# projects

application_id: 7720898
project_number: 5P20RR020171-05
project_title: KY COBRE: IMAGING CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7025
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The imaging core facility houses three epifluorescence microscopes (Nikon Eclipse 600 Zeiss Axiovert 100 and 200M) with digital image capture capability (Spot CE and Orca ER digital cameras with Metaview and Open Lab software). The Eclipse 600 will allow the high resolution imaging of cells and sub-cellular compartments. This instrument can be used for detailed analysis of various cellular structures. The core also contains two inverted epifluorescence microscopes. The Axiovert 200M is equipped with stage controllers to allow long term analysis of live cells. The Axiovert 100 can be used for analysis of cells in tissue culture dishes or fixed samples on slides. The flexibility of the instruments in the facility will enable the core users a wide range of analytical techniques with which to pursue their individual projects. The facility contains two computers for image processing. The computers have complete Internet access and network access to color printers and to data storage. The core director Dr. Whiteheart will be available to offer advice on sample preparation on data analysis and on imaging procedures. In addition Dr. Whiteheart will also advise in the preparation of figures and selection of images for publication.

project_terms:
Cells;Cellular Structures;Color;Computer Retrieval of Information on Scientific Projects Database;Computer software;Computers;Core Facility;Data Analyses;Data Storage and Retrieval;Funding;Grant;Housing;Image;Imaging Techniques;Individual;Institution;Internet;Life;Microscope;Pliability;Preparation;Publications;Range;Research;Research Personnel;Resolution;Resources;Sampling;Slide;Source;Spottings;Staging;Techniques;United States National Institutes of Health;cellular imaging;digital;digital imaging;image processing;instrument;tissue culture


application_id: 7720897
project_number: 5P20RR020171-05
project_title: KY COBRE: TISSUE CULTURE & PROTEIN PRODUCTION CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7024
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Tissue Culture and Protein Production Core is designed to facilitate cell culture and recombinant protein production by the COBRE investigators key components of their proposed projects. It will make available well-maintained equipment and instrumentation that would not normally be found within individual laboratories particularly those of junior investigators. The approach is to provide training and priority access to members of the investigators'' teams rather than maintaining the personnel required to accomplish the tasks on a service basis. In this way costs will be kept to a minimum.
The Core will provide tissue culture hoods and incubators for mammalian cell culture. In addition fermenters bioreactors cell cracking equipment and chromatography instrumentation will be available for production of recombinant proteins. Instrumentation to characterize recombinant proteins will also be available in the Core.
A single staff member will maintain the Core equipment provide training to new users and oversee scheduling.

project_terms:
Bioreactors;Cells;Centers of Research Excellence;Chromatography;Computer Retrieval of Information on Scientific Projects Database;Cultured Cells;Equipment;Funding;Grant;Human Resources;Incubators;Individual;Institution;Laboratories;Mammalian Cell;Production;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Services;Source;Training;United States National Institutes of Health;base;cost;design;instrumentation;member;tissue culture


application_id: 7720896
project_number: 5P20RR020171-05
project_title: KY COBRE: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7023
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Administrative Core is designed to facilitate and coordinate the research and training objectives of the Molecular Basis of Human Disease (MBHD)-COBRE. This core will provide the organizational and administrative structure needed to insure that the faculty members to be mentored have access to an environment that will facilitate their success in obtaining independent ROl-type research funding. This core will:
1) Provide administrative leadership and coordination of the overall research effort.
2) Provide support for grants accounting preparation of progress reports and grant writing.
3) Insure that the trainees have access to state-of-the-art training
4) Provide a mentoring environment that will enhance the ability of the junior faculty to obtain grant funding
5) Facilitate the use of modern research core facilities and provide funds to enhance and utilize the services of these research cores.
6) Fund pilot projects to expand research efforts in studying human disease at the molecular level.
7) Facilitate the hiring of new faculty to increase the critical mass of investigators conducting research on the molecular basis of human disease.
8) Oversee a website dedicated to the program.

project_terms:
Accounting;Arts;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Environment;Faculty;Funding;Grant;Health Services Research;Institution;Leadership;Mentors;Molecular;Pilot Projects;Preparation;Reports Progress;Research;Research Personnel;Research Training;Resources;Source;Structure;Training;United States National Institutes of Health;Writing;base;design;human disease;member;programs;success


application_id: 7720895
project_number: 5P20RR020171-05
project_title: KY COBRE: MECHANISM OF TRANSCRIPTIONAL CONTROL BY TWO DIABETES GENE PRODUCTS
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7022
contact_pi_person_id: 8224062
contact_pi: CHI, YOUNG-IN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Gene-specific transcription factors initiate transcription by specifically recognizing promoter regions of the target genes and mediating interactions with coregulators to recruit the remainder of the main transcriptional machinery. A large number of Mendelian human diseases have been linked to the mutations in genes encoding these transcription factors and in fact a recent complete human genome analysis revealed that transcription factors represent one of the four major functional groups of proteins whose germline mutations result in various human diseases. Our long-term goal is to understand the molecular mechanisms of gene regulation by these transcription factors and the molecular basis of disease-causing mutations found in them. This project focuses on diabetes. The transcription factors HNFI alpha and HNF4c alpha play vital roles in organ development and adult homeostasis and have been identified as culprit gene products for the monogenic dominant inherited forms of diabetes. Despite their similar physiological roles they belong to completely different transcription factor families and possess distinctive mechanisms of gene regulation through their unique structures and interactions with different sets of coregulators. Detailed structural information on how the molecular interactions occur during the multicomplex formation is not completely known. Therefore we propose to (1) solve the crystal structure of HNFlc alpha and HNF4a in complex with its target DNA and other functional partners and (2) examine the effects of diabetes-causing mutations on protein stability DNA binding protein-protein interaction in vitro and overall transcriptional activity in vivo to understand the molecular basis of gene regulation complex formation and functional loss by mutations. These findings should aid in the overall understanding of transcription control involved in insulin action and secretion and rational targeting of these transcription factors in order to modulate their activities and reverse the adverse effects by mutations thus potential treatment for diabetes.

project_terms:
Adult;Adverse effects;Binding (Molecular Function);Complex;Computer Retrieval of Information on Scientific Projects Database;DNA;DNA-Binding Proteins;Development;Diabetes Mellitus;Family;Funding;Gene Expression Regulation;Gene Targeting;Genes;Genome Human;Germ-Line Mutation;Goals;Grant;Homeostasis;In Vitro;Inherited;Institution;Insulin;Link;Mediating;Molecular;Mutation;Numbers;Organ;Physiological;Play;Promoter Regions (Genetics);Proteins;Recruitment Activity;Research;Research Personnel;Resources;Role;Source;Structure;Transcription Genetic;Transcriptional Regulation;United States National Institutes of Health;base;disease-causing mutation;functional group;functional loss;human disease;in vivo;protein protein interaction;transcription factor


application_id: 7720771
project_number: 2P20RR018733-06
project_title: COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6898
contact_pi_person_id: 8945910
contact_pi: KUCIA, MAGDALENA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Magdalena Kucia PI

     Stem cells provide a novel potential source to replace dead neurons and supporting tissue in brain damaged by chronic ischemia as seen for example in sleep apnea (SA). Some investigations of animals and short-term human bone marrow (BM) transplants have demonstrated that bone marrow cells provide a source of neurons and can repair brain damage (e.g. during stroke). The mechanisms of this functional improvement are currently the focus of intense research creating a need for new study methodologies to assess the effectiveness of such strategies. Elucidation of stem cell-related mechanisms of regeneration is crucial to developing effective stem cell-based therapies that could extend the lifespan of patients with diseases that are treatable by tissue regeneration. One such disorder is chronic brain damage due to hypoxia resulting from sleep apnea. 

      Based on preliminary data a novel hypothesis is presented that the pool of CXCR4+ epiblast derived VSEL is deposited in the BM during early development.  These cells subsequently serve as a reserve mobile pool of stem cells that may be mobilized into peripheral blood and play an important role in brain regeneration - where they are chemoattracted by an SDF-1 gradient.  Furthermore it is hypothesized that an age-related decrease in the marrow pool of these circulating VSEL may contribute to aging of the central nervous system (CNS) resulting in less effective repair.  To investigate these issues four specific aims are proposed.

