07
project_title: Detection of presymptomatic Alzheimer's disease by fMRI
administering_ic: NINDS
award_notice_date: 2005-12-22
application_type: 5
activity_code: R01
ic: NS
serial_number: 036660
program_official: REFOLO, LORENZO
project_start_date: 1997-09-30
project_end_date: 2007-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)S]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant):  Alzheimer's disease (AD) is preceded by a period when detectable changes in brain function occur without warning symptoms. This period may be twenty years or longer. Activation measured by functional magnetic resonance imaging is reduced during confrontation naming in normal women who have increased risk of late-onset Alzheimer's disease at an average age of only 53 years. These same individuals have reduced activation in the posterior cingulate cortex during a memorization task among other disparities. Our hypothesis is that the altered functional MRI responses in naming working memory and memorization will quantifiably worsen with age due to progressive underlying Alzheimer's disease pathology. Disease-modifying treatments applied in this early pre-symptomatic stage of AD could have profound impact by preventing the onset of cognitive symptoms. Millions are currently being spent on large-scale prevention trials with AD symptoms as end-points. By providing a biomarker of pre-symptomatic AD progression fMRI could potentially reduce the duration and costs of such trials. This continuation proposal is designed to detect changes in brain function in high-AD risk individuals over time. We will study normal education-matched groups of high- and low-AD risk subjects in the age ranges 40-65 and 65-90 years using fMRI stimulus tasks which have previously demonstrated regional disparities in high-AD risk individuals. In addition we will repeat the naming and fluency fMRI studies performed previously in high- and low-AD risk individuals after an interval of five years in order to detect longitudinal changes in activation. The convergence of evidence from these cross-sectional and longitudinal studies could provide powerful evidence for a model of Alzheimer's disease as a relentless slowly progressive brain pathology that begins early in adult life but remains compensated until it produces clinical symptoms in its late stages.


application_id: 7001590
project_number: 5K08DE014845-04
project_title: Nuclear Co-Activators in Developing Craniofacial Tissue
administering_ic: NIDCR
award_notice_date: 2005-12-15
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: DE
serial_number: 014845
program_official: HARDWICK, KEVIN S
project_start_date: 2003-01-01
project_end_date: 2007-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7031215
contact_pi: PHILIPOSE, JOHN T
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 purpose of this application is to seek training support for a well-defined period of specialized study that will enable the applicant to develop into an outstanding clinician and research scientist. The applicant's commitment to a career in laboratory research is substantial and in the judgment of the candidate's mentors his potential to develop into an independent investigator is excellent. A comprehensive six-year plan for the applicant's training program is presented in the current application. The training program includes didactic coursework and supervised basic science research experiences that will culminate in attainment of the PhD degree in Pharmacology &Toxicology as well as completion of specialized postgraduate residency training in Orthodontics. A senior well-funded and experienced basic science research mentor and a clinical mentor with substantial research experience have been identified to provide cohesion and integration of the scientific growth and development of the applicant. A detailed research thesis proposal is presented in the current application that integrates the applicant's research training area (molecular mechanisms of craniofacial growth) with his orthodontic clinical training and future interests in academic dentistry. One hundred percent of the applicant's full-time professional effort as outlined in the training program proposed in the current application will be devoted to the goals of this K08 award.


application_id: 7001345
project_number: 5R01ES011295-05
project_title: Dioxin and Keratinocyte Differentiation
administering_ic: NIEHS
award_notice_date: 2005-11-30
application_type: 5
activity_code: R01
ic: ES
serial_number: 011295
program_official: HUMBLE, MICHAEL C
project_start_date: 2002-02-04
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-SSS-3(03)M]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): 2378Tetrachlorodibenzo-p-dioxin            \(TCDD\) is a ubiquitous environmental contaminant that promotes tumor              formation and modulates cellular differentiation via actions thought to involve     the aryl hydrocarbon receptor (AHR) signaling pathway. Given that study of          keratinocyte differentiation has been shown to lend important insights into the     mechanism(s) by which tumor promoters exert their effects and that this model       is amenable to a number of molecular techniques we have initiated studies of       differentiation to fulfill our long-term goal of understanding the role of TCDD     in carcinogenesis. Using normal human keratinocytes (NHK) we have shown that       administration of TCDD to NHK cells ultimately results in suppression of            differentiation and that this effect is accompanied by decreased levels of the      tumor suppressor protein p27Kipl Additional studies using the ARR antagonist      3'-methoxy-4'nitroflavone implied a role of the AHR in mediating TCDD's             suppression of differentiation. Finally it is apparent that TCDD suppresses        differentiation by decreasing the number of differentiating cells while             increasing the number of non-differentiating cells. These results and others       form the basis of our overall hypothesis that the ability of TCDD to suppress       differentiation is mediated by a decrease in the expression levels of the tumor     suppressor protein p27Kipl thereby diminishing the p27Kipl differentiation         signal. To test this hypothesis we will use flow cytometry western blot           analysis real time PCR and adenovirus-mediated over expression systems to          determine whether: 1) the ability of TCDD to suppress differentiation requires      suppression of the expression of p27Kipl 2) TCDD regulates the p27Kipl protein     at the transcriptional or post-transcriptional levels 3) the ability of TCDD       to suppress the expression of p27Kipl and differentiation requires the AHR and      ARNT proteins 4) suppression of differentiation by TCDD results in increased)      proliferation and 5) and the actions of TCDD on differentiation occur at the)      genomic level.

project_terms:
aromatic hydrocarbon receptor;carcinogenesis;cell differentiation;cell growth regulation;cell line;cell proliferation;chemical structure function;dioxins;environment related neoplasm /cancer;environmental contamination;flow cytometry;gene environment interaction;gene induction /repression;genetic regulation;green fluorescent proteins;intermolecular interaction;keratinocyte;microarray technology;molecular pathology;neoplasm /cancer genetics;polymerase chain reaction;receptor coupling;time resolved data;transcription factor;tumor suppressor proteins;western blottings


application_id: 6999788
project_number: 5R01DE015720-03
project_title: Oral Pathogens: Polymicrobial Virulence Interactions
administering_ic: NIDCR
award_notice_date: 2005-12-22
opportunity_number: PA-03-047
application_type: 5
activity_code: R01
ic: DE
serial_number: 015720
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-04-01
project_end_date: 2006-10-15
study_section: Oral Biology and Medicine Subcommittee 1[OBM-1]
contact_pi_person_id: 7875070
contact_pi: LAKSHMYYA, KESAVALU NAIDU
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: The predominant polymicrobic infection of mankind is expressed clinically as periodontal disease which afflicts nearly one-half of the population by 50 years of age and is related to development of a microbial biofilm colonizing the subgingival sulcus. The suggested mechanisms of pathogenesis are varied in most part due to the complex microbial community consisting of numerous bacterial taxa viruses and fungi. Nevertheless certain of these subgingival microbial consortia are consistently correlated with a progressive destruction of sot_ and hard tissue that have been well documented to occur in clinical settings (i.e. periodontitis). Various in vivo and in vitro investigations have suggested that the dominance of selected species in the subgingival ecology results from both microbial synergistic and antagonistic relationships. These have been linked to the nature of available surfaces for colonization available nutrients and physiologic "food webs" that exists within the community. Molecular microbiologic studies have described nearly 500 species of bacteria that can inhabit this ecological niche although several specific microbial complexes have been described at sites of progressing tissue destruction. A predominant consortia identified in a majority of adult periodontitis patients consists of Porphyromonas gingivalis TannereIla forsythensis [Bacteroides forsythus] and Treponema denticola. The correlation of this consortium with disease has been proposed to result from synergistic physiological host evasion and/or tissue destructive capabilities among the component species. The objectives of this R01 application are to test a hypothesis that this polymicrobic consortium comprises a "virulence web" that synergistically increases tissue destructive host responses and the consortia to be less effective modify that host immune responses. Three Specific Aims are proposed using an animal model system to test this hypothesis: (1) To determine molecular interbacterial synergistic virulence effects of P. gingivalis T. forsythensis and T denticola in an in vivo calvarial bone resorption model (2) To determine the characteristics of acquired humoral immune responses to a polymicrobial infection and the ability of this response to modulate in vivo calvarial bone resorption and (3) To determine the characteristics of active humoral immune responses to polymicrobial immunization and ability of this response to modulate bone resorption. The long-range goals from this study will be to document microbial interactions virulence synergisms characterize both acquired and active immune responses and relate these to alterations in tissue destruction and bone resorption. The significance of this application is that clinical observations have shown the ability of oral microorganisms to translocate into the circulation and manifest systemically as endocarditis brain/kidney/lung and intra-abdominal infections and contributing to risks of diabetes coronary artery disease osteoporosis obesity and preterm birth. Consequently the host response to these chronic infections must be considered as critical to general health.

project_terms:
Bacteroides gingivalis;Treponema;bacterial cytopathogenic effect;bacterial vaccines;chemokine receptor;chronic disease /disorder;cytokine receptors;drug interactions;enzyme linked immunosorbent assay;gene induction /repression;host organism interaction;humoral immunity;immune response;leukocyte activation /transformation;microarray technology;microorganism growth;microorganism interaction;oral bacteria;pathologic bone resorption;pathologic process;periodontitis;periodontium disorder;polymerase chain reaction;secondary infection;transcription factor;virulence


application_id: 6999698
project_number: 5R01CA035635-21
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2005-12-12
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: FU, YALI
project_start_date: 1984-03-01
project_end_date: 2007-12-31
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
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: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA-targeted drugs is that the fundamental molecular mechanisms that govern sequence and structural-selective ligand binding to DNA are poorly understood. The rational design of new DNA-targeted drugs requires a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of specificity. The long-range goal of the proposed research is to understand the molecular mechanism of intercalation reactions with emphasis on the energetic basis of their sequence and structural selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Research in the next funding period will focus on innovative studies designed to clarify the mechanisms that govern structural and sequence selective ligand binding to nucleic acids. Specific aims include: 1. Use and refinement of a highthroughput competition dialysis assay for the identification and characterization of structural selective ligand binding to nucleic acids. 2. Characterization of ligand binding to DNA:RNA hybrid structures. 3. Characterization of regional-selective drug binding by a novel calorimetric "bootprinting" method. The results of these studies will: 1. Provide a definitive taxonomy of structural selective ligand binding to nucleic acids along with a description of the energetic basis of that structural selectivity 2. Provide fundamental information to guide the rational design of compounds targeted to DNA:RNA hybrid structures a target of enormous biological significance. 3. Provide a new tool for the quantitative study of drug-DNA interaction in long (genomic) pieces of DNA.