     Specific Aim 1. Neural differentiation of bone marrow-derived VSEL. We have presented evidence that BM contains a population of VSEL and that these epiblast-derived cells are deposited there early in development during rapid body growth/expansion. We will optimize their isolation from bone marrow and neural differentiation (ability to grow neurospheres). Next we will evaluate the age-related presence of VSEL in bone marrow tissue. Once it is determined whether VSEL circulate under normal steady-state conditions in the peripheral blood (PB) at very low but detectable levels we will study their mobilization in a murine model of sleep apnea.

    Specific Aim 2. Optimize mobilization of VSEL into peripheral blood. Since mobilized peripheral blood (mPB) may be a source of VSEL for potential neural regeneration we will optimize their mobilization into PB.  We will test the effect of various mobilizing agents involving selected growth factors (G-CSF Flt3-ligand VEGF HGF) and small-molecule inhibitors (CXCR4-antagonist T140 C3aR antagonist) on the efficacy of their mobilization.  We also will investigate mobilization of these cells in response to hypoxia damage and the role of the SDF-1CXCR4 axis in this process. It is hypothesized that CXCR4+ VSEL are mobilized and subsequently chemoattracted into a damaged brain in an SDF-1-dependent manner. 

      Specific Aim 3. Develop an approach to expand VSEL.  Since the number of VSEL that can be isolated from the BM and mPB of older individuals is relatively low an efficient ex vivo expansion system may be needed to obtain a sufficient number of these cells for neural regeneration.  It also is possible that ex vivo culture-derived VSEL will better engraft and regenerate brain.  We will employ selected strategies to expand these cells ex vivo involving cocktails of selected growth factors BM stroma support and our new strategy based on the expansion of stem cells in the presence of membrane-derived microvesicles isolated from embryonic stem cells (ESMV). We observed that purified VSEL cells are able to form spheres in co-cultures with C2C12 myoblastic cell line feeder layer that resemble embryoid bodies.  Cells from these spheres may again (up to 5-7 passages) grow new secondary spheres or if plated into cultures promoting tissue differentiation expand into cells from all three germ-cell layers.  We will employ this system to expand neural cells from VSEL-derived spheres.

     Specific Aim 4. Determine the efficacy of VSEL in brain regeneration in vivo in a murine model of sleep apnea (SA).  The contribution of VSEL to functional regeneration of damaged tissues will be tested in an in vivo mouse model of SA. We will compare the regeneration potential of syngeneic VSEL isolated from enhanced green immunofluorescence protein (EGFP+) transgenic mice to rescue brain damaged by hypoxia and the role of the SDF-1CXCR4 axis in this process.  We will employ freshly isolated VSEL from BM or mPB as well as VSEL expanded in ex vivo cultures.  As a read-out of brain regeneration we will use selected behavioral tests.

project_terms:
Aging;Animals;Apnea;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Brain;Brain Damage Chronic;Brain Injuries;CXCR4 gene;Cell Count;Cell Line;Cells;Coculture Techniques;Computer Retrieval of Information on Scientific Projects Database;Condition;Data;Deposition;Development;Disease;Effectiveness;Epiblast;Funding;Germ Cells;Grant;Growth;Growth Factor;Human;Hypoxia;Immunologic Immunofluorescence;Individual;Institution;Investigation;Ischemia;Ligands;Longevity;Marrow;Membrane;Methodology;Mice Transgenic;Modeling;Mus;Natural regeneration;Nerve Regeneration;Neuraxis;Neurons;Numbers;Patients;Play;Population;Process;Reading;Research;Research Personnel;Resources;Role;Sleep;Sleep Apnea Syndromes;Source;Stem cells;Stromal Cell-Derived Factor 1;System;T140 peptide;Testing;Therapy Cell;Tissue Differentiation;Tissues;United States National Institutes of Health;Vascular Endothelial Growth Factors;age related;base;behavior test;embryonic stem cell;enhanced green fluorescent protein;functional improvement;in vivo;in vivo regeneration;inhibitor/antagonist;mouse model;novel;peripheral blood;relating to nervous system;repaired;response;small molecule;stroke;tissue regeneration


application_id: 7720770
project_number: 2P20RR018733-06
project_title: COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6897
contact_pi_person_id: 6088353
contact_pi: CUNNINGHAM, ALBERT R
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Albert Cunningham PI

     Dr. Albert Cunningham who arrived on April 1 2007 has finalized his project description which includes the specific aims of discovering molecular targets of chemical carcinogens that (1) can be used to study the etiology of tissue-specific chemical carcinogenesis and (2) can also serve as potentially new therapeutic targets for drug discovery.  He concurrently employs computational structure-activity relationship modeling and proteomic/genomic analyses to look at chemical carcinogens with differing tissue specificity in order to accomplish two things: first to identify structural attributes of chemical carcinogens associated with tissue-specific carcinogenesis; second to use these attributes as chemical probes to search for tissue-specific molecular targets associated with chemical carcinogenesis.

project_terms:
Attributes of Chemicals;Carcinogens;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Etiology;Funding;Genomics;Grant;Institution;Modeling;Molecular Target;Proteomics;Research;Research Personnel;Resources;Source;Specificity;Structure;Structure-Activity Relationship;Tissues;United States National Institutes of Health;carcinogenesis;chemical carcinogen;chemical carcinogenesis;drug discovery;novel therapeutics;therapeutic target


application_id: 7720769
project_number: 2P20RR018733-06
project_title: COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6896
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Qiutang Li PI

     The long-term goal is to elucidate the cellular and molecular mechanism by which IKKalpha exerts its effects on epidermal homeostasis. IKKalpha is a subunit of IKK complexes in NF-kappa B signaling pathway. IKKalpha knockout mice die at birth with the skin defects associated with increased proliferation and impaired terminal differentiation in keratinocytes.  The function of IKKalpha in keratinocytes is independent from its kinase activity and NF-kappa B signaling pathway. The mechanism by which the IKKalpha regulates keratinocyte proliferation and differentiation remains unclear. In the present studies we will test the hypothesis that IKKalpha regulates keratinocyte cell cycle and functions as a tumor suppressor gene in skin. 

     Specifically the following questions will be addressed: (1) What are the roles of the IKKalpha in regulation of the keratinocyte cell cycle and cell cycle checkpoint? (2) What are the IKKalpha-interacting proteins in keratinocyte? (3) How do those interacting proteins participate in the IKKalpha signaling in the keratinocytes? (4) Does IKKalpha function as a tumor suppressor in skin? 

     Cell cycle analysis and functional studies will be performed in the primary keratinocytes isolated from either wild-type or the IKKalpha deficient embryos at embryonic day 18.5 using a combination of genetics cytological and biochemical approaches. The data that have been generated from IKKalpha immunoprecipitation and mass spectrometry will be further validated and characterized to understand the IKKalpha function at a molecular level. We will examine skin tumor susceptibility and metastatic potential in IKKalpha+/- mice exposed to mutagenic carcinogen and check the loss of heterozygosity frequency at the IKKalpha locus in IKKalpha+/- mouse tumors. The knowledge will be important for elucidating clinically relevant problems such as skin cancers.

project_terms:
Address;Biochemical;Birth;Carcinogens;Cell Cycle;Cell Cycle Checkpoint;Complex;Computer Retrieval of Information on Scientific Projects Database;Data;Defect;Development;Dysplasia;Embryo;Frequencies (time pattern);Funding;Genetic;Goals;Grant;Homeostasis;Immunoprecipitation;Institution;Knowledge;Loss of Heterozygosity;Mice Knockout;Molecular;Mus;NF-kappa B;Phosphotransferases;Predisposition;Proteins;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Source;Spectrum Analysis Mass;Testing;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;clinically relevant;day;keratinocyte;tumor


application_id: 7720768
project_number: 2P20RR018733-06
project_title: COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6895
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Geoffrey Clark PI

Specific Aim 1:  Investigation of the RASSF family of Ras effectors in transformation
      The Ras oncogene has been implicated as a key player in the development of more than a third of human cancers.  Ras appears to function by activating multiple heterologous effector proteins that regulate synergistic signaling pathways controlling growth and development.  Experimentally excess Ras activation leads to vigorous transformation and the best characterized Ras effector proteins are themselves oncoproteins.  However excessive activation of Ras can also cause cells to undergo growth arrest and apoptosis.  This suggests that Ras proteins may activate a sub-set of effectors that rather than promoting transformation mediate growth inhibition.  It would seem reasonable to suppose that such effector systems would have to be subverted during the transformation process to allow progression to tumorigenicity. 

Specific Aim 2:  Development of novel small molecule inhibitors of Ras action
       Ras has been identified as a prime candidate for targeted anti-cancer therapy for more than two decades but attempts to develop specific inhibitors of Ras have so far proved ineffective.  The best known attempt involved a series of Farnesyl transferase inhibitors that actually do work well on H-Ras but are ineffective against the most important member of the family K-Ras.  Recent work has shown that the most important Ras effector for transformation in human systems is the RalGDS group of effectors.  This contrasts with results in murine systems which have implicated Rafs as the key effectors.  No inhibitors of RalGDS function have been described.

project_terms:
Apoptosis;Cells;Computer Retrieval of Information on Scientific Projects Database;Development;Family;Family member;Farnesyl Transferase Inhibitor;Funding;Grant;Growth;Growth and Development function;HRAS gene;Human;Institution;Investigation;Malignant Neoplasms;Mediating;Mus;Oncogene Proteins;Process;Proteins;RALGDS gene;RAS Superfamily Proteins;Ras Inhibitor;Research;Research Personnel;Resources;Series;Signal Pathway;Source;System;Tumorigenicity;United States National Institutes of Health;Work;cancer therapy;inhibitor/antagonist;novel;ral Guanine Nucleotide Exchange Factor;ras Oncogene;ras Proteins;small molecule;tumor growth


application_id: 7720767
project_number: 2P20RR018733-06
project_title: COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6894
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Chi Li PI

      The aims of this proposal have not changed. They are designed to examine the molecular mechanisms that regulate programmed cell death initiated from the endoplasmic reticulum (ER).  Programmed cell death plays an important role in cancer development and one of the hallmarks of cancer is the inhibition of programmed cell death.  Upon a variety of death signals cells can initiate death pathways from different subcellular compartments.  Although a lot of attention has been focused on the death pathway initiated from mitochondria relatively little is known about the involvement of the ER during programmed cell death.  It remains unclear how signals from ER stress are transduced to induce cell death.  To address this question three specific aims are envisioned:

     1. Study the mechanisms of releasing death-inducing factors from the ER lumen during ER stress-induced cell death.

     2. Investigate the signaling pathway activated by death-inducing factors from the ER.

    3. Determine how the ER-specific death pathway communicates with the death pathway initiated from mitochondria.

project_terms:
Address;Apoptosis;Attention;Cell Death;Cell Death Signaling Process;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Development;Endoplasmic Reticulum;Funding;Grant;Institution;Malignant Neoplasms;Mitochondria;Molecular;Pathway interactions;Play;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Source;Stress;United States National Institutes of Health;design;programs


application_id: 7720766
project_number: 2P20RR018733-06
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE E: PROTEOMICS FACILITY
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6893
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.   The Core Proteomics Laboratory is uniquely equipped with robotic workstations that increase gel throughput image analysis spot excision in-gel peptide digestion and MALDI-MS sample preparation.  The automated workstations include a Propic gel spot picker that visualizes and excises spots from fluorescence-stained gels and a ProGest station that automates in-gel trypsin digestion in a 96- or 384-well format.  The laboratory also contains a ProMS robot that automates desalting concentrating and spotting of peptide samples onto MALDI targets allowing fully integrated high-throughput analysis of protein samples.  MALDI-MS analysis is performed using a Micromass Inc. TOF-Spec 2E.  The lab recently instituted automated analysis of high-resolution 2D gels using Progenesis software significantly decreasing analysis time of 2D gels accelerating throughput. The CPL maintains active collaborations and provides instruction to COBRE-affiliated faculty and graduate students.

project_terms:
Collaborations;Computer Retrieval of Information on Scientific Projects Database;Computer software;Digestion;Excision;Faculty;Fluorescence;Funding;Gel;Grant;Image Analysis;Institutes;Institution;Instruction;Laboratories;Peptides;Preparation;Progest;Proteins;Proteomics;Research;Research Personnel;Resolution;Resources;Robot;Robotics;Sampling;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spottings;Staining method;Stains;Students;Time;Trypsin;United States National Institutes of Health;high throughput analysis


application_id: 7720765
project_number: 2P20RR018733-06
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE D: NMR & PROTEIN PURIFICATION FACILITIES
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6892
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Andrew Lane Core D Director

      The primary aims of the core are to provide infrastructure for and support to structural analysis and metabolomics of cancer cells and tissue and for producing proteins in high yield suitable for NMR analysis. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways. 
      Established researchers and new recruits to the program are seeing the benefits of the core facility for their research. This includes both protein production for biophysical analyses by X-ray crystallography NMR and Biophysics as well as extensive use of the metabolomics capabilities of the Core (see below). Efforts are being made to ensure that new recruits are fully cognizant of the core facilities and will be actively encouraged to use the unique capabilities.
      Dr. Chi Li (Project 6) will use metabolomics approaches for understanding metabolic consequences of apoptotic proteins on isolated mitochondria. 
      Dr. Geoffrey Clark (Project 7) is using the Protein Expression core to produce human DNMT3b (DNA (cytosine-5-)-methyltransferase 3 beta) as a GST fusion that will be used for characterization and biological experiments.
     Dr. Magda Kucia (Project 10) is working on stem cells for regenerative therapy. In addition to characterizing the gene expression profile of such cells during expansion she is interested in determining the metabolic phenotype of such cells to learn about the precise requirements for growth and differentiation in terms of energy and anabolic metabolism.
      Dr. Hong Ye (COBRE graduate) makes use of the expression core facilities for protein production advice and analysis and will need the NMR capabilities for some functional analyses of the proteins whose structures she has solved by X-ray diffraction methods.
      Dr. Jason Chesney (COBRE graduate) has continued to make extensive use of the facility and has been analyzing the metabolic consequences of expression of iPFK2 and ras (and effects of RNAi knockdowns) as well as the effects of immortalization via hTERT and large T antigen expression in a number of cell types including Jurkat cells MCF-7 bronchial epithelia and fibroblasts. Metabolite profiles and isotopomer analyses using the NMR facility have been instrumental in discovering consequences of cellular perturbations on the road to transformation (with sometimes surprising results) as well as validating (or otherwise) potential anticancer target enzymes. Some of this work has now been published and other manuscripts are in preparation.
      Dr. Binks Wattenberg (COBRE graduate) is expressing sphingosine kinase using transient expression in insect cells and also in bacteria (E. coli). The enzyme in the latter case enters inclusion bodies and has to be refolded after purification. The protein expression laboratory is working on purification schemes based on hexahis affinity chromatography as well as calmodulin affinity chromatography which has been shown to separate folded SK from unfolded enzyme. This will be used for biophysical studies including crystallography ligand binding and NMR analyses. In addition he has been analyzing the solution properties of targeting peptides using the NMR facility.

project_terms:
Apoptotic;Bacteria;Biological;Biophysics;Calmodulin;Cells;Centers of Research Excellence;Chromatography Affinity;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Crystallography;Crystallography X-Ray;Cytosine;DNMT3B gene;Data Collection;Differentiation and Growth;Ensure;Enzymes;Escherichia coli;Fibroblasts;Funding;Gene Expression Profile;Glutathione S-Transferase;Goals;Grant;Human;Inclusion Bodies;Insecta;Institution;Jurkat Cells;Label;Laboratories;Large T Antigen;Learning;Ligand Binding;Manuscripts;Metabolic;Metabolic Pathway;Metabolism;Methods;Methyltransferase;Mitochondria;Numbers;Peptides;Phenotype;Preparation;Production;Property;Proteins;Publishing;RNA Interference;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resources;Scheme;Solutions;Source;Stable Isotope Labeling;Stem cells;Structure;Tissues;United States National Institutes of Health;Work;X ray diffraction analysis;X-Ray Diffraction;base;bronchial epithelium;cancer cell;cell type;interest;metabolomics;programs;protein expression;protein purification;research study;sphingosine kinase


application_id: 7720764
project_number: 2P20RR018733-06
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE C: MOLECULAR MODELING FACILITY
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6891
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: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.       The goals of the COBRE in Molecular Targets Molecular Modeling Core Facility have not changed. The Molecular Modeling Core Facility operated by Dr. John Trent is a state-of-the-art molecular modeling facility that has the capability of providing models based on structural data obtained from either X-ray crystallographic or NMR studies.  In particular this facility has provided important molecular modeling services for Projects 1 2 3 and 4.  Using homology modeling and virtual screening of potential inhibitors Dr. Trent has made very important contributions on a collaborative basis to members of each COBRE-MT project.  This facility is located within the Brown Cancer Center.  The capabilities of the facility include techniques such as explicitly solvated molecular dynamics homology modeling docking virtual screening ESP calculations and conformational searching.
        For Dr. Geoffrey Clark's project (7) the Core C is performing virtual screens on two targets. Finding new drug templates for two projects demonstrates excellent progress and represents a relatively unique hit rate.