application_id: 6998848
project_number: 5R01NS038126-09
project_title: GENE THERAPY FOR SPINAL CORD REGENERATION
administering_ic: NINDS
award_notice_date: 2005-12-01
application_type: 5
activity_code: R01
ic: NS
serial_number: 038126
program_official: KLEITMAN, NAOMI
project_start_date: 1999-01-01
project_end_date: 2006-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-2(01)]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): Neurons have the intrinsic ability to                      regenerate after injury to the adult mammalian spinal cord as demonstrated by       transplantation of either peripheral nerves Schwann cells or fetal spinal         cord tissue. These axons regenerate into and throughout these transplants but      fail to grow significant distances back into the adult central nervous system       (CNS). Axons that do regenerate into the adult CNS are randomly organized and       not directed specifically towards their targets. Several hypotheses indicate        that changes in the growth promoting state either by active inhibition or the      lack of a good growth supportive substrate produce an environment that is          refractory to axonal regeneration. This application is designed to examine the      hypothesis that a selective expression of growth-supportive and guidance            molecules can be used to increase axonal regeneration and direct these axons to     select target regions. To test this hypothesis we will examine axonal growth       in two models. The first is the well-established dorsal root entry zone model       to examine regeneration from separate sensory populations through the dorsal        root entry zone (DREZ) and into the spinal cord. We have previously                 demonstrated robust axonal regeneration into both appropriate and aberrant          targets. The first two specific aims will use this model. The second is a novel     in vivo guidance model that uses an expression pathway to guide axonal growth       from neuronal transplants towards a distant target location. We propose to          accomplish the following specific aims: 1) to determine if co-expression of         nerve growth factor (NGF) and semaphorin 3a within the adult spinal cord will       direct the regeneration of sensory axons to appropriate target locations. 2) To     enhance proprioceptive axonal regeneration by selective expression of               neurotrophin (NT)-3 or tyrosine kinase (trk) C-receptor. 3) To direct the           growth of axons from a neuronal transplant along a complex pathway to a distant     target location. 4) To generate an expression pathway that can induce axonal        growth from a transplant through or around a lesion site and towards a            distant target location. For the proposed experiments recombinant adenovirus       will be used to transfer cellular adhesion molecules (CAMs) laminin                neurotrophins or chemorepulsive (e.g. semaphorin 3a) into the endogenous CNS      environment. Regeneration of sensory axons through the DREZ and into the spinal     cord will be examined using behavioral assessments for functional recovery and      tract tracing techniques. This grant application is designed to better define       the molecular mechanisms that influence axonal regeneration and guidance within     the adult CNS with the ultimate goal of inducing axonal regeneration in the        spinal cord to appropriate locations while discouraging aberrant connections.

project_terms:
Adenoviridae;astrocytes;axon;gene delivery system;gene expression;gene targeting;gene therapy;immunocytochemistry;laboratory rat;nerve growth factors;nervous system regeneration;nervous system transplantation;neurogenesis;proprioception /kinesthesia;spinal cord;spinal ganglion;transfection /expression vector


application_id: 6998414
project_number: 5R01DK067581-02
project_title: Histone Acetylation and Insulin Gene Expression
administering_ic: NIDDK
award_notice_date: 2006-02-09
opportunity_number: PA-02-100
application_type: 5
activity_code: R01
ic: DK
serial_number: 067581
program_official: SATO, SHERYL M
project_start_date: 2005-02-01
project_end_date: 2010-01-31
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 7875121
contact_pi: OZCAN, SABIRE
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
DNA binding protein;acetylation;blood glucose;chromatin immunoprecipitation;gene expression;genetic transcription;histones;insulin;laboratory rat;mass spectrometry;pancreatic islets;phosphorylation;polymerase chain reaction;recombinant proteins;site directed mutagenesis;tissue /cell culture;transcription factor


application_id: 6998397
project_number: 5R01CA060872-10
project_title: Mechanism of Apoptosis by Par4
administering_ic: NCI
award_notice_date: 2005-12-08
opportunity_number: PA-99-081
application_type: 5
activity_code: R01
ic: CA
serial_number: 060872
program_official: YASSIN, RIHAB R
project_start_date: 1995-09-30
project_end_date: 2007-12-31
study_section: Special Emphasis Panel[ZRG1-ET-2(01)M]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prostate cancer is the second leading          cause of cancer death in American men. It has been recognized that prostate         cancer progression results from inhibition of apoptotic mechanisms rather than      from uncontrolled cell proliferation. In addition to the loss of wild-type          tumor suppressor and pro-apoptotic functions of p53 or PTEN elevated               expression of anti-apoptotic proteins including Bcl-2 Bcl-xL and activated        Akt or NF-kappaB have been noted in human prostate cancer specimens or cell         lines. Toward the goal of identifying molecules that can potentially antagonize     or override the anti-apoptotic mechanisms and prevent progression of the            disease we performed a differential screen for genes whose expression was          upregulated when androgen-independent prostate cancer cell cultures were            induced to undergo apoptosis. One such gene induced exclusively during              apoptosis of cancer cell lines and of the rat ventral prostate after castration     was prostate apoptosis response-4 (par-4). Ectopic expression of par-4 induces      apoptosis in prostate cancer cells that show aberrantly elevated NF-kappaB          activity. Apoptosis by par-4 occurs in the absence of wild type p53 or PTEN        and in the presence of Bcl-2 or Bcl-xL protein. Apoptosis by par-4 is not           restricted to cell culture paradigms; solid tumors resulting from implants of       prostate cancer cells in nude mice undergo apoptosis and remarkable reduction       in tumor volume upon adenoviral expression of par-4. These findings indicate        that Par-4 expression is sufficient on its own in the absence of another           genotoxic insult to induce apoptosis in prostate cancer cells.                                                                                                         The proposed study will: (1) determine whether inhibition of NF-kappaB              transcription activity is functionally essential for apoptosis by Par-4;            determine the mechanism of NF-kappaB inhibition by Par-4; and functionally          characterize the downstream targets of NF-kappaB that are regulated by Par-4;       (2) identify the domains of Par-4 that induce NF-kappaB inhibition and              apoptosis; and (3) identify the pro-death pathway activated by Par-4. The           studies will provide an insight into the molecular determinants of apoptosis in     prostate cancer cells. Because Par-4 on its own does not induce apoptosis in        normal or non-transformed cells these studies may provide the groundwork to        develop Par-4 or its active domains as candidate molecules for therapy of           prostate cancer.

project_terms:
apoptosis;gene induction /repression;laboratory rat;neoplasm /cancer genetics;nuclear factor kappa beta;prostate neoplasms;protein protein interaction;protein structure function;transcription factor;tumor suppressor proteins


application_id: 6992786
project_number: 1R41GM075628-01
project_title: Enhancement of the Baculovirus Expression Vector System
administering_ic: NIGMS
award_notice_date: 2005-08-29
application_type: 1
activity_code: R41
ic: GM
serial_number: 075628
program_official: PREUSCH, PETER
project_start_date: 2005-08-29
project_end_date: 2007-08-05
study_section: Special Emphasis Panel[ZRG1 BCMB-L (11)]
contact_pi_person_id: 1857794
contact_pi: WEBB, BRUCE A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-29
project_abstract:
DESCRIPTION (provided by applicant):  The baculovirus expression vector system (BEVS) is one of the most powerful and versatile eukaryotic expression systems. The BEVS is being used to produce antigens for vaccine development to manufacture human therapeutics to develop faster acting biological insecticides and as a protein expression system for a multitude of research project. However a limitation of any lytic viral expression system including BEVS is that lysis of the infected cells interrupts protein expression and requires repetitive infections which results in decreased productivity levels and high production cost. ParaTechs and the Webb laboratory at the University of Kentucky have identified a gene family from an insect virus that delayed death and lysis of baculovirus infected cells and significantly enhanced recombinant protein production. This enhanced protein production presents a significant commercial opportunity that is the focus of this proposal. ParaTechs is seeking STTR support to define the potential utility and commercial value of our enhanced BEVS technology by determining the level of enhanced protein production and evaluating alternative methods of delivering the protein to virus-infected cells. In this proposal we seek support to quantify enhancement of expression of common intracellular reporter proteins and to quantify the effect of the enhanced BEVS technology on the expression of membrane bound and secreted proteins. We envision that ParaTechs' enhanced BEVS will be more efficacious in synthesis of membrane-bound and secreted proteins because the prolonged integrity of the cells infected with the enhanced BEVS may support more efficient protein secretion.     A critical element for many modern medical treatments entails the ability to produce biologically active proteins with a high degree of safety. Baculovirus expression vectors have proven to have multiple advantages for protein production in a variety of applications such as production of proteins for vaccine development and human therapeutics for a number of diseases which will improve the quality of life for millions of people. The technology to be developed with this award has potential to significantly improve efficacy of protein production in all such medical applications.

project_terms:
Baculoviridae;biotechnology;cell line;cell transformation;gene delivery system;gene expression;genetic translation;insect virus;membrane proteins;protein quantitation /detection;recombinant virus;secretory protein;technology /technique development;transfection /expression vector


application_id: 6992720
project_number: 5R01DK054774-08
project_title: DHEA:PPAR-Dependent and Independent Mechanisms of Action
administering_ic: NIDDK
award_notice_date: 2006-01-06
application_type: 5
activity_code: R01
ic: DK
serial_number: 054774
program_official: MARGOLIS, RONALD N
project_start_date: 1999-03-15
project_end_date: 2007-12-31
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
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: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): We hypothesize that the protective action of DHEA in part involves the modulation of the expression of cytochrome P450 monooxygenase(s) and/or other detoxification enzymes required for the bioactivation and disposition of chemicals through both Peroxisome Proliferator Activated Receptor Alpha dependent and independent pathways. Several studies have demonstrated that DHEA ameliorates environmental diseases at dosages lower than those required for DHEA-dependent peroxisome proliferation. The goal of Specific Aim 1 is to establish whether metabolites of DHEA serve as proximal activators of PPAR or other nuclear receptors using cell-based reporter assays. We will test the ability of DHEA metabolites to activate PPAR-alpha PXR CAR LXR and FXR/BAR using reporter assays. The goal of Specific Aim 2 is to test the hypothesis that 7a-hydroxy-DHEA and 7-oxo-DHEA are formed from DHEA in the hippocampus of rats and to characterize the gene regulation of these enzymes. The effect of DHEA treatment on levels of 7a-hydroxy- and 7-oxo-DHEA in the dentate gyrus region of hippocampus in rats will be determined. The goal of Specific Aim 3 is to test the hypothesis that DHEA treatment activates PPAR by altering PPAR phosphorylation. Therefore we will test the hypothesis that DHEA activates PPAR by affecting its phosphorylation status in rat hepatocytes and increases its action in transcription. The goal of Specific Aim 4 is to test the hypothesis that the induction of Cyp3all in mouse liver by DHEA treatment is a PXR-dependent process. We will use PPAR-alpha and PXR-null mice to test the hypothesis that induction of Cyp3a11 and other target genes by DHEA is PXR-dependent. The goal of Specific Aim 5 is to test the hypothesis that DHEA induces gene expression through processes other than those mediated by PPAR-alpha and PXR. We will test changes in gene expression after DHEA treatment of wild-type PPAR -null and PXR-null mice using a mouse gene array to assess common pathways of regulation of these genes through PPAR PXR or unknown signaling pathways.


application_id: 6992446
project_number: 1R43AR052984-01
project_title: Partial-Thickness Wound Healing via Topical ATP Delivery
administering_ic: NIAMS
award_notice_date: 2005-09-06
application_type: 1
activity_code: R43
ic: AR
serial_number: 052984
program_official: BAKER, CARL
project_start_date: 2005-09-09
project_end_date: 2007-02-28
study_section: Special Emphasis Panel[ZRG1 MOSS-D (12)]
contact_pi_person_id: 3148961
contact_pi: EHRINGER, WILLIAM D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 177868366
duns_number: 177868366
fips: US
organization_id: 10002342
organization_name: NOVERA, LLC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021250
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-09
budget_end_date: 2007-02-28
assistance_listing_number: 93.846
project_abstract:
DESCRIPTION (provided by applicant): Autologous skin grafts are the preferred method for covering large burn surfaces. The healing of autologous skin grafts and the re-harvesting of skin donor sites for autologous skin grafts is often slowed by the altered metabolic state of burn victims. Accelerating the healing of the skin graft donor site would increase the number of sites that could be used and decrease the re-harvest time between grafts. One of the single most important factors in healing a skin graft donor site is the neovascularization and reestablishment of oxygen tension and nutrient levels in the wound. Ultimately the oxygen and some of the nutrients are used to produce adenosine triphosphate (ATP). ATP is used for nearly every aspect of the wound healing process including protein synthesis growth factor production and mitosis. We have developed a technique for the rapid and controlled delivery of ATP using fusogenic lipid vesicles (VitaSol). VitaSol when applied topically provides wounds with ATP during hypoxic periods and accelerates the healing process of acutely wounded skin. The long-term objective of this proposal is to develop a safe and effective technique to accelerate the healing of partial-thickness wounds in swine using VitaSol and prepare the compound for a Phase I clinical trial for autologous skin grafts. The specific aims of phase I project are: 1) Determine the mechanism by which VitaSol accelerates partial-thickness wound healing in swine. We hypothesize that the beneficial effects of increasing wound ATP levels are related to increased angiogenesis increased angiogenic growth factor synthesis and accelerated mitosis of keratinocytes and fibroblasts; 2) Optimize the formulation of VitaSol for maximal acceleration of partialthickness wound healing in swine. Once the mechanism of how VitaSol accelerates wound healing is known the formulation will be mixed with an excipient to create a hydrogel which can be easily applied to wounds and helps maintain ATP levels during a 24 hour period; and 3) Stabilize the optimized VitaSol formulation and examine efficacy in swine. The optimized VitaSol formulation will be prepared as freezedried powder and examined for stability and efficacy in partial-thickness wound healing. The success of this project is likely to have a major impact on medicine. It will enhance our understanding of how ATP delivery to wounds affects the wound closure rate and time to complete wound closure. Our paradigm shift in wound healing will provide a totally new therapeutic approach that could significantly increase number and frequency with which skin grafts can be harvested and used clinically.