project_terms:
Arts;Cancer Center;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Data;Docking;Extrasensory Perception;Funding;Goals;Grant;Homology Modeling;Institution;Modeling;Molecular Target;Pharmaceutical Preparations;Rate;Research;Research Personnel;Resources;Roentgen Rays;Screening procedure;Services;Source;Techniques;United States National Institutes of Health;base;inhibitor/antagonist;member;molecular dynamics;molecular modeling;virtual


application_id: 7720763
project_number: 2P20RR018733-06
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE B: MICROARRAY FACILITY
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6890
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.     The Microsequence Array Core Facility is located in the Baxter II Biomedical Research Building one block from the Brown Cancer Center. This facility contains an Affymetrix Genechip instrument which is available to all MT-COBRE members. Plans are underway for the development of a tissue array component of this facility as well. The Microsequence Array Facility is under the direction of Dr. Wolfgang Zacharias and has been fully operational for the past four and one-half years. It contains a full-time staff member Sabine Waigel who provides technical assistance in sample processing hybridization and data analysis. The Microsequence Array Core has a close relationship with the Laser Capture Microscopy facility in the Department of Pathology and an established Tumor Bank in the J.G. Brown Cancer Center. This allows the preparation of samples with known pathologic characteristics and appropriate control specimens. Dr. Zacharias remains available for assistance with experimental design and data analysis. 
     The new high-resolution Affymetrix Scanner 3000 upgrade purchased and installed in March 2005 now allows all COBRE investigators to use the newest generation of high-density whole genome v2.0 arrays for human or mouse. We continue to organize and hold software/data analysis workshops on campus to train microarray technology users.

project_terms:
Biomedical Research;Cancer Center;Centers of Research Excellence;Characteristics;Computer Retrieval of Information on Scientific Projects Database;Computer software;Core Facility;Data Analyses;Development;Educational workshop;Experimental Designs;Funding;Generations;Genome;Grant;Human;Institution;Lasers;Microarray Analysis;Microscopy;Mus;Pathologic;Pathology;Preparation;Process;Research;Research Personnel;Resolution;Resources;Sampling;Source;Specimen;Time;Tissue Microarray;Training;Tumor Bank;United States National Institutes of Health;density;instrument;member


application_id: 7720762
project_number: 2P20RR018733-06
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE A:ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2008-06-26
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2008-07-01
project_end_date: 2009-06-30
subproject_number: 6889
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Core A the Administrative Core is responsible for the day-to-day operations of the Molecular Targets Center of Biomedical Research Excellence (MT-COBRE).  Core A manages the scientific and administrative aspects of the COBRE.  In collaboration with Nancy Roseberry the COBRE Coordinator Drs. Miller and Eaton are responsible for oversight of all administrative aspects of the COBRE.  This funding has provided an opportunity to recruit five additional faculty to the MT-COBRE as the original faculty have received new funding and left the COBRE.

project_terms:
Centers of Research Excellence;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Faculty;Funding;Grant;Institution;Left;Molecular Target;Operative Surgical Procedures;Recruitment Activity;Research;Research Personnel;Resources;Source;United States National Institutes of Health;day


application_id: 7720699
project_number: 2P20RR017702-06A1
project_title: THE GENETIC BASIS OF CONGENITAL HEART DEFECTS (CHD)
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6827
contact_pi_person_id: 8320904
contact_pi: TOMITA-MITCHELL, AOY
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Congenital heart disease (CHD) is one of the most common birth defects. Infants born with 
CHD often require multiple medical and/or surgical interventions and will nonetheless experience significant morbidity if not mortality. Despite their prevalence and clinical significance the etiology of CHD remains largely unknown. The pervading view is that the disease is heterogeneous and complex with bothenvironmental and inherited genetic risk factors. Mutations in a few cardiac development genes such as NKX2.5 GATA4 and TBX5 have been implicated as inherited risk factors. We propose using a novel highly sensitive mutation detection technology called Constant Denaturant Capillary Electrophoresis (CDCE) combined with High-Fidelity PCR (HiFi PCR) to determine whether mutations in each candidate gene are enriched in the patient population as compared to a large control population. This new technology enables the rapid and cost-effective analysis of large populations by pooling and screening DNA from 96 individuals at a time. The analyses of large populations are necessary to discover low frequency causal mutations and to quantitate low effect relationships between mutations and disease.  Once enriched mutations are identified we will examine the potential biological effect of each mutation. These mutations may or may not lead to obvious changes in the encoded proteins via nonsense or missense mutations. Indeed there is increasing evidence that even translationally silent mutations and polymorphisms can have a phenotypic affect by altering pre-mRNA splicing. An additional layer of complexity is that a separate genetic mechanism for congenital heart disease has been proposed. Somatic mutations were recently identified in NKX2.5 and/or TBX5 in greater
than 95% of hearts with septal defects. These mutations were identified within the septal defects and were not found in unaffected regions taken from the same heart indicating a somatic and mosaic nature for these mutations and suggest that these mutations are etiologic. Moreover multiple mutations as well as multiple haplotypes were observed within the same patient in a majority of these congenital heart disease patients. The occurrence of two or more somatic mutations in a gene is an exceedingly rare event and suggests a condition of extreme genomic instability reminiscent of that observed in cancer.
In this proposal we will examine the genetic contribution of both inherited and somatic 
mutations in NKX2.5 GATA4 and TBX5 to cardiac malformations. Specifically we will:
Specific Aim 1: Examine the contribution of molecular deficits in NKX2.5 GATA4 and TBX5 to 
the etiology of CHD.
A. Test the hypothesis that mutations in NKX2.5 GATA4 and TBX5 increase risk for CHD 
using CDCE/HiFi PCR.
B. Test the hypothesis that alternative splicing of NKX2.5 GATA4 and TBX5 confer an increased or decreased susceptibility to CHD.
C. Determine if silent sequence variants observed in NKX2.5 GATA4 and TBX5 in CHD 
patients result in alternative splicing.
D. Continue the ascertainment of a large well-characterized cohort of subjects with CHD
Specific Aim 2: Examine the contribution of somatic mutations to the etiology of CHD.
A. Test the hypothesis that somatic mutations in cardiac developmental genes are etiologic in 
CHD.
B. Determine the mutation rate of cardiomyocytes during cardiogenesis in normal and malformed hearts.
C. Use mutational spectrometry to discover primary mutagenic pathways in normal and malformed hearts.
Our goal is to identify inherited mutations that are causally related to CHD determine the
mechanisms by which they can increase risk of congenital heart disease and test the hypothesis that somatic mutations are etiologic in congenital heart disease. We will assess the biological significance of mutations found in these genes with the goal of identifying improved management strategies for the disease.

project_terms:
Affect;Alternative Splicing;Biological;Candidate Disease Gene;Cardiac;Complex;Computer Retrieval of Information on Scientific Projects Database;Condition;Congenital Abnormality;DNA;Development;Disease;Electrophoresis Capillary;Etiology;Event;Frequencies (time pattern);Funding;Gene Developmental;Genes;Genetic;Genomic Instability;Goals;Grant;Haplotypes;Heart;Heart Defects Congenital;Heart Septal Defects;Heterogeneous Nuclear RNA;Individual;Infant;Inherited;Institution;Lead;Malignant Neoplasms;Medical;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mutation;Mutation Detection;Mutation Missense;Myocytes Cardiac;Nature;Operative Surgical Procedures;Pathway interactions;Patients;Polymerase Chain Reaction;Polymorphism Genetic;Population;Population Control;Predisposition;Prevalence;Proteins;RNA Splicing;Rate;Research;Research Personnel;Resources;Risk;Risk Factors;Screening procedure;Silent Mutation;Somatic Mutation;Source;Spectrometry;Technology;Testing;Time;United States National Institutes of Health;Variant;base;cardiogenesis;clinically significant;cohort;congenital heart disorder;cost;experience;genetic risk factor;improved;mRNA Precursor;new technology;novel


application_id: 7720698
project_number: 2P20RR017702-06A1
project_title: FACTORS ASSOCIATED WITH INTRAVENTRICULAR HEMORRHAGE IN THE PRETERM NEONATE
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6826
contact_pi_person_id: 3121451
contact_pi: MAINOUS, ROSALIE O
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The purpose of this research is to identify and describe factors that may impact
or demonstrate the preterm infant?s response to noxious stimuli via three pilot projects to be undertaken within the next year.  The primary grant proposal will identify cerebral blood flow dynamics and vital signs associated withnoxious stimuli in the preterm infant population of  less than and equal to 32 weeks gestational age as a first step in developing a predictive model for intraventricular hemorrhage. Three specific pilot projects are proposed. First a study entitled ?Measurement Issues Related to Cerebral Blood Flow in the Neonatal Brain? will serve to provide the engineers on the major proposal with data on the use of Near Infrared Spectroscopy (NIRS) in the neonate. The second project ?Peak and Sustained Noise Levels in the NICU? will document an environmental variable that may be a confounder in the NICU. The third project to take place after the completion of projects one and two will be ?Correlation of Maternal and Infant factors with Incidence of IVH in one NICU?. This project will be a retrospective chart review to provide demographic and care variables that may be of interest in the predictive model.

project_terms:
Brain;Caring;Cerebrovascular Circulation;Computer Retrieval of Information on Scientific Projects Database;Data;Engineering;Funding;Gestational Age;Grant;Grants Applications;Incidence;Infant;Infant Premature;Institution;Measurement;Neonatal;Noise;Pilot Projects;Population;Purpose;Research;Research Personnel;Resources;Source;Spectroscopy Near-Infrared;Stimulus;United States National Institutes of Health;Week;interest;intraventricular hemorrhage;neonate;predictive modeling;response


application_id: 7720697
project_number: 2P20RR017702-06A1
project_title: THE EFFECT OF INTERNEURON LOSS ON MINICOLUMN STRUCTURE
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6825
contact_pi_person_id: 8634532
contact_pi: SEELAN, RATNAM SATHIAGANA
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The correct balance between excitation and inhibition is pivotal to the fundamental operation 
of the brain whether primary unimodal or heteromodal neocortex. Studies have suggested 
that minicolumns in the brains of patients with autism are narrower than those of controls 
with an altered internal configuration. (1) More specifically their minicolumns reveal less 
peripheral neuropil space and increased spacing among their constituent cells. The peripheral 
neuropil space is the conduit for among other things inhibitory local circuit projections. A 
defect in these GABAergic fibers may correlate with the increased prevalence of seizures 
among autistic patients. Unsurprisingly it has been argued that some of the behavior 
exhibited by autistic patients may be rooted in an imbalance between excitation and 
inhibition. A recent study shows that ?a single gene mutation can selectively alter the 
development of cortical interneurons in a region-and cell subtype-specific manner with 
deficits leading to long-lasting changes in circuit organization and behavior.? The mi(uPAR) 
were targeted with a mutation that affects interneuron migration. Anterior cingulate and 
parietal cortical areas contained 50 % fewer GABAergic interneurons compared with Wild 
Type (WT) littermates. No differences were found in visual or piriform cortex. There was a 
complete loss of parvalbumin (PV) subtypes with other classes remaining intact. GABAergic 
type cells known to be immunoreactive for PV include the basket and chandelier cells. The 
ability of a single gene mutation to cause a major loss in certain populations of specific 
GABAergic interneurons is especially significant in regards to genetic defects related to 
autism. The most prevalent genetic or environmental factor found among the first 100 cases 
in the South Carolina autism project is an abnormality of chromosome 15q that has three 
GABA receptor subunit genes. Furthermore mice of the uPAR strain demonstrated certain 
behaviors associated with autism which included a propensity for seizure disorders and
both increased anxiety and timidity or recluse-like behavior.
Thus we seek to determine whether the cortical minicolumn as represented by cell soma 
and apical dendrite bundles is narrower in the uPAR mouse than the WT. Secondly we will 
identify the distribution of GABAergic interneurons in the uPAR mice. Positive results would 
show that the loss of GABAergic interneurons can cause a narrowing of minicolumns similar 
to that found in the minicolumns of patients withautism. The manifestations of autistic like 
behavior in the uPAR mouse in conjunction with positive results from this study could 
promote its use as an animal model for autism.
Specific Aim 1: To determine whether a reduction in GABAergic inhibitory interneurons is 
associated with the narrowing of pyramidal cell arrays.
Specific Aim 2: To determine whether a reduction in GABAergic cells is associated with a 
narrowing between layer V apical dendrite bundles.
Specific Aim 3: To determine the extent of GABAergic cell loss in barrel cortex in the uPAR 
mouse.

project_terms:
15q;Affect;Animal Model;Anterior;Anxiety;Apical;Area;Autistic Disorder;Behavior;Brain;Cells;Chromosome abnormality;Class;Computer Retrieval of Information on Scientific Projects Database;Defect;Dendrites;Development;Environmental Risk Factor;Epilepsy;Equilibrium;Exhibits;Fiber;Funding;GABA Receptor;Gene Mutation;Genes;Genetic;Grant;Institution;Interneurons;Mus;Mutation;Neocortex;Neuropil;Operative Surgical Procedures;Parietal;Parvalbumins;Patients;Peripheral;Plant Roots;Population;Prevalence;Pyramidal Cells;Research;Research Personnel;Resources;Seizures;Source;South Carolina;Structure;Timidity;United States National Institutes of Health;Visual;Wild Type Mouse;barrel cortex;cell body (neuron);cell type;migration;piriform cortex


application_id: 7720696
project_number: 2P20RR017702-06A1
project_title: TOBACCO EXPOSURE BIOMARKERS AND MUTATIONS OF MSX1 AND IRF6 GENES IN PREGNANCY
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6824
contact_pi_person_id: 1868682
contact_pi: MYERS, STEVEN 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
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Exposure to tobacco smoke during pregnancy places the developing fetus at an elevated risk of severe outcomes related to smoke exposure. Most notably intrauterine growth retardation as well as decrease in birth weight have been measured as direct consequence of tobacco exposure in utero. However other harmful effects of tobacco smoking during pregnancy have also been identified including an elevated risk of birth defects. Of the thousands of compounds found in tobacco only a few have been studied in detail with respect to these changes. Most notably are the tobacco specific nitrosamines which have clearly been linked to experimental orofacial defects in animal models. Epidemiological studies have established a significant positive correlation between maternal smoking and an increased risk for orofacial clefts in humans. Studies analyzing the effect of tobacco constituents on mouse craniofacial development have provided clear evidence that the morphologic events can be disrupted by exposure to tobacco smoke. Specific genes related to the development of birth defects especially orofacial defects have been widely studied but the link between these genes and specific compounds in tobacco that may alter these genes expression and the metabolism and detoxification of specific tobacco carcinogens has not been carried out. In the proposed study we will recruit mothers that have smoked during pregnancy and investigate the relationship between smoking during pregnancy and the effects that tobacco exposure has in utero on specific genes related to birth defects. We will qualitatively and quantitatively assess exposure to tobacco and specifically to the tobacco specific nitrosamines NNN (N'-nitrosonornicotine) and NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) as well as benzo(a)pyrene by assessment of protein adducts to the compounds in maternal and fetal blood samples obtained at delivery. We will carry out genotyping to specific enzymes related to metabolic activation and deactivation of tobacco carcinogens CYP1A1 and microsomal epoxide hydrolase (MeH). We will isolate maternal and fetal DNA and characterize genes that are potentially related to the birth defects caused by tobacco smoke. In order to link tobacco exposure with specific genes related to birth defects we will examine and sequence two genes that are known to play a role in the etiology of orofacial defects the MSX1 and IRF6 genes. We will correlate mutations in the various genes with smoking status as well as biomarkers detected for the tobacco specific compounds. This link will assist in determining the relationships between smoking especially during pregnancy specific known teratogens in tobacco and mutations in specific genes that are known to be related to birth defects.