project_terms:
adenosine triphosphate;angiogenesis;angiogenesis factor;autologous transplantation;biomaterial development /preparation;biotechnology;burn therapy;cell growth regulation;fibroblasts;gel;injury;keratinocyte;microcapsule;nonhuman therapy evaluation;regeneration;skin disorder;skin transplantation;swine;topical drug application;vesicle /vacuole;wound healing


application_id: 6991727
project_number: 1R41EY015336-01A2
project_title: AMD-FCRx to Restore Damaged Pigment Epithelium
administering_ic: NEI
award_notice_date: 2005-09-19
application_type: 1
activity_code: R41
ic: EY
serial_number: 015336
suffix: A2
program_official: WUJEK, JEROME R
project_start_date: 2005-09-30
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-F (12)]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140644969
duns_number: 140644969
fips: US
organization_id: 10001459
organization_name: REGENEREX, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-30
budget_end_date: 2007-08-31
project_abstract:
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. The hallmark of the disease is retinal pigment epithelial (RPE) dysfunction with subsequent death of the foveal photoreceptors. Hematopoietic stem cells (HSC) have been demonstrated to repair damaged tissues including heart muscle and nerve under selected conditions. Allogeneic RPE transplantation has been attempted to restore the damaged RPE. However allogeneic RPE cells do not attach to senescent Bruch's membrane efficiently and do not efficiently repair the defect.  Furthermore rejection occurs after allogeneic adult RPE transplantation unless immunosuppression is employed. Thus the development of a syngeneic HSC product (AMD-FCRx) to treat AMD and avoid the need for systemic immunosuppression would be a major advance. We were the first to discover CD8+/TCR- graft facilitating cells (FC) a novel cell in bone marrow that significantly enhances HSC engraftment in syngeneic recipients. FC express SDF-1 a critical chemokine for HSC homing and CXCR4 its unique receptor that is also present on HSC We have strong preliminary data to show that FC enhance homing of HSC to damaged RPE. As such FC may play a critical role in HSC-mediated repair of damaged RPE. In phase I of this application we will define the optimal composition of HSC and FC for transplantation to replace damaged RPE. Specifically we will optimize strategies to promote homing of HSC to areas of RPE damage or loss attach to normal Bruch's membrane proliferate and fill in the defect created and differentiate into mature RPE cells. These studies will lay the groundwork for Phase II in which the AMD-FCRx product will be tested in a more rigorous model of AMD and then translated into a phase I clinical protocol.  Regenerex LLC has been incorporated to commercialize the benefits of bone marrow graft engineering technologies for treatment of blood disorders and tissue repair. We have assembled a highly talented team with expertise in ophthalmology stem cell biology and transplantation. A unique collaboration between the Louisville Medical Center Development Corporation Jewish Hospital the State of Kentucky and the University of Louisville to develop a biomedical incubator has allowed Regenerex LLC to move into office space located at 201 East Jefferson Street. Our long-term goal is to exploit the potential of the facilitating cell by marketing a well-defined HSC cellular therapeutic product for worldwide distribution to treat AMD. Regenerex is a woman-owned business in Kentucky an EPSCoR state.

project_terms:
cell differentiation;cell migration;cell proliferation;eye surgery;hematopoietic stem cells;hematopoietic tissue transplantation;laboratory mouse;macular degeneration;retinal pigment epithelium;stem cell transplantation;therapy design /development;visual photoreceptor


application_id: 6990582
project_number: 5R01AI053101-04
project_title: Borrelia burgdorferi LuxS-mediated quorum sensing
administering_ic: NIAID
award_notice_date: 2005-11-14
application_type: 5
activity_code: R01
ic: AI
serial_number: 053101
program_official: PERDUE, SAMUEL S
project_start_date: 2003-06-15
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-BM-1(01)Q]
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: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): The spirochete Borrelia burgdorferi the causative agent of Lyme disease is transmitted to humans and other warm-blooded animals through the bite of infected Ixodes spp. ticks. The establishment of B. burgdorferi infection involves numerous interactions between the bacteria and a variety of vertebrate host and arthropod vector tissues. Different bacterial proteins are required at specific points of this infectious cycle and precise regulation of the synthesis of such proteins is essential for successful infection to occur. We have discovered that these spirochetes utilize a regulatory mechanism to control protein expression patterns that involves a chemical signal known as autoinducer-2 (AI-2). This molecule is produced by the B. burgdorferi LuxS protein which we have demonstrated to be a functional enzyme. Our preliminary studies suggest that B. burgdorferi can regulate LuxS synthesis. Addition of AI-2 to cultured B. burgdorferi dramatically alters the expression of more than 50 different proteins increasing expression levels of some proteins while decreasing expression of others. Through this mechanism a population of Lyme disease spirochetes may synchronize production of proteins needed for infection processes. We hypothesize that B. burgdorferi uses AI-2 as an important signaling molecule to control expression of proteins during the natural infectious cycle of the Lyme disease spirochetes. The proposed studies will characterize the expression of LuxS during bacterial infection the mechanisms by which B. burgdorferi controls synthesis of AI-2 and functions of AI-2-regulated proteins. Results from these studies will enhance our understanding of the complex interactions between B. burgdorferi and its hosts as well as identifying potential bacterial targets for improved therapies to prevent and treat Lyme disease.


application_id: 6990425
project_number: 3R01HL059225-06S1
project_title: Metallothionein and Adriamycin Cardiotoxicity
administering_ic: NHLBI
award_notice_date: 2004-12-10
application_type: 3
activity_code: R01
ic: HL
serial_number: 059225
suffix: S1
program_official: MASSICOT-FISHER, JUDITH
project_start_date: 1999-04-01
project_end_date: 2006-11-30
study_section: Alcohol and Toxicology Subcommittee 1[ALTX]
contact_pi_person_id: 1877629
contact_pi: KANG, Y JAMES
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EXCEED THE SPACE PROVIDED. Cardiotoxicity due to oxidative stress compromises effective use of Adriamycin in cancer reatment. Metallothionein (MT) a potent antioxidant protects the heart from Adriamycin-induced toxicity. To develop experimental and clinical approaches to preventing cardiotoxicity of Adriamycin in the dose-schedules that tumors are eradicated we propose this continuation study to test the hypothesis that MT protects from chronic and late-onset cardiotoxicity induced by efficacious treatment of tumors with Adriamycin. A novel MT-overexpressing and tumor-bearing mouse model will be used to carry out the following aims: (1) to determine the efficacy of MT protection from Ariamycin-induced chronic and late-onset cardiotoxicity newly developed breast tumor-bearing transgenic and non-transgenic BALB/c mice will be treated with dose-schedules of Adriamycin to which the tumors are fully responsive. Chronic cardiotoxicity will be determined by morphometric analysis functional assessment and molecular markers for myocardial remodeling and heart failure. (2) To explore possible clinical application of MT induction as an approach to preventing Adriamycin chronic and late-onset cardiotoxicity we will develop an experimental strategy for a long-term cardiac MT induction by bismuth or hinokitiol in BALB/c mice. The dose-effect of these inducers on MT expression in multiple organs including the heart as well as potential toxic effects for their long-term application will be examined. (3) To develop experimental procedures for application of MT myocardial protection in cancer therapy several murine tumor cell lines that have proven to grow in the BALB/c mice will be implanted. The tumor-bearing mice will be treated with the defined MT-induction protocol. The expression of MT in tumors as well as Adriamycin cardiac toxicity and cancer therapeutic efficacy will be examined. This study would provide a substantial base of information for understanding MT protection against Adriamycin chronic and late-onset cardiotoxicity potentially leading to an improved use of this highly effective antJcancer drug. PERFORMANCE SITE ========================================Section End===========================================

project_terms:
apoptosis;bismuth;breast neoplasms;cardiovascular stress test;cell line;disease /disorder model;doxorubicin;drug adverse effect;gene expression;genetically modified animals;heart failure;laboratory mouse;metallothionein;monoterpenes;morphometry;muscle function;myocardium;myocardium disorder;neoplasm /cancer chemotherapy;nonhuman therapy evaluation;protooncogene;terminal nick end labeling;toxicology


application_id: 6989747
project_number: 5R01NS040592-06
project_title: Axonal growth and guidance for nervous system repair
administering_ic: NINDS
award_notice_date: 2005-12-15
application_type: 5
activity_code: R01
ic: NS
serial_number: 040592
program_official: KLEITMAN, NAOMI
project_start_date: 2000-03-27
project_end_date: 2009-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(02)M]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_terms:
Adenoviridae;afferent nerve;behavior test;biodegradable product;brain derived neurotrophic factor;dorsal horn;dorsal root;ephrins;functional ability;gene expression;heat stimulus;immunocytochemistry;implant;laboratory rat;mechanoreceptors;motor neurons;nerve growth factors;nerve injury;nervous system regeneration;neuronal guidance;pain;recombinant virus;transfection /expression vector


application_id: 6989042
project_number: 5R01NS045726-03
project_title: Calpain Inhibition Strategies for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2005-12-15
application_type: 5
activity_code: R01
ic: NS
serial_number: 045726
program_official: KLEITMAN, NAOMI
project_start_date: 2004-01-01
project_end_date: 2007-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-3(01)Q]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-01-01
project_abstract:
DESCRIPTION (provided by applicant): Calcium-activated neutral proteases (calpains) are excessively activated soon after spinal cord injury (SCI) with elevated activity persisting for at least 24h postinjury. Calpain substrates include cytoskeletal proteins signaling proteins and cell life/death proteins. While calpains play normal roles in cell signaling and plasticity their over activation following SCI is strongly implicated in secondary neuron death axonal degeneration and oligodendrocyte death and demyelination. Calpain inhibition represents a rational and feasible therapeutic target for postinjury intervention following SCI. In previous studies postinjury administration of calpain inhibitors attenuated axonal damage and loss of neurofilament proteins but functional outcome was not examined and the magnitude of calpain inhibition was not measured. In some studies the inhibitors used were not cell permeable and in others the low inhibitor concentrations may not have inhibited calpain activity. Therefore the hypothesis that calpain inhibition is neuroprotective following SCI has not been tested. Effective calpain inhibition following SCI presents a number of challenges. Synthetic calpain inhibitors are not specific for calpain have relatively weak potency and have a plasma half-life of only 2h. While short-term calpain inhibition may be beneficial long-term inhibition can be detrimental to normal cell function. The first Specific Aim of this proposal will examine the hypothesis that postinjury administration of synthetic calpain inhibitors can significantly attenuate calpain activity and the proteolysis of calpain substrates following spinal cord injury. We will use both active site-directed peptide calpain inhibitors and a non-peptide inhibitor acting at the calcium-binding domain and will examine both intravenous intrathecal and intraspinal delivery of the calpain inhibitors. Having identified conditions that provide effective calpain inhibition the second Aim will examine the hypothesis that postinjury calpain inhibition can significantly attenuate lesion volume and improve functional outcome. The third Specific Aim will focus on the endogenous calpain inhibitor calpastatin and will examine the hypothesis that fusion proteins consisting of calpastatin and the Tat protein transduction domain will result in a potent and specific cell-permeable calpain inhibitor. The fourth Specific Aim examines the hypothesis that expression and secretion of the Tat-catpastatin will provide effective calpain inhibition in neighboring cells. Together the goal of the proposed studies is to develop effective strategies for calpain inhibition following SCI.