project_terms:
4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone;Animal Model;Benzo(a)pyrene;Biological Markers;Birth Weight;Blood specimen;CYP1A1 gene;Cleaved cell;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;DNA;Defect;Development;Enzymes;Epidemiologic Studies;Etiology;Event;Exposure to;Fetal Growth Retardation;Fetus;Funding;Gene Expression;Genes;Genotype;Grant;Human;Institution;Link;MSX1 gene;Measures;Metabolic Activation;Metabolic Detoxication Drug;Metabolism;Microsomal Epoxide Hydrolase;Mothers;Mus;Mutation;N'-nitrosonornicotine;Nitrosamines;Outcome;Play;Pregnancy;Proteins;Recruitment Activity;Research;Research Personnel;Resources;Risk;Role;Smoke;Smoking;Smoking Status;Source;Teratogens;Tobacco;Tobacco smoke;Tobacco smoking;Tobacco-Associated Carcinogen;United States National Institutes of Health;adduct;craniofacial;fetal;fetal blood;in utero;maternal cigarette smoking;orofacial;tobacco exposure


application_id: 7720695
project_number: 2P20RR017702-06A1
project_title: U-SHAPED DEVELOPMENT IN INFANT COGNITION AND PERCEPTION
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6823
contact_pi_person_id: 8436880
contact_pi: CASHON, CARA HELEN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Although development is traditionally thought to follow an increasing monotonic pattern in which infants or children improve with age closer examination indicates that infants may regress temporarily to a lower level subsequent to achieving a higher level of performance (Cashon & Cohen 2003 2004; Werker Fennell Corcoran & Stager 2002).  In some cases this regression may be permanent (Pascalis de Haan & Nelson 2002).  Such regression patterns certainly negate the traditional notion that development only entails steady improvement.  Accordingly since these regressions are not predicted by theories when they do appear they are usually unexpected and not understood.  Given the paucity of information in this area and the critical need for elucidating this process and its consequences for predicting developmental outcomes our overall GOAL for the proposed research is to investigate the underlying mechanisms involved in U-shaped patterns of development found during infancy. More specifically we will determine whether such patterns reflect a domain-general adaptive learning process that allows the infant to become more tailored to his/her environment or whether they reflect changes that are artifacts of the experimental task.
When infants display a U-shaped pattern of development it is often viewed as a result of "reorganization" (Werker & Tees 1984).  We recently argued (Cashon & Cohen 2003; 2004) that such regressions are necessary as infants adapt to their environment.  Infants must incorporate important information en route to becoming "experts" in the world around them. As a result of the reorganization process however infants may temporarily regress to a lower level. Two specific aims will address the GOAL of the proposed research which is to elucidate the underlying mechanisms involved in U-shaped patterns of development during infancy. Both aims will be met by testing infants in a visual habituation task whereby infants' looking times are measured while they view a series of faces and moving objects.  Aim 1 will build upon previous research indicating that infants' face processing follows a U-shaped pattern.  Aim 2 will empirically test the prediction that U-shaped development occurs prior to the development of an adaptive constraint.  Aim 2 will be achieved by investigating infants' perception of form-function correlations. 
Aim 1 investigates the bases for the U-shaped pattern of development in infants' processing of faces. In a previous set of studies we found that between 3 and 7 months of age infants' processing of faces produces a U-shaped pattern with a drop in performance occurring at approximately 6 months of age (Cashon & Cohen 2004). We argue this regression is a necessary but temporary change resulting from overload as infants try to incorporate important information about faces. This notion is consistent with research in other areas of infant cognition and perception showing that when integrating new information infants regress to a lower level of processing (Cohen Chaput & Cashon 2002).  Alternatively the apparent U-shape could be the result of 6-month-olds shifting their attention to focus exclusively on the eyes and eyebrows of a face.  Aim 1 will investigate these two alternate hypotheses.  It is predicted that 6 month olds will show evidence of overload and not of simply processing the eyes and eyebrows of a face. 
Aim 2 investigates the bases for U-shaped pattern of development in infants' processing of form-function correlations.  Predictions of when U-shaped development will occur are lacking.  We argue that U-shaped patterns occur just prior to perceptual of cognitive pruning. Accordingly we would expect infants to show a U-shaped developmental pattern in their processing of form-function correlations.  Previous research by Madole and Cohen (1995) indicates that infants develop an adaptive constraint on their processing these correlations between 14 and 18 months of age.  Based on our hypothesis we predict that a drop in performance occurs between these two ages.  More specifically Madole and Cohen reported finding that 14-month-olds are sensitive to the correlation between the appearance (form) of a feature of an object and its function (within-feature form-function correlation) as well as the form of one feature and the function of another (between-feature form-function correlation).  Importantly they also reported that 18-month-olds are sensitive only to the within-feature form-function correlation.  Our specific prediction is that infants at approximately 16 months will regress and show no sensitivity to either correlation.

project_terms:
Address;Age;Age-Months;Appearance;Area;Attention;Child;Cognition;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Development;Disease regression;Drops;Environment;Eye;Eyebrow structure;Face;Face Processing;Form Perception;Funding;Goals;Grant;Infant;Institution;Learning;Measures;Morphologic artifacts;Outcome;Pattern;Perception;Performance;Process;Reporting;Research;Research Personnel;Resources;Route;Series;Shapes;Source;Testing;Thinking function;Time;United States National Institutes of Health;Visual;base;improved;infancy;theories


application_id: 7720694
project_number: 2P20RR017702-06A1
project_title: RING OR ZINC FINGER PROTEINS DURING GAMETOGENESIS AND EMBRYONIC DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6822
contact_pi_person_id: 6574851
contact_pi: LAN, ZI-JIAN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Reproductive development and function are complex processes involving both genetically determined and physiological events. Identification of the critical genes involved in regulating these processes is necessary to characterize how these processes are coordinated. In particular the generation of mature gametes involves many steps of development and differentiation as well as the distinctive cellular process meiosis that are collectively termed gametogenesis. In general differentiation and development and other processes that lead to the acquisition and maintenance of a cellular phenotype are dependent on the differential and coordinate regulation of gene expression. However the regulation of gene expressioin many aspects of gametogenesis such as proliferation of spermatogonial stem cells signals for meiotic arrest and meiotic exit and spermiogenesis and cross-talk between germ cells and adjacent somatic cells are not clearly understood. In addition the roles of maternal and paternal genes in zygotic development are also not well defined. Identification and functional characterization of germ cell-specific molecules such as zinc finger proteins during
gametogenesis and early embryonic development would advance our knowledge regarding gamete and zygotic development and will provide new leads for development of diagnostic reagents for reproductive diseases novel therapeutic medicines for the treatment of infertility gonadal cancers pre-natal death and
novel contraceptive agents.
The RING (Really interesting novel genes) finger is a specialized type of zinc finger proteins. It contains an evolutionarily conserved structure found in more than 300 proteins from the human genome database in which two loops of amino acids are pulled together at their base by eight cysteine or histidine residues that bind two zinc ions. There are two different variants the C3HC4-type and the C3H2C3-type
which is clearly related despite the different cysteine/histidine patterns. These ring finger domains are found in two major classes of proteins: (1) transcriptional activators repressors or cofactors and (2) subunits of complexes that modulate chromatin. These proteins likely interact with other proteins participate in ubiquitination and play roles in cell growth control such as apoptosis tumorigenesis DNA damage repair and gene expression. In silico analyses have demonstrated that a large number of ring/zinc finger proteins with human homologs are expressed in the germ cells or early embryos indicating that these proteins may play a role in germ cell and zygotic development. Recent studies have shown that ring finger proteins zygote arrest 1 (Zar1) and NEURL are critical for zygotic development and male fertility and mammary gland maturation during pregnancy respectively. Ablation of another ring finger protein Siah1a also caused male infertility due to defects in meiosis. In addition another oocyte specific ring finger protein RFPL4 interacts with oocyte proteins and likely functions as an E3 ubiquitin protein ligase to regulate protein degradation and meiotic cell cycle progression. Therefore we are just in the beginning to understand the functional roles of these ring/zinc finger proteins during gametogenesis and early embryonic development.
Having searched mouse and human genomic databases I found that seven uncharacterized genes likely play a role during gametogenesis and zygotic development as the expressed sequence tags (ESTs) of these genes are present in the cDNA libraries of mouse human germ cells or early embryos. I am particularly interested in five of these genes (named unknown 1-5) which are located in different mouse chromosomes and all have human orthologs. Unknown-1 -2 and -3 are C3HC4 ring finger proteins while unknown?4 and ?5 are C2H2 zinc finger proteins similar to zfp148 nanos2 and nanos3 which are required for male or female germ cell development. I will combine genetic molecular and cellular
approaches to address whether these genes are involved in the gametogenesis and early embryonic development.