project_terms:
calpain;drug delivery systems;embryo /fetus tissue /cell culture;enzyme activity;enzyme induction /repression;enzyme therapy;fluorescence microscopy;histology;intravenous administration;laboratory rat;lumbar puncture;nervous system disorder chemotherapy;neuropeptides;neurophysiology;neuroprotectants;nonhuman therapy evaluation;protease inhibitor;spinal cord injury;western blottings


application_id: 6988175
project_number: 2P20RR015576-06
project_title: Mechanisms of plasticity and repair after SCI
project_terms: nervous system regeneration;neural plasticity;spinal cord injury
administering_ic: NCRR
award_notice_date: 2005-08-01
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015576
program_official: GOROSPE, RAFAEL
project_start_date: 2000-09-15
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRR1 RI-8 (02)]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT
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
project_abstract:
DESCRIPTION (provided by applicant):    
This COBRE renewal brings together 5 junior or just recently funded Principal Investigators whose research focuses on spinal cord injury (SCI) and repair. They will be mentored by 3 senior Investigators with strong track records in SCI research. Five Cores will be extensively used by all of these Projects. This COBRE represents a true Research Center and not a collection of individual Projects as the expertise of these Investigators is broad based and the success of individual Projects will depend on strong collaborations with other Projects and Cores. The Specific Aims of this COBRE are:  
1. To develop new therapeutic approaches to the treatment of SCI that can be utilized clinically.  
2. To further strengthen the independent research programs of each Principal Investigator that will ultimately lead to additional R01 or P01 support.  
3. To continue to develop and support the KSCIRC infrastructure through its Core facilities.  
4. To facilitate collaborative research projects between the COBRE Principal Investigators as well as other University of Louisville faculty that will lead to significant scientific findings that are unlikely to be achieved by individual research activities.  
5. To continue to be a leading SCI Research Center recognized both nationally and internationally and develop a reputation that will attract outstanding graduate students postdoctoral fellows and faculty.  
The five Projects are: 1) Heat shock proteins in spinal cord neural survival 2) GSK3B as a target for pro-neuronal survival in CMS neurons 3) Remyelination as a mechanism for spinal cord repair 4) PKC regulation of sensory regeneration across CSPG after SCI and 5) Gender differences in chronic SCI pain. The 5 Cores are: Administrative and Research Support Cell Culture and Molecular Biology Surgery and Veterinary Care Electrophysiology and Behavior and Microscopy.


application_id: 6988062
project_number: 2P20RR015592-06
project_title: Center of Biomedical Research Excellence- Women's Health
administering_ic: NCRR
award_notice_date: 2005-08-29
opportunity_number: RFA-RR-04-008
application_type: 2
activity_code: P20
ic: RR
serial_number: 015592
program_official: SAYRE, MICHAEL
project_start_date: 2000-09-15
project_end_date: 2010-04-30
study_section: Special Emphasis Panel[ZRR1 RI-8 (02)]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
The objectives of the Center of Biomedical Research Excellence in Women's Health (COBRE-WH) are to deepen our understanding of the unique role of gender and female reproductive hormones in the manifestation of health and disease and use this multi-disciplinary focus as a platform to develop research teams comprised of senior and junior level investigators capable of successfully competing for NIH grant support as independent research centers. We will achieve these objectives by: (1) assembling a cadre of junior and senior level scientists paired together as a research team to examine timely and important questions related to gender reproductive hormones and hormone action (2) providing junior faculty with state-of-the-art multidisciplinary training in concepts relevant to women's health (3) mentoring junior faculty in research projects focused on women's health that will insure that they successfully establish independent NIH-funded research careers (4) supporting shared core facilities to optimize use by COBRE-WH faculty in cutting edge methods and (5) building research teams that will be competitive for extramural funding to establish stand alone Centers. A critical challenge for the COBRE-WH during the next funding period is to become an independent extramurally supported Center(s). To meet this challenge we have structured our COBRE-WH program in a manner that we will have 5 "research teams" or projects that interact with each other in terms of concepts and methods. Each project will be directed by a senior investigator that will incorporate current or previous COBRE-WH supported junior investigators into the project. These research projects are included because they attack critical questions in women's health. Thus junior investigators will be mentored by established NIH-funded faculty who utilize a broad spectrum of state-of-the-art integrative clinical cellular and molecular approaches to probe critical questions in women's health research. This organizational structure will insure that the proposed COBRE-WH program will meet the challenge of increasing the NIH-funded research in the Commonwealth of Kentucky while pursuing the goal of developing the COBRE-WH into as many as 3 separate yet interactive independent program projects or Centers.

project_terms:
clinical research;estradiol;estrogen receptors;female;hormone regulation /control mechanism;women&apos;s health


application_id: 6987008
project_number: 3R25HG002503-03S1
project_title: Education in Genetic Ethics ('EDGE')
administering_ic: NHGRI
award_notice_date: 2004-11-30
opportunity_number: PA-00-134
application_type: 3
activity_code: R25
ic: HG
serial_number: 002503
suffix: S1
program_official: MCEWEN, JEAN
project_start_date: 2002-05-03
project_end_date: 2006-04-30
study_section: National Human Genome Research Institute Initial Review Group[GNOM]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
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 MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The Institute for Bioethics Health Policy and Law at the University of Louisville and collaborators from The Hastings Center Stanford University Center for Biomedical Ethics and Michigan State University propose to develop offer and evaluate a research ethics training program in human genetics called EDGE or Education in Genetics Ethics. Course development will be responsiveness to identified unmet needs in research ethics training based upon a large scale national needs assessment conducted among a target audience of investigators involved in genetics research including academicians clinicians laboratory practice professionals genetic counselors nurses and others involved in human genetics research. he target audience will be recruited as course participants with special effort made to recruit those who have been traditionally under-represented in the field of research ethics. Interactive instruction for course participants will occur through a 2-day on-site workshop offered at different locations throughout the U.S. six times a year and a computer-mediated Web-based course. The on-site course will include short didactic sessions that address genetic research issues using general ethics principles; small group problem-solving and discussion sections involving genetics research ethics issues using specially developed case studies; plenary sessions highlighting historical and developing trends in the field provided by experienced investigators and scholars in the field; and evaluation sessions to assess research ethics experience and knowledge gained. The computer-mediated interaction through a specially developed Web site that includes instructor-provided electronic text or recorded presentation option on- line readings asynchronous participant problem-solving case study modules interactive e-mail chat room and e-board facilities links to relevant Web-based resources and on-line evaluation materials. Both courses will provide continuing education credit and are easily sustainable. The specific aims of this project are to: 1) develop a specialized and transportable research ethics training program based upon the unmet needs of genetics research; 2) deliver the EDGE training program using on-site and online methods; and 3) evaluate the impact of the course. The project includes a curriculum steering committee comprised of experts in the field of genetics research and genetics education as well as select project team members to provide on-going advance to the project.

project_terms:
clinical research;computer assisted instruction;curriculum;education evaluation /planning;educational resource design /development;ethics;genetics;health related legal;health science research;social perception


application_id: 6986800
project_number: 5R01NS046517-02
project_title: Estrogen androgen neprilysin and amyloid peptides.
administering_ic: NINDS
award_notice_date: 2005-12-13
application_type: 5
activity_code: R01
ic: NS
serial_number: 046517
program_official: MURPHY, DIANE
project_start_date: 2004-12-01
project_end_date: 2008-11-30
study_section: Special Emphasis Panel[ZRG1-CDIN(01)Q]
contact_pi_person_id: 7875201
contact_pi: HERSH, LOUIS B
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): Model studies have shown that in mice ovariectomy increases amyloid B (AB) peptide levels while ovariectomy followed by estrogen replacement lowers the concentration of AB peptides to normal or below normal levels.  We recently found that ovariectomy in rats leads to a decrease in the activity of the peptidase neprilysin and that ovariectomy followed by estrogen replacement increases neprilysin gene transcription and neprilysin enzyme activity in the brain.  Neprilysin has been shown to be the major or one of the major enzymes involved in AB peptide clearance in the brain.  We thus postulate that the effect of the estrogen depletion in raising AB peptide levels and estrogen replacement in lowering AB peptide levels occurs at least in part as a result of estrogen effects on neprilysin activity.  Similarly it has recently been shown that gonadectomy increases AB peptide levels in rats and androgen replacement reverses this effect.  Since the neprilysin gene is also regulated by androgens we speculate that the effect of gonadectomy and androgen replacement on AB peptide levels is also mediated through effects on the neprilysin gene.  Two Specific Aims are proposed to test this hypothesis:  (1) we will compare the effect of estrogen in reducing AB peptide levels in mice expressing a mutant human amyloid precursor protein containing the Swedish and Indiana mutations (J20 mouse line) to the effect of estrogen in the J20 mouse crossed with a neprilysin knockout mouse and the J20 mouse crossed with an estrogen receptor knockout mouse.  These experiments will establish whether the estrogen dependent decreases in AB peptide levels is a result of the estrogen dependent increased in neprilysin activity and whether an estrogen receptor dependent mechanism is responsible for reported effect of androgen depletion increasing AB peptide levels and androgen replacement lowering AB peptide levels is due to androgen effects on neprilysin.  
  
Using mouse models we will determine whether steroid hormone mediated effects on AB peptide levels are a result of their affects on neprilysin activity and whether steroid hormones or their selective receptor modulators can serve as a target for the development of drugs for the prevention of Alzheimer's disease.

project_terms:
amyloid proteins;amyloidosis;androgen receptor;androgens;corticosteroid receptors;disease /disorder prevention /control;enzyme activity;estrogen receptors;estrogens;genetic transcription;genetically modified animals;hormone regulation /control mechanism;laboratory mouse;male castration;neprilysin;ovariectomy;progesterone receptors;protein metabolism


application_id: 6986045
project_number: 5R01NS050311-02
project_title: Stem Cell Adaptability in Parkinson' Disease
administering_ic: NINDS
award_notice_date: 2005-12-28
opportunity_number: PAS-03-172
application_type: 5
activity_code: R01
ic: NS
serial_number: 050311
program_official: MURPHY, DIANE
project_start_date: 2004-12-01
project_end_date: 2009-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Parkinson&apos;s disease;aging;cell differentiation;corpus striatum;dopamine;embryonic stem cell;experimental brain lesion;gene therapy;growth factor receptors;immunocytochemistry;in situ hybridization;laboratory rat;mathematical model;nervous system disorder therapy;neurons;neurotrophic factors;stem cell transplantation;substantia nigra


application_id: 6984490
project_number: 1R03NS050289-01A1
project_title: Modeling Brain Hypoxia to Predict Clinical Outcomes
administering_ic: NINDS
award_notice_date: 2005-05-24
opportunity_number: PA-03-108
application_type: 1
activity_code: R03
ic: NS
serial_number: 050289
suffix: A1
program_official: GOLANOV, EUGENE V
project_start_date: 2005-05-24
project_end_date: 2007-04-30
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
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 6 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 1 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: 6984084
project_number: 5R01NS045131-05
project_title: Pathology of traumatic injury to CNS axons
administering_ic: NINDS
award_notice_date: 2005-11-23
application_type: 5
activity_code: R01
ic: NS
serial_number: 045131
program_official: HICKS, RAMONA R
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: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant):  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.


application_id: 6984063
project_number: 5R01DE014605-05
project_title: Intra-and interspecies communication in oral bacteria
administering_ic: NIDCR
award_notice_date: 2005-11-30
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2007-11-30
study_section: Special Emphasis Panel[ZRG1-OBM-1(01)Q]
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: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): Periodontal disease is caused by bacterial pathogens that thrive in a complex microbial community which forms in the gingival pocket. The initiation and growth of this bacterial biofilm likely requires sophisticated molecular communication among the bacterial various species in this community. A chemical signal produced by the LuxS gene has recently been suggested to represent a broadly distributed mechanism for interspecies communication.  We have shown that LuxS is present in periodontal pathogens (A. actinomycetemomitans and P. gingivalis) and that the LuxS-dependent signal directs specific interspecies responses in these organisms. In this application we will determine the range and specificity of LuxS-dependent communication among various oral and non-oral organisms the mechanism by which this signaling pathway modulates iron acquisition by Aa and Pg and the role that signaling plays in the virulence of these organisms. We will complement LuxS-deficient strains of Aa and Pg with signals and/or/luxS genes from other oral and non-oral organisms. We will also determine if Aa or Pg respond differently to cognate and heterologous signals. Next we will examine the growth of signal deficient strains in various iron sources and determine the role that LuxS dependent signaling plays in controlling genes involved in the uptake of iron by Pg and Aa.  We have also shown that signaling regulates the expression of virulence-associated genes thus the contribution of signaling to virulence will be determined in vivo using a mouse model. Finally we will determine how signal information is transmitted within the bacterial cell to generate a specific response. Potential candidate proteins that may function in signal transduction have been identified; their genes will be inactivated and the resulting bacterial strains will be tested for their response to signal. These studies will provide some of the first evidence showing that LuxS-dependent signaling mediates intra- and interspecies communication among periodontal pathogens. This in turn may lead to the development of new therapeutics that may control growth and development of complex bacterial communities by blocking their communication pathways.

project_terms:
Actinobacillus actinomycetemcomitans;Bacteroides gingivalis;bacteria infection mechanism;bacterial DNA;bacterial genetics;biofilm;biological signal transduction;cell cell interaction;disease /disorder model;gene expression;genetic strain;heme;iron metabolism;laboratory mouse;microorganism culture;molecular cloning;nucleic acid sequence;oral bacteria;phosphotransferases;plasmids;polymerase chain reaction;protein structure function;site directed mutagenesis;species difference;transfection /expression vector;virulence


application_id: 6982803
project_number: 5R01NS035377-11
project_title: Cholinergic Influences on Corticothalamic Transmission
administering_ic: NINDS
award_notice_date: 2005-12-01
application_type: 5
activity_code: R01
ic: NS
serial_number: 035377
program_official: BABCOCK, DEBRA J
project_start_date: 1995-09-30
project_end_date: 2008-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-F(05)M]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
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: 2005-12-01
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. We propose to study the rodent lateral posterior (LP) nucleus a region comparable to inferior regions of the primate pulvinar nucleus. We will use a combination of tract tracing immunocytochemistry electron microscopy and in vitro electrophysiology to examine the synaptic organization and functional properties of LP neurons. We propose that the rat LP nucleus contains at least 2 subdivisions that are characterized by distinct synaptic inputs axonal projection patterns and cellular firing properties. Regular spiking cells in the caudal LP nucleus are predicted to receive tectal input and project to the striatum. The synaptic arrangements of tectothalamic terminals coupled with the linear firing properties of caudal LP neurons may serve to accurately transfer signals related to the movement of visual stimuli. This circuitry may underlie the coordination of visually guided movements. Clustered spiking cells in the rostral LP nucleus are predicted to receive input from layer 5 of the visual cortex and in turn project to cortical layer 1. The synaptic arrangements of layer 5 corticothalamic terminals coupled with the non-linear firing properties of rostral LP neurons may serve to amplify and synchronize cortical activity providing a substrate for the selective enhancement of visual signals. A thorough understanding of the firing characteristics of LP neurons and the organization and dynamic properties of their synaptic connections is necessary to begin to formulate reasonable hypotheses regarding the function of the rat LP nucleus and ultimately the human pulvinar nucleus.

project_terms:
acetylcholine;attention;brain electrical activity;electron microscopy;electrophysiology;immunocytochemistry;laboratory mouse;laboratory rat;neural information processing;neural transmission;pulvinar thalami;synapses;thalamic nuclei;thalamocortical tract;thalamus;visual perception;visual stimulus;visual tracking


application_id: 6979806
project_number: 5R01HL059378-09
project_title: Cardiac Metabolism of Enals
administering_ic: NHLBI
award_notice_date: 2005-11-23
application_type: 5
activity_code: R01
ic: HL
serial_number: 059378
program_official: LIANG, ISABELLA Y
project_start_date: 1997-12-15
project_end_date: 2008-07-14
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI BHATNAGAR
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): Unsaturated aldehydes (enals) are the major end products generated during the oxidation of biological membranes and lipids. These compounds are also present in the environment and industrial pollutants and are generated during the metabolism of several foods and drugs. In vitro enals are highly toxic however there contribution to oxidative injury and the pathophysiological consequences of lipid peroxidation has not been assessed. Our previous work has led to the identification of the major biochemical pathways that metabolize enals in the heart and other cardiovascular tissues. Our studies show that the enzyme aldose reductase (AR) plays a central role in the cardiovascular toxicity of enals. We find that inhibition of AR abolishes ischemic preconditioning of the heart and increases the accumulation of the prototypical enal - 4-hydroxy trans-2-nonenal (HNE) during myocardial ischemia and reperfusion (I/R). Based on these observations we propose that enals derived from lipid peroxidation are a significant cause of myocardial ischemic injury. To test this hypothesis we plan to examine how enals are metabolized in the ischemic heart (Aim 1) and whether ischemic changes in cofactor availability and metabolite extrusion compromise enal detoxification. Using isolated perfused hearts subjected to global ischemia and a conscious rabbit model of regional ischemia in situ we will examine the generation of enals and their metabolites during I/R. Developing on our previous observations we will investigate the role of AR in enal metabolism during I/R and delineate its contribution to enal detoxification in ischemic hearts (Aim2). Finally we will examine how ischemic preconditioning causes long-term changes in enal metabolism and how the aerobic and ischemic preconditioned hearts metabolize and detoxifies enals (Aim 3). The results of these investigations will result in a better understanding of the mechanisms by which lipid peroxidation contributes to ischemic injury and to the elucidation of the role of enals and their metabolic pathways in the development of ischemic injury and dysfunction. Outcomes of this project could form the basis of future studies for assessing individual variations in susceptibility to ischemia and for understanding a host of pathological states associated with enal toxicity or exposure.

project_terms:
acrolein;aldehyde reductase;aldehydes;cardiac myocytes;enzyme activity;free radicals;heart metabolism;ischemic preconditioning;laboratory rat;toxin metabolism


application_id: 6970896
project_number: 5R01HL059225-07
project_title: Metallothionein and Adriamycin Cardiotoxicity
administering_ic: NHLBI
award_notice_date: 2005-11-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 059225
program_official: MASSICOT-FISHER, JUDITH
project_start_date: 1999-04-01
project_end_date: 2007-11-30
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
contact_pi_person_id: 1877629
contact_pi: KANG, Y JAMES
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: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): Cardiotoxicity due to oxidative stress compromises effective use of Adriamycin in cancer treatment.  Metallothionein (MT) a potent antioxidant protects the heart from Adriamycin-induced toxicity.  To develop experimental and clinical approaches to preventing cardiotoxicity of Adriamycin in the dose-schedules that tumors are eradicated we propose this continuation study to test the hypothesis that MT protects from chronic and late-onset cardiotoxicity induced by efficacious treatment of tumors with Adriamycin.  A novel MT-overexpressing and tumor-bearing mouse model will be used to carry out the following aims: (1) to determine the efficacy of MT protection from Adriamycin-induced chronic and late-onset cardiotoxicity newly developed breast tumor-bearing transgenic and non-transgenic BALB/c mice will be treated with dose-schedules of Adriamycin to which the tumors are fully responsive.  Chronic cardiotoxicity will be determined by morphometric analysis functional assessment and molecular markers for myocardial remodeling and heart failure. (2) To explore possible clinical application of MT induction as an approach to preventing Adriamycin chronic and late-onset cardiotoxicity we will develop an experimental strategy for a long-term cardiac MT induction by bismuth or hinokitiol in BALB/c mice.  The dose-effect of these inducers on MT expression in multiple organs including the heart as well as potential toxic effects for their long-term application will be examined.  (3) To develop experimental procedures for application of MT myocardial protection in cancer therapy several murine tumor cell lines that have proven to grow in the BALB/c mice will be implanted.  The tumor-bearing mice will be treated with the defined MT-induction protocol.  The expression of MT in tumors as well as Adriamycin cardiac toxicity and cancer therapeutic efficacy will be examined.  This study would provide a substantial base of information for understanding MT protection against Adriamycin chronic and late-onset cardiotoxicity potentially leading to an improved use of this highly effective anticancer drug.

project_terms:
apoptosis;bismuth;breast neoplasms;cardiovascular stress test;cell line;disease /disorder model;doxorubicin;drug adverse effect;gene expression;genetically modified animals;heart failure;laboratory mouse;metallothionein;monoterpenes;morphometry;muscle function;myocardium;myocardium disorder;neoplasm /cancer chemotherapy;nonhuman therapy evaluation;protooncogene;terminal nick end labeling;toxicology


application_id: 6970894
project_number: 5R01HL075241-03
project_title: Regulation of Ras Signaling by Rlf In Hypertrophy
administering_ic: NHLBI
award_notice_date: 2005-11-17
application_type: 5
activity_code: R01
ic: HL
serial_number: 075241
program_official: BUXTON, DENIS B
project_start_date: 2003-12-01
project_end_date: 2008-11-30
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 7875399
contact_pi: POST, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-12-01
project_abstract:
DESCRIPTION (provided by applicant): Important recent advances derived from experimental models of cardiac hypertrophy suggest that distinct signaling pathways regulate compensated hypertrophy and decompensated heart failure. Ras is a small GTP binding protein that signals through multiple effectors including the Raf-MEK-ERK pathway PI3 kinase (PI3K) guanine exchange factors for Ral (RalGEFs) and cJun N-terminal kinase (JNK). In transgenic mice V12Ras-mediated hypertrophy is associated with JNK activation and depressed cardiac function. However certain Ras-dependent signaling cascades including ERK and PI3K activate compensatory hypertrophic responses that preserve contractile activity. To identify novel Ras effectors we screened a human heart cDNA library using Ras as bait and isolated Ral guanine nucleotide exchange factor-like factor (RIf). To examine the functional consequence of the Ras-RIf interaction we expressed V12Ras in concert with RIf in neonatal ventricular rat myocytes (NRVM). Expression of RIf suppressed V12Ras-induced JNK activity and ANF expression but not other Ras effectors. RIf also inhibited sorbitol-induced JNK activation indicating that RIf expression negatively regulates JNK activation in response to multiple stimuli. These results demonstrate that RIf suppresses an effector pathway suggested to mediate depressed function of myocardial cells. We will test the hypothesis that RIf negatively regulates JNK activation and that function inhibits the development of hypertrophic cardiomyopathy in vivo. The signaling pathways that couple Ras to JNK activation are not known but may involve MEKK1 (MAPWERK kinase kinase 1) a Ras binding protein that preferentially activates JNK. In aim #1 we will define the role of MEKK1-JKK-JNK in RIf-mediated inhibition of V12Ras- and stress- signaling. In aims #2 and #3 the pathophysiological implications of RIf function will be investigated in transgenic mice that overexpress RIf. We will test the potential protective role of RIf on the pathogenesis of cardiac hypertrophy in response to pressure overload isoproterenol infusion and V12Ras overexpression and investigate the signaling cascades involved. Elucidation of the mechanisms by which RIf regulates hypertrophic signaling pathways may lead the development of novel therapeutic approaches to prevent cardiac dysfunction.

project_terms:
biological signal transduction;congestive heart failure;echocardiography;gene expression;genetically modified animals;guanine nucleotide binding protein;guanine nucleotide exchange factors;hypertrophic myocardiopathy;laboratory mouse;laboratory rat;myocardium disorder;pathologic process;phosphotransferases;ventricular hypertrophy;western blottings


application_id: 6967149
project_number: 1K23DE015298-01A1
project_title: Central Pain Processing in Chronic Face Pain:fMRI Study
administering_ic: NIDCR
award_notice_date: 2006-01-26
opportunity_number: PA-00-004
application_type: 1
activity_code: K23
ic: DE
serial_number: 015298
suffix: A1
program_official: HARDWICK, KEVIN S
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7351795
contact_pi: DE LEEUW, RINSKJE
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal for a K23 "Mentored Patient-Oriented Research Career Development Award" will provide the candidate with five years of continuous funding to gain a broad knowledge in the design and conduct of complex clinical oral health trials. This training will enhance the research environment of the Orofacial Pain Center and mentoring capacity of the University of Kentucky College of Dentistry. The candidate earned a PhD in General Medicine from the University of Groningen and received three years of postgraduate graduate training in Orofacial Pain at the University of Kentucky. This award would allow the candidate to evolve to an independent investigator and would prepare the candidate to successfully mentor MS and PhD candidates in orofacial pain research. The training program consists of two phases: a didactic component emphasizing courses in research design biostatistics data analysis and epidemiology and a research phase involving a neuroimaging investigation of central pain processing in patients with chronic face pain.  
  