project_terms:
Ablation;Address;Amino Acids;Apoptosis;Binding (Molecular Function);C2H2 Zinc Finger;Cell Cycle Progression;Cell physiology;Cessation of life;Chromatin;Chromosomes;Class;Complex;Computer Retrieval of Information on Scientific Projects Database;Computer Simulation;Contraceptive Agents;Cysteine;DNA Repair;Databases;Defect;Development;Development Other;Diagnostic Reagent;Disease;Embryo;Embryonic Development;Event;Expressed Sequence Tags;Female;Fertility;Fingers;Funding;Gametogenesis;Gene Expression;Gene Expression Regulation;Generations;Genes;Genomics;Germ Cells;Grant;Histidine;Homologous Gene;Human;Infertility;Infertility Male;Institution;Ions;Knowledge;Lead;Maintenance;Malignant Neoplasms;Mammary gland;Medicine;Meiosis;Molecular Genetics;Mus;NEURL gene;Names;Numbers;Oocytes;Orthologous Gene;Pattern;Phenotype;Physiological;Play;Pregnancy;Process;Proteins;Research;Research Personnel;Resources;Ring Finger Domain;Role;Role playing therapy;Signal Transduction;Somatic Cell;Source;Spermiogenesis;Stem cells;Structure;Structure of zygote;Transcription Coactivator;Ubiquitination;United States National Institutes of Health;Variant;Zinc;Zinc Fingers;base;cDNA Library;cell growth;cofactor;genome database;interest;male;novel;novel therapeutics;protein degradation;reproductive;reproductive development;tumorigenesis;ubiquitin-protein ligase


application_id: 7720693
project_number: 2P20RR017702-06A1
project_title: THE ROLE OF TFII-I TRANSCRIPTION FACTOR IN THE NEURAL TUBE CLOSURE DEFECTS
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6821
contact_pi_person_id: 6065455
contact_pi: BAYARSAIHAN, DASHZEVEG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Neural tube closure defects (NTDs) in particular anencephaly and spina bifida are 
common human birth defects.  Risk of NTDs is inherited in humans but usually not as a 
single dominant or recessive gene.  The incidence of NTDs varies with ethnic group 
socioeconomic group and time but remains on the order of 1 in 1000 births despite the 
use of folate supplementation in early pregnancy.  Thus the use of mouse mutants and 
strains implicated in phenotype causation is very critical in our understanding of NTDs.  
TFII-I is a transcription factor with multiple helix-loop-helix repeat domains.  The TFII-I 
knockout mice generated in our laboratory display several phenotypic manifestations 
including NTDs.  In an effort to establish the molecular basis of NTDs we will search for 
the downstream target genes regulated by the TFII-I family of transcription factors.  We 
believe that certain set of genes in this category may be profoundly deregulated in the 
neural tube closure and are therefore most probably the immediate causal factors in NTDs.  
The establishment of the developmental genetic basis of NTDs is important beyond the 
understanding it brings to neural tube closure itself.  The identification of genes that 
regulate neural tube development allows further investigation of genetic interactions that 
may be causal to NTD conditions.

project_terms:
Anencephaly;Birth;Categories;Causations;Computer Retrieval of Information on Scientific Projects Database;Condition;Congenital Abnormality;Defect;Ethnic group;Family;Folate;Funding;Gene Targeting;Genes;Genes Recessive;Genetic;Grant;Helix-Turn-Helix Motifs;Human;Incidence;Inherited;Institution;Investigation;Laboratories;Mice Knockout;Mice Mutant Strains;Molecular;Neural Tube Closure;Neural Tube Development;Phenotype;Pregnancy;Research;Research Personnel;Resources;Risk;Role;Source;Spinal Dysraphism;Supplementation;Time;United States National Institutes of Health;base;developmental genetics;socioeconomics;transcription factor


application_id: 7720692
project_number: 2P20RR017702-06A1
project_title: COBRE: UL: ADMIN: ALTERATION & RENOVATION
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6820
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This application requests $500000 for alterations and renovations to 2097 sq ft for three laboratories within the School of Dentistry.

project_terms:
Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Funding;Grant;Institution;Laboratories;Request for Applications;Research;Research Personnel;Resources;School Dentistry;Source;United States National Institutes of Health


application_id: 7720691
project_number: 2P20RR017702-06A1
project_title: COBRE: UL: P4: DVMT PROCESSES OF PITUITARY DIFFERENTIATION & MATURATION
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6819
contact_pi_person_id: 2050006
contact_pi: MOORE, JOSEPH P
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The sequence of events in sexual development is very important. An inappropriate hormonal environment can result in infertility of the adult male. Infertility affects approximately 15% of couples 40% are male infertility. An understanding of hormonal regulation of male sexual development may allow for early detection and prevention of infertility. The goals of this plan are to develop an understanding of regulation of the differential expression of the pituitary gonadotropins during maturation. There is data suggesting that pituitary adenylate cyclase activating polypeptide (PACAP) can differentially regulate the pituitary gonadotropins. PACAP increases the actions of gonadotropin releasing hormone (GnRH) and alone PACAP enhances the production of luteinizing hormone while decreasing follicle stimulating hormone expression. Our overall hypothesis is that during embryonic and early postnatal development the pituitary is exposed to very high levels of PACAP that selectively suppress FSH until the juvenile stage of sexual maturity. The specific aims of this proposal are: 1) To determine whether PACAP plays a role in the differential expression of the gonadotropin subunit genes during fetal pituitary development; 2) To determine if the rise in FSHb mRNA in immature male rats is related to weaning and is coincident with a change in PACAP expression; 3) To determine if pituitary cells from fetal and infant male rats are more responsive to PACAP than are cells from juvenile rats; and 4) To explore the developmental effects of PACAP through pituitary specific expression of the PACAP antagonist PACAP-(6-38). The proposed experiments will develop the PIs skills in the techniques of pituitary cell culture in situ hybridization laser capture microdissection single cell RT-PCR in situ hybridization Northern hybridization Southern hybridization and cDNA cloning. Successful completion of this proposal should provide insight into developmental regulation of gonadotropins and invaluable experience that the candidate can utilize to propagate a successful career.

project_terms:
Adolescent;Adult;Affect;Cells;Cloning;Computer Retrieval of Information on Scientific Projects Database;Couples;Cultured Cells;DNA Complementary;Data;Development;Early Diagnosis;Embryo;Environment;Event;Follicle Stimulating Hormone;Funding;Genes;Goals;Gonadotropin Hormone Releasing Hormone;Gonadotropins;Grant;Hormonal;In Situ Hybridization;Infant;Infertility;Infertility Male;Institution;Luteinizing Hormone;Pituitary Gland;Pituitary Gonadotropins;Play;Prevention;Process;Production;RNA Messenger;Rattus;Regulation;Research;Research Personnel;Resources;Reverse Transcriptase Polymerase Chain Reaction;Role;Sexual Development;Source;Staging;Techniques;United States National Institutes of Health;Weaning;career;experience;fetal;fetus cell;hormone regulation;insight;laser capture microdissection;male;northern hybridization;pituitary adenylate cyclase activating polypeptide;postnatal;research study;skills;southern hybridization


application_id: 7720690
project_number: 2P20RR017702-06A1
project_title: COBRE: UL: P3: C-SKI TRANSCRIPTION OF NEURAL TUBE ONTOGENESIS: CRANIAL NEURAL
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6818
contact_pi_person_id: 7842814
contact_pi: MUKHOPADHYAY, PARTHA
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Neural tube defects are amongst the most common birth defects occurring with a frequency of 1 in 1000 births.  Although nearly 100 single gene mutations have been documented in animal models to cause neural tube defects few if any of these gene mutations have been characterized at a cellular and/or molecular level.  It has been demonstrated that mutation in the gene encoding the protein c-ski (a regulator of gene transcription) in mice causes neural tube defects. Studies proposed within the present application will attempt to elucidate the cellular and molecular basis of c-ski gene inactivation in the genesis of neural tube defects.  The hypothesis to be examined is that during the genesis of NTDs the cranial neural crest is a highly susceptible cellular target of c-ski loss of function.  Loss of c-ski function as a transcriptional regulator may result in significant alterations in neural crest gene expression that will be assessed by microarray based molecular profiling of isolated neural crest cells. Attendant perturbations in neural crest formation migration proliferation or neural crest cell death will be examined in a unique animal model system that offers the ability to track the functional consequences of c-ski gene deletion (mutation) in labeled neural crest cells in intact animals. The studies proposed in the current application offer a novel approach to address genetic differences in susceptibility to NTDs as well as serve to initiate investigation at a mechanistic level of potential cellular and molecular targets of Ski during cranial neural tube morphogenesis.