Three specific aims are proposed in this training application: Specific Aim 1. To assess the presence of pain augmentation in patients with chronic masticatory myofascial pain; Specific Aim 2. To investigate differences in location and extent of activation of brain regions involved in trigeminal pain processing between patients with chronic masticatory muscle pain and pain-free volunteers; and Specific Aim 3. To investigate the influence of estrogen level on cerebral activation in response to an acute experimental pain stimulus in patients with chronic masticatory muscle pain and pain-free volunteers. Dr. Charles Carlson PhD Professor Departments of Psychology and Oral Health Science and research director of the Orofacial Pain Center and Dr. Don Gash PhD Alumni Professor and Chair Department of Anatomy and Neurobiology and director of the Magnetic Resonance Imaging and Spectroscopy Center will mentor the candidate. There is limited information on cerebral activation in response to stimulation of trigeminal structures in healthy pain-free volunteers as well as in chronic face pain patients. The available data support that there are important differences in the cerebral processing of pain in chronic pain patients compared to pain-free subjects. Moreover the existing data suggest that in chronic pain conditions the medial pain system the structures associated with the processing of the emotional-affective component of pain exhibits altered activity. Additionally there is a lack of information about the influence of estrogen on the central processing of pain. The available data suggest that estrogen may have an inhibitory / anxiolytic effect on the perception of pain possibly by modulating the endogenous opioid system. Because neuroimaging data on this topic are scarce and chronic pain conditions are predominant in women of reproductive age the role of estrogen on pain should be further explored.

project_terms:
analgesia;anxiety;bioimaging /biomedical imaging;brain imaging /visualization /scanning;brain morphology;brain regulatory center;chronic pain;clinical research;emotions;estrogens;experimental designs;female;functional magnetic resonance imaging;heat stimulus;human subject;hyperalgesia;menstrual cycle;neural information processing;neuroimaging;oral facial pain;patient oriented research;statistics /biometry;temporomandibular joint syndrome;trigeminal nerve


application_id: 6960767
project_number: 1R24MH074722-01
project_title: Crafting Kentucky's Evidence-Based Practice Agenda
administering_ic: NIMH
award_notice_date: 2005-09-30
opportunity_number: RFA-MH-05-004
application_type: 1
activity_code: R24
ic: MH
serial_number: 074722
program_official: FREED, MICHAEL C
project_start_date: 2005-09-30
project_end_date: 2007-09-29
study_section: Special Emphasis Panel[ZMH1 ERB-B (06)]
contact_pi_person_id: 8142560
contact_pi: ROBBINS, VESTENA S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kentucky's evidence-based practices planning grant will bring together key stakeholders to increase the state's capacity to implement evidence-based practices in its public mental health system. Increased capacity will be achieved by developing a state-level evidence-based practices strategic planning advisory group; conducting case studies of evidence-based practices implementation in two distinct service environments; and creating an infrastructure to support the development of Science-to-Service Collaboratives. At the end of the planning period the following outcomes will be achieved:  
- Increased awareness of and support for the implementation of EBPs by a large constituency  
- Development of a research agenda for the Department related to EBP implementation  
- Creation of at least one new Science-to-Service Collaborative  
- Identification of researchers at Kentucky universities and their area of interest in EBPs  
This planning grant will increase Kentucky's capacity to undertake studies that will add to the knowledge base on implementation of EBPs improve the public mental health service delivery system and ultimately improve outcomes for individuals who suffer from mental health problems.

project_terms:
biomedical resource;clinical research;community mental health services;geographic site;health care service evaluation;health care service planning;health science research support;health services research tag;human subject;patient oriented research;public health


application_id: 6953955
project_number: 1R15HL084654-01A1
project_title: Murine CMV Pneumonitis in Allogeneic BMT
administering_ic: NHLBI
award_notice_date: 2005-08-11
opportunity_number: PA-03-053
application_type: 1
activity_code: R15
ic: HL
serial_number: 084654
suffix: A1
program_official: PEAVY, HANNAH H
project_start_date: 2005-08-15
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZRG1 IDM-G (90)]
contact_pi_person_id: 8004671
contact_pi: OAKLEY, OLIVER R
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
project_abstract:
DESCRIPTION (provided by applicant): Despite the practice of antimicrobial prophylaxis Cytomegalovirus (CMV) infection in immunocompromised patients causes potentially life-threatening disease especially in recipients of bone marrow transplantation (BMT). CMV-associated pneumonitis is frequently a fatal complication of human CMV (hCMV) disease in BMT recipients. We will study an allogeneic murine BMT model in which BALB/c mice previously infected with murine CMV (MCMV) receive bone marrow from B10.D2 donors. Previous studies have demonstrated that animals previously infected with MCMV exhibit a more severe disease progression following transplantation. To test our hypothesis: The mechanism by which reactivation of latent MCMV infection exacerbates pneumonitis after minor antigen mismatched bone marrow transplantation is through augmentation of T cell infiltration and cytokine production we have developed three specific aims. The specific aims to be addressed are 1) To determine the role of viral replication on the development of IP after allo BMT 2) To define the role of continued infiltration of T cells into the lungs of previously infected mice in the absence of replicating virus and 3) To determine the role of adhesion molecules in the development of viral interstitial pneumonitis following allo BMT. Using this model we will investigate the role viral replication following reactivation on disease progression. We will examine the specificity of lymphocytes in the lungs using MCMV specific MHC II tetramers and V|33. Also we will investigate the role of viral or host up-regulation of adhesion molecules in recruiting lymphocytes to the lungs. These experiments will provide insights into the interaction of host responses to CMV following BMT and may serve as a basis for developing new strategies to protect and treat BMT patients susceptible to chronic CMV infections. This research will also provide the opportunity for students to participate actively in the solution to an important clinical problem.

project_terms:
T lymphocyte;bone marrow transplantation;cell adhesion molecules;cell migration;cytomegalovirus;homologous transplantation;laboratory mouse;latent virus infection;postoperative complications;pulmonary fibrosis /granuloma;viral pneumonia;virus replication


application_id: 6953752
project_number: 5R01HL070784-04
project_title: The Metabolic Syndrome in Pediatric Obstructive Apnea
administering_ic: NHLBI
award_notice_date: 2005-08-05
opportunity_number: RFA-HL-01-006
application_type: 5
activity_code: R01
ic: HL
serial_number: 070784
program_official: TWERY, MICHAEL
project_start_date: 2002-09-01
project_end_date: 2006-07-31
study_section: ZHL1-CSR-P(M1)
contact_pi_person_id: 8907488
contact_pi: SCHURR, AVITAL
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): This project will evaluate the association between obstructive sleep apnea (OSA) in childhood and the presence of the "metabolic syndrome". Our aims are:  1. To confirm the association between OSA in children and the presence of known risk factors for future cardiovascular disease. 2. To confirm that the physiological disruptions caused by OSA can induce the same metabolic abnormalities in an animal model and 3. To confirm that treatment of OSA can reverse the abnormalities underlying the metabolic syndrome.  The metabolic syndrome is a combination of hypertension insulin resistance and dyslipidemia. The first abnormality to appear in children is insulin resistance. The presence of insulin resistance in children has been associated with development of all three abnormalities in adulthood and thus with increased risk for later cardiovascular disease. Studying OSA in children provides a unique opportunity to study the mechanisms underlying the association between OSA the metabolic syndrome and cardiovascular disease. The majority of children with OSA are NOT obese so it is possible to determine the relative contribution of factors including obesity chronic sympathetic activation and chronic inflammation if a sufficiently large group is studied. Children who present to a sleep unit already have some combination of symptoms suggestive of OSA. Therefore a parallel study will seek to understand the earliest associations between OSA and the metabolic syndrome. To do this piglets will be exposed to repetitive hypercapnic hypoxia and equivalent studies of metabolic abnormalities will be undertaken. This component of the study will examine the specific sequence of disturbances underlying the metabolic syndrome with the goal of determining preventative strategies that could be translated into the clinical setting. Finally children who have OSA will undergo treatment followed by re-evaluation. If treatment of OSA can reverse the metabolic disturbances present in association with OSA this will support the need for early and aggressive intervention in childhood OSA.

project_terms:
beta adrenergic receptor;cardiovascular disorder risk;children;clinical research;disease /disorder etiology;electrocardiography;human subject;hyperlipidemia;hypertension;immature animal;inflammation;insulin sensitivity /resistance;metabolic syndrome;obesity;patient oriented research;sleep apnea;swine;urinalysis


application_id: 6951195
project_number: 5R01HL079574-02
project_title: Molecular Mechanism of Severe Congenital Neutropenia
administering_ic: NHLBI
award_notice_date: 2005-08-13
opportunity_number: RFA-HL-04-008
application_type: 5
activity_code: R01
ic: HL
serial_number: 079574
program_official: QASBA, PANKAJ
project_start_date: 2004-09-30
project_end_date: 2005-09-30
study_section: ZHL1-CSR-D(S1)
contact_pi_person_id: 1868623
contact_pi: GRIMES, H LEIGHTON
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):   Severe Congenital Neutropenia (SCN) predisposes affected humans to opportunistic infections because of a profound deficiency in the production of neutrophils.  The majority of SCN patients express mutant forms of neutrophil elastase (a serine protease encoded by ELA2). To date mouse models of SCN using ELA2 mutants from SCN patients have not reproduced the disease; limiting dissection of the molecular mechanisms underlying SCN. Growth Factor Independence-1 (GFI1) is a transcriptional repressor oncoprotein with a classic C2-H2 zinc-finger DNA-binding domain. We have recently shown that the affected individuals in a family of SCN patients are heterozygous for mutations in GFI1.  Importantly GFI1-/- mice and GFI1-mutant SCN humans exhibit a strikingly similar disease and dramatically lack any mature neutrophils.   Granulopoiesis is controlled by transcription factors. GFI1 is a transcription factor.  Thus GFI1 mutations may be more clearly associated with blocks in both human and murine granulopoiesis than other SCN-associated mutations. An exploration of GFI1 in neutrophil differentiation provides a unique opportunity to identify biochemical pathways disrupted in SCN patients and to develop an animal model of this inherited bone marrow failure syndrome.  Our preliminary evidence indicates that GFI1 targets ELA2.  We hypothesize that GFI1-mutant proteins found in SCN patients cause neutropenia because they act as dominant negative proteins; interfering with GFI1 transcriptional control over ELA2 and myeloid specific genes.  We propose to utilize retroviral vector transduction to validate SCN-mutant-GFI1 proteins as disease-causing entities in murine and human hematopoietic stem cells.  Moreover the role of wild-type GFI1 gene dosage in controlling mutant GFI1 molecules and their mechanism of action will be discerned then correlated to functional and molecular analyses of patient blood.  Finally we will molecularly characterize ELA2 as a GFI1-target gene in myelopoiesis and we will biologically test suggested genetic interactions. These studies will provide an animal model of SCN and are designed to dissect the molecular mechanism underlying this bone marrow failure syndrome.  More generally this work should impact our understanding of hematopoiesis as well as engender greater understanding of GFI1 function.

project_terms:
Retroviridae;bone marrow transplantation;cell line;cell morphology;chemotaxis;chromatin immunoprecipitation;clinical research;congenital blood disorder;flow cytometry;gel mobility shift assay;gene interaction;gene mutation;genetic regulation;genetic regulatory element;genetically modified animals;granulocyte;hematopoietic stem cells;human subject;hydrogen peroxide;laboratory mouse;molecular pathology;neutropenia;phagocytosis;transcription factor;transfection /expression vector


application_id: 6950670
project_number: 5R21RR019693-02
project_title: A non-surgical method for producing gene-modified mice
administering_ic: NCRR
award_notice_date: 2005-08-02
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: RR
serial_number: 019693
program_official: RALL, WILLIAM F
project_start_date: 2004-09-15
project_end_date: 2008-07-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
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
project_abstract:
DESCRIPTION (provided by applicant): We propose to develop a novel non-surgical technique that will allow us to reintroduce embryos and blastocysts into pseudopregnant female mice. This technology is based on methods that were published a number of years ago and involves the introduction of cells into the uterus by way of the vagina. These earlier methods used glass pipets to introduce blastocysts; we have developed a novel plastic device which can be used with a P-2 pipetman to introduce embryos and blastocysts intravaginally into female mice. This procedure takes several seconds and the pain and discomfort level is minimal so the females do not have to be anesthetized.  
We have generated some preliminary data and have shown that we can introduce embryos with an efficiency that is comparable to surgical transfer into the oviduct. We have also shown that we can use this technique with embryo aggregates to generate chimeric mice. Thus this novel technology should be able to replace surgical techniques used for the production of genetically altered mice via DNA microinjection and ES-cell mediated gene knock-outs. We believe that this is a dramatic improvement over current methods and would become adopted as the method of choice for transgenic researchers if it is truly as successful as our preliminary data suggests.

project_terms:
biological models;early embryonic stage;embryo /fetus;embryo /fetus transplantation;embryonic stem cell;gene expression;genetically modified animals;green fluorescent proteins;laboratory mouse;method development;microinjections;polymerase chain reaction


application_id: 6950503
project_number: 1R15AI060667-01A1
project_title: Microbial altruists: Helping cohorts survive lethal drugs
administering_ic: NIAID
award_notice_date: 2005-07-04
opportunity_number: PA-03-053
application_type: 1
activity_code: R15
ic: AI
serial_number: 060667
suffix: A1
program_official: KORPELA, JUKKA K
project_start_date: 2005-07-05
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1 IDM-A (90)]
contact_pi_person_id: 1930609
contact_pi: PERLIN, MICHAEL H
other_pis: Not Applicable
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Microbial diversity is important in a variety of contexts in particular having implications for infectious diseases bioremediation and environmental engineering. Examination of the mechanisms underlying such diversity and its evolution are important for providing a roadmap that can lead to better understanding of the above-mentioned and other related areas. Several examples are available where mutualism in microbial communities can lead to the maintenance of microbial diversity. Fewer examples have been presented where some individuals provide protection to others in a population without a concomitant benefit being returned to the protector. Protection of sensitive members of a population against antimicrobials by resistant genotypes has been observed in biofilms. In these cases spatial proximity to the protector/producer was a prerequisite or at least an important component for survival by otherwise sensitive individuals. We intend to extend these studies to shaking liquid or planktonic populations in order to examine the dynamics of such unrewarded protection or altruism. We have developed a family of mathematical models that have examined antibiotic resistance in such systems and have generated preliminary data which support some aspects of these models. Our results so far show that such altruists can provide frequency-dependent antibiotic resistance to other members in the population. Furthermore frequency-dependent selection of the traits of these altruists promotes microbial diversity. In the current proposal we will undertake more detailed experiments designed to test our model's predictions and use the results obtained to further refine the models. Specifically we will use competitions between near-isogenic Escherichia coli strains that are either sensitive to ampicillin or are resistant by virtue of a plasmid-encoded ?-lactamase.  Among those strains that are resistant we will compare the outcome for those strains that only protect themselves from ampicillin versus those strains that can also provide protection to others in their vicinity i.e. by destroying ampicillin nearby in the medium. These analyses will also be extended to competition experiments with greater relevance for natural clinical or human settings. For the latter analyses the engineered E. coli strains described above will be competed against ampicillin-sensitive Enterococcus faecalis strains and in a separate set of experiments against a mixture of human fecal bacteria. The population dynamics of sensitive and resistant individuals in these trials will be explored. We predict that the altruistic E. coli will provide protection to their sensitive cohorts and thereby maintain diversity in a setting otherwise unfavorable for such diversity.

project_terms:
Escherichia coli;ampicillin;bacterial genetics;drug metabolism;drug resistance;enteric bacteria;gene environment interaction;genetic polymorphism;genetic susceptibility;mathematical model;microorganism culture;microorganism interaction;microorganism population study;model design /development;natural selections;pharmacogenetics;plasmids


application_id: 6950294
project_number: 5R21CA108162-02
project_title: Bortezomib and Idarubicin in the Treatment of AML
administering_ic: NCI
award_notice_date: 2005-08-05
opportunity_number: PAR-03-005
application_type: 5
activity_code: R21
ic: CA
serial_number: 108162
program_official: WU, ROY S
project_start_date: 2004-09-20
project_end_date: 2007-08-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 8535501
contact_pi: HOWARD, DIANNA S
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Acute myeloid leukemia (AML) is a clonal malignant disease of hematopoietic cells characterized by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients with favorable cytogenetics have increasingly favorable outcomes with dose intensive chemotherapy they represent a distinct minority of patients with this disease. Patients with unfavorable cytogenetics advanced age (>=60) and antecedent hematologic disorders have a decreased incidence of complete remission; even in those who achieve an initial remission the majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies are needed. Studies from our laboratory have demonstrated that the combination of the proteasome inhibitor bortezomib with the anthracycline idarubicin at concentrations readily achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from our laboratory have demonstrated that apoptosis induced in this fashion correlates with several specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong inhibition of NF-kappaB is rapidly observed indicating inhibition of important survival signals. In addition levels of p53 protein are strongly increased in treated AML cells suggesting p53 mediated changes in gene expression might be involved in the apoptosis induced by this combination. Based on our observations we propose a phase I and II clinical trial with the novel agent bortezomib and idarubicin given to newly diagnosed elderly or relapsed AML patients. Monitoring for in vivo induction of apoptosis as well as important correlative studies assaying for inhibition of NF-kappaB and increased p53 expression are proposed. We anticipate that with this novel treatment regimen we will observe potent anti-leukemic activity and complete clinical remissions.

project_terms:
acute myelogenous leukemia;adult human (21+);anthracyclines;antineoplastics;apoptosis;clinical research;clinical trial phase I;clinical trial phase II;combination chemotherapy;dosage;drug screening /evaluation;human old age (65+);human subject;human therapy evaluation;neoplasm /cancer chemotherapy;neoplasm /cancer relapse /recurrence;nuclear factor kappa beta;p53 gene /protein;patient oriented research;protease inhibitor;proteasome


application_id: 6950009
project_number: 5R01HL079636-02
project_title: Cardiac Neuropathy in Type 1 Diabetic and Aging
administering_ic: NHLBI
award_notice_date: 2005-09-16
opportunity_number: RFA-HL-04-013
application_type: 5
activity_code: R01
ic: HL
serial_number: 079636
program_official: RABADAN-DIEHL, CRISTINA
project_start_date: 2004-09-30
project_end_date: 2005-10-31
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 6615011
contact_pi: CHENG, ZIXI JACK
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): Diabetes mellitus and aging are commonly associated with increased incidence and severity of cardiovascular diseases. However our understanding of the neural mechanisms underlying these dysfunctions is impeded by a lack of structural information on autonomic nerve terminals and the circuitry within the cardiac tissues (brain-heart connections). Vagal projections to the heart originate from a sensory ganglion i.e. the nodose ganglion and the two motor nuclei i.e. the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). The overall goal of the present application is to determine the functional deficits of the vagal control of the heart induced by diabetes aging or both and to identify the damage to the cardiac neural circuitry specifically to the vagal axonal projections to the heart. Vagal control of particular cardiac functions will be measured in two murine models of type 1 diabetes (strepozotocin-treated and transgenic OVE 26 mice). The vagal cardiac axons and terminals glutamatergic transmission and oxygen reactive species (ROS) within the parasympathetic system will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing stereological counting confocal microscopy Neurolucida digitization multichannel injections dual immunohistochemistry and intercellular measurement of ROS. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships. Aim 1 will assess diabetes-associated attenuation of baroreflex and vagal control of the heart and the associated structural changes of vagal projections to the heart and aortic arch and examine whether diabetes and aging interact to induce more severe functional and anatomical damage to the vagal cardiac axons. Aim 2 will study diabetes and aging-associated changes in glutamatergic transmission within the brainstem. Aim 3 will determine ROS productions in parasympathetic neurons in diabetic and aging mice and study whether chronic antioxidant treatment may reduce/prevent cardiovascular dysfunctions and structural damages Collectively the proposed experiments will provide unique insights into the remodeling of vagal outflow to cardiac tissues following long-term diabetes.

project_terms:
AMPA receptors;NMDA receptors;aging;antioxidants;aorta;baroreceptors;baroreflex;brain stem;confocal scanning microscopy;diabetic neuropathy;free radical oxygen;ganglions;genetically modified animals;heart innervation;immunocytochemistry;insulin dependent diabetes mellitus;laboratory mouse;microinjections;neuroanatomy;neuropathology;neurophysiology;neuroregulation;parasympathetic nervous system;phenylephrine;receptor expression;streptozotocin;tocopherols;vagus nerve


application_id: 6949904
project_number: 5R01EY014069-02
project_title: NaK-ATPase studies on optic nerve head astrocytes
administering_ic: NEI
award_notice_date: 2005-07-22
application_type: 5
activity_code: R01
ic: EY
serial_number: 014069
program_official: LIBERMAN, ELLEN S
project_start_date: 2004-09-30
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1-AED(01)Q]
contact_pi_person_id: 1872319
contact_pi: DELAMERE, NICHOLAS A
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: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): Studies are proposed on Na K-ATPase in optic nerve head astrocytes. The ability of astrocytes to regulate pH potassium calcium and glutamate in the neuronal microenvironment is linked to Na K-ATPase. Astrocytes express two NaK-ATPase isoforms alpha1 and alpha2. The two isoforms appears to have different functions but we do not have complete information on their respective roles or the implications for astrocyte physiology. NaK-ATPase alpha1 has a vital housekeeping function regulating the cell-wide concentration of cytoplasmic sodium. We are particularly interested in the NaK-ATPase alpha2 isoform because Preliminary Studies suggest it has a different role. It does not  appear control cell-wide sodium concentration but instead we think NaK-ATPase alpha2 may be specialized in a way that causes it to have a major influence on glutamate uptake cell calcium balance and possibly cell growth. Experiments are proposed to study how and astrocytes has the potential to impair the ability of the cell to accumulate extracellular potassium transport glutamate and protons and regulate cytoplasmic calcium. We also propose studies to examine the potential impairment of NaK-ATPase function by in vitro episodes of ATP depletion and nitric oxide exposure and by elevated intracellular pressure in vivo. The aims are: (AIM 1) Determine the influence of Na K-ATPase alpha2 activity on glutamate uptake; (AIM 2) Determine how altered NaK-ATPase alpha2 activity leads to changes in cytoplasmic calcium stores and subsequent changes in astrocyte behavior; (AIM 3) Study how abnormal NaK-ATPase activity could impact proton transport mechanisms; (AIM 4) Study the factors that cause abnormal NaK-ATPase function or expression.

project_terms:
animal tissue;astrocytes;biological signal transduction;biological transport;calcium;cell growth regulation;disease /disorder model;gene expression;genetic regulation;glaucoma;glutamates;hydrogen transport;laboratory rat;molecular pathology;neurogenetics;neuroregulation;nitric oxide synthase;optic nerve;potassium;protein isoforms;protein structure function;sodium potassium exchanging ATPase


application_id: 6949896
project_number: 5R03AG022121-02
project_title: Oxidative Stress and Nitric Oxide in Aged Myocardium
administering_ic: NIA
award_notice_date: 2005-07-20
opportunity_number: PAR-03-056
application_type: 5
activity_code: R03
ic: AG
serial_number: 022121
program_official: FINKELSTEIN, DAVID B
project_start_date: 2004-09-30
project_end_date: 2006-07-31
study_section: Biological Aging Study Section[NIA-B]
contact_pi_person_id: 7875462
contact_pi: LASLEY, ROBERT D.
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This pilot research grant proposal focuses on research objective 2: Cardiovascular and Cerebrovascular Aging. Aging is associated with increased oxidative stress and mitochondrial dysfunction in numerous tissues. These factors are thought to play a role in aging-associated decreases in ventricular function coronary vascular reserve and tolerance to myocardial ischemia-reperfusion all of which may contribute to the increase in cardiovascular disease with aging. Significant evidence has accumulated that mitochondria in addition to maintaining the energy stores for the high work demands of ventricular myocardium play a role in determining the cell's transition from reversible injury to apoptosis and necrosis. However there have been limited studies of ischemia-reperfusion injury in in vivo aged myocardium and few systematic investigations of mitochondrial function in intact ventricular myocytes of aged animals. This proposal will test the hypothesis that aged myocardittm exhibits less tolerance to ischemia-reperfusion injury and oxidative stress in part due to altered nitric oxide (NO) metabolism and signaling. Specific Aim 1 will determine whether in vivo myocardium and isolated ventricular myocytes from aged rats exhibit less tolerance to ischemia-reperfusion andhypoxia-reoxygenation respectively. Specific Aim 2 will test the hypothesis that aging associated oxidative stress and mitochondrial dysfunction is due to increased formation of reactive nitrogen species. In Aim 1 studies adult (6 month) and aged (24 month) Fischer 344 x Brown Norway F1 hybrid (F344xBN) rats will be submitted to in vivo coronary artery occlusion and reperfusion and infarct size will be measured. Left ventricular myocytes isolated from adult and aged rats will be submitted to hypoxia-reoxygenation and twitch amplitude and intracellular oxidative stress will be measured. In Aim 2 studies isolated ventricular myocytes will be exposed to/-/202 tO induce oxidative stress.Mitochondrial ([Ca2+]) mitochondrial redox state and intracellular oxidative stress will be measured under baseline conditions and during and following exposure to H202. The role of NO in modulating aged myocyte response to oxidative stress will be determined by modulating NOS activity and arginine levels and with a NO donor. The expression and subcellular compartmentation of anti-oxidant enzymes and NOS isoforms will be determined byWestern blotting of subcellular fractions. The proposed studies will provide significant insight into the role of acute and chronic oxidative stress in aged myocardium and its modulation by NO. The results obtained may lead to the development of new therapies for treating cardiovascular disease in the elderly.

project_terms:
age difference;aging;animal old age;antioxidants;biological signal transduction;cardiac myocytes;cardiovascular disorder risk;caveolins;fluorescence microscopy;gene expression;laboratory rat;mature animal;metabolism;mitochondrial disease /disorder;myocardial ischemia /hypoxia;myocardium;nitric oxide;nitric oxide synthase;oxidative stress;protein isoforms;reperfusion;respiratory oxygenation;western blottings


application_id: 6949186
project_number: 5G08LM008373-02
project_title: ARH Plan for Clinical Standards Platform
administering_ic: NLM
award_notice_date: 2005-09-15
opportunity_number: PAR-02-079
application_type: 5
activity_code: G08
ic: LM
serial_number: 008373
program_official: SMITH, CRISTAN
project_start_date: 2004-09-30
project_end_date: 2007-09-29
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 7839487
contact_pi: BENTLEY, POLLY M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 058685439
primary_uei: MXUKTEJZLNL4
duns_number: 058685439
uei: MXUKTEJZLNL4
fips: US
organization_id: 5326001
organization_name: APPALACHIAN REGIONAL HEALTHCARE, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405054808
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The project will produce a plan for a standards-based platform for the nursing documentation component of electronic clinical data management for Appalachian Regional Healthcare's (ARH) information system. In addition ARH wishes to integrate those standards with a plan for point of care and supply chain bar coding throughout its patient care delivery system. ARH is an integrated rural healthcare delivery system serving 20 counties in Eastern Kentucky and Southern West Virginia.    The project will use the principles of uniform medical language system (UMLS) ARH's own adaptive skills with computer system integration ARH's stable Information System (IS) leadership an established system wide ARH Clinical Information Steering Committee composed of informatics and clinical staff and consultants from experienced IAIMS programs at Vanderbilt and Duke Universities. It will build on ARH's successful entrepreneurial culture and system commitment to standardize processes. The program will extend ARH's well-developed unified integrated human resources and business information systems into a clinical realm. ARH has a single e-mail system for all settings and locations and will make use of its system wide video teleconferencing in preparation of the plan. The plan will complement and extend the existing ARH 5-year strategic IS plan's efforts to adopt UMLS bar code platforms for patient and supply management and DICOM standards for teleradiology management. The focus of the proposed plan is to standardize communication reduce errors and improve patient care management with a uniform system that integrates data real-time across the system's clinic inpatient outpatient and home care delivery services.


application_id: 6949180
project_number: 5R21DE016064-02
project_title: Dental Anxiety Pain & Melanocortin-1 Receptor Mutations
administering_ic: NIDCR
award_notice_date: 2005-06-27
opportunity_number: PA-03-152
application_type: 5
activity_code: R21
ic: DE
serial_number: 016064
program_official: CANTO, MARIA TERESA
project_start_date: 2004-09-15
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-F(03)M]
contact_pi_person_id: 7839565
contact_pi: LIEM, EDWIN B
other_pis: Not Applicable
congressional_district: 03
department: ANESTHESIOLOGY
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 exploratory biobehavioral pain research will study differences anxiety pain in dental and in natural red-haired men and women compared with dark-haired men and women. Red hair results from mutations of the melanoncortin-1 receptor gene (MC1R). Our specific aims are to 1) determine the association between perceived dental pain dental anxiety and dental utilization with MC1R gene status and hair color; 2) determine experimental pain thresholds and dose-dependent local anesthetic sensitivity as a function of hair color and MC1R gene variation in volunteers; and 3) determine local anesthetic requirement for restorative dental treatment as a function of hair color and MC1R gene variation. This proposal is collaboration between the School of Dentistry the Department of Anesthesiology the OUTCOMES RESEARCH Institute the Genetics Core Laboratory and the Department of Psychology -- all at the University of Louisville. All participating male and female subjects will be genotyped for MC1R alleles and new technology will be used that provides consistent and objective assessment of dental pain. The study will be accomplished in three phases: 1) In the Observational Phase 74 redheads and 74 dark-haired participants (aged 18 to 40) will each complete validated survey instruments designed to measure psychological symptomatology global and dental-specific anxiety constructs associated with dental pain and avoidance (e.g. anxiety and pain sensitivity) and previous dental history including dental care utilization. 2) In the Experimental Phase we will recruit 60 redheaded and 60 dark-haired volunteers from those completing the Observational phase. Pain perceived as a result of electrical current and thermal stimuli on unrestored lateral incisor teeth will be measured after intra-oral injection of various lidocaine concentrations. The concentrations which will be used in a randomized and double-blinded sequence will be 0 0.5 1.0 and 1.5%. And 3) in the Clinical Phase we will recruit 60 redheaded and 60 dark-haired volunteers requiring non-surgical dental treatment from those completing the Observational phase. We will use the Dixon "up-and-down" method to determine local anesthetic requirement in each group. The proposed research will contribute to the knowledge of the role of gender and genetics in peripheral nerve function pain perception and behavior. The research will also explore the feasibility of an innovative dental pain assessment approach that may provide a basis for future research projects and could guide the development of biobehavioral interventions to manage dental anxiety and prevent pain.

project_terms:
adrenocorticotropic hormone;anesthesia;behavioral /social science research tag;clinical research;dental anxiety;drug administration rate /duration;gene mutation;genetic screening;genetic susceptibility;hair;health behavior;health care service utilization;hormone receptor;human subject;oral facial pain;oral health;pain threshold;questionnaires


application_id: 6948923
project_number: 5R21AG024899-02
project_title: Use of bone marrow stem cells to treat Alz. Dis
administering_ic: NIA
award_notice_date: 2005-06-17
opportunity_number: RFA-AG-04-008
application_type: 5
activity_code: R21
ic: AG
serial_number: 024899
program_official: SUNEJA, SANOJ
project_start_date: 2004-09-15
project_end_date: 2007-06-30
study_section: ZAG1-ZIJ-7(O1)
contact_pi_person_id: 7875201
contact_pi: HERSH, LOUIS B
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): It has recently been shown that anti-amyloid beta peptide (A?) antibodies or agents that bind to and sequester A??in the periphery produce a "sink effect" in which brain A? levels are appreciably diminished. This peripheral clearance provides the opportunity to develop new strategies for reducing brain A? as a therapeutic treatment in Alzheimer's disease (AD). We propose to develop a novel method for treating AD in which bone marrow stem cells are infected with a lentiviral vector directing expression of the peptidase neprilysin. The infected bone marrow cells are then transplanted to a recipient whereby the recipient will express neprilysin on the surface of red blood cells. Since neprilysin efficiently degrades A? the serum A? levels will decrease followed by a decrease in brain A? levels through the "sink effect". To test this strategy the following specific aims are proposed: (1) to express neprilysin on red blood cells and determine its effect on plasma and brain A? levels and amyloid plaque formation in young amyloid precursor protein transgenic (APP Tg) mice. A lentivirus vector will be used to introduce neprilysin into bone marrow progenitor cells from a donor mouse and transplant these infected cells into a recipient APP Tg mice. Brain and plasma A? levels neprilysin activity in the plasma and amyloid plaque formation in the brain will be monitored for up to 18 months. (2) To determine if expression of neprilysin on red blood cells can reverse the number of amyloid plaques in older APP Tg mice. This aim will be essentially the same as the first except that the recipient mice will be 18-20 months old and we will determine if clearance of plasma A? can lead to dissolution of preformed amyloid deposits in the brain.  
  
Taken together these studies represent a novel use of stem cells to provide a mechanism for the clearance of peripheral A? which should lead to clearance of brain  A??through a described "sink effect". This represents a novel and potential useful therapeutic approach for preventing and treating Alzheimer's disease.

project_terms:
Alzheimer&apos;s disease;Lentivirus;aging;amyloid proteins;bone marrow;bone marrow transplantation;enzyme linked immunosorbent assay;erythrocytes;flow cytometry;gene expression;genetically modified animals;hematopoietic stem cells;laboratory mouse;neprilysin;neuritic plaques;neurofibrillary tangles;peptidases;plasma;technology /technique development;transfection /expression vector