project_terms:
Address;Animal Model;Animals;Biological Models;Birth;Cell Death;Cephalic;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Frequencies (time pattern);Funding;Gene Deletion;Gene Expression;Gene Mutation;Gene Silencing;Genes;Genetic;Grant;Institution;Investigation;Label;Molecular;Molecular Target;Morphogenesis;Mus;Mutation;Neural Crest;Neural Crest Cell;Neural Tube Defects;Neural tube;Predisposition;Proteins;Research;Research Personnel;Resources;Skiing;Source;Transcription Genetic;United States National Institutes of Health;base;cellular targeting;loss of function;migration;novel strategies;relating to nervous system


application_id: 7720689
project_number: 2P20RR017702-06A1
project_title: COBRE: UL: P2: AN ANTIOXIDANT TRANSGENE PROTECT OFFSPRING FROM MATERNAL DIABETE
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6817
contact_pi_person_id: 8340262
contact_pi: LIU, YE Q
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Prenatal environment greatly affects fetal programming and development. Various factors lead to low birth weight (LBW) which is associated with adult disorders such as type 2 diabetes. However the mechanism is still uncertain and controversial. We have started to establish LBW and maternal diabetic animal models to investigate how prenatal environment affects pancreatic beta cell programming and development. Methods: For LBW model we feed pregnant animals with low protein (LP 6% normal is 20%) diet and thiamine deficient diet; for diabetic model we use Bic mice (beta cell is destroyed by overexpression of calmodulin) and more than 90% pancreatectomy or streptozotocin-induced SD female rats as type 1 and Agouti/kk mice as type 2 diabetic models. We test fetal beta cell development and offspring pancreatic beta cell function. Results: We have obtained some results from 10 week old Wister rat offspring. In LP group (fed mother and pups with LP diet during pregnancy nursing and after nursing) body weight was only 30% of normal group; blood glucose was normal in these two groups; pancreatic islet protein and DNA contents were approximately 50% decreased; islet function glucose utilization and glucose oxidation were also decreased to 60% of normal. We tested thiamine deficiency in cultured the beta cell line INS-1 and found that a thiamine antagonist significantly inhibited tritium-thymidine incorporation into INS-1 cell DNA. In diabetic models hyperglycemia would be an important factor to affect beta cell; we tested cultured islets with high glucose and found that 3-day high glucose treatment decreased islet pyruvate dehydrogenase and pyruvate carboxylase activities but high free fatty acid only inhibited pyruvate dehydrogenase activity. Discussion: These results suggest many factors affect offspring beta cell function by different mechanisms. We will continuously test fetal beta cell development offspring beta cell function and specific gene expression.

project_terms:
Adult;Affect;Animal Model;Animals;Antioxidants;Beta Cell;Blood Glucose;Body Weight;Calmodulin;Cell Line;Cell physiology;Cells;Computer Retrieval of Information on Scientific Projects Database;DNA;Diabetes Mellitus Non-Insulin-Dependent;Diabetic Diet;Diet;Discipline of Nursing;Disease;Environment;Fatty Acids Nonesterified;Female;Funding;Gene Expression;Glucose;Grant;Hyperglycemia;Institution;Islets of Langerhans;Lead;Low Birth Weight Infant;Methods;Modeling;Mothers;Mus;Pancreatectomy;Patient currently pregnant;Ploidies;Pregnancy;Program Development;Protein Overexpression;Proteins;Pyruvate Carboxylase;Rattus;Research;Research Personnel;Resources;Source;Streptozocin;Structure of beta Cell of islet;Testing;Thiamine;Thiamine Deficiency;Thymidine;Transgenes;Tritium;United States National Institutes of Health;Week;day;diabetic;feeding;fetal;fetal programming;islet;oxidation;prenatal;pup;pyruvate dehydrogenase


application_id: 7720688
project_number: 2P20RR017702-06A1
project_title: TGF BETA & WNT SIGNALING: CROSSTALK DURING CRANIOFACIAL DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6816
contact_pi_person_id: 7839734
contact_pi: WARNER, DENNIS RAY
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Development of the craniofacial region in mammals is a complex and multifactorial process.  The focus of our laboratory is to understand the underlying mechanisms involved in  the control of craniofacial development since perturbations can lead to birth defects of the head and face.  Many signaling molecules have been demonstrated to play critical roles in growth proliferation and differentiation of cells that populate the craniofacial region.  Included in these are the transforming growth factor  (TGF) and Wnt signaling pathways.  Our hypothesis  in the current proposal is that the TGF and Wnt signaling pathways exhibit cross-talk leading to unique signaling outcomes not observed with either alone. This hypothesis was developed following our discovery via a yeast two-hybrid screen of developing craniofacial tissue  that Smads the central mediators of TGF signaling interact with dishevelled (Dvl) the proximal cytosolic signaling protein in the Wnt signaling pathway.  To examine the role of Wnt signaling in craniofacial development and in particular the Smad-Dvl interaction the following specific aims are proposed:  1) characterize the temporal and spatial expression of Wnt signaling components in developing  murine embryonic craniofacial tissue and in cultured cells derived from developing craniofacial tissue through Western blot analysis and immunohistochemistry.   2) identify specific protein domains and post-translational modifications  that mediate the interaction between Smad and Dvl.  3)  examine the effect of the Smad-Dvl interaction on the outcome of signaling from both the  TGF and Wnt signaling pathways through the use of transcriptional reporter assays and in vivo signaling through the use of specific inhibitors of TGF and Wnt signaling.  These studies will further our understanding of the nature  and role of the cross-talk between TGF and Wnt signaling in developing craniofacial tissue.

project_terms:
Biological Assay;Blotting Western;Cell Differentiation process;Complex;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Cultured Cells;Development;Embryo;Exhibits;Face;Funding;Grant;Growth;Head;Immunohistochemistry;Institution;Laboratories;Lead;Mammals;Mediating;Mediator of activation protein;Mus;Nature;Outcome;Play;Process;Protein Processing Post-Translational;Reporter;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Signaling Protein;Source;Tertiary Protein Structure;Tissues;Transforming Growth Factors;United States National Institutes of Health;Yeasts;craniofacial;in vivo;inhibitor/antagonist;yeast two hybrid system


application_id: 7720687
project_number: 2P20RR017702-06A1
project_title: COBRE: UL: ADMIN CORE: MOLECULAR DETERMINANTS OF DEVELOPMENTAL DEFECTS
administering_ic: NCRR
award_notice_date: 2008-07-25
opportunity_number: RFA-RR-07-001
application_type: 2
activity_code: P20
ic: RR
serial_number: 017702
suffix: A1
project_start_date: 2008-08-01
project_end_date: 2009-05-31
subproject_number: 6815
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.DESCRIPTION (provided by applicant): The purpose of this application for a Center of Biomedical Research Excellence (COBRE) is to foster health-related research and increase the competitiveness of junior unfunded investigators at the Birth Defects Center at the UL School of Dentistry for independent funding. If funded this COBRE will augment and strengthen the biomedical research capacity at the Birth Defects Center through provision of flexible support to expand and develop biomedical faculty research capability. The program is led by an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal. The application seeks support for junior investigators from several complementary disciplines each of whom will be mentored by an established well-funded senior biomedical research faculty member recognized for his/her scientific expertise in the area of the junior investigator's research proposal. This approach is a critical assurance of success of this initiative. This application represents an integrated series of studies focusing on two common themes - molecular mechanisms of birth defects and cellular signal transduction - that encompass a number of diverse scientific disciplines. Faculty from the Schools of Dentistry Medicine Nursing Engineering and the College of Arts and Sciences representing a multiplicity of scientific disciplines present a multifunctional approach to questions of the molecular basis of developmental anomalies. This application if funded will substantially enhance the development of eleven young investigators with outstanding potential to develop into competitive independent and collaborative investigators. A detailed plan for their research career development has been formulated expectations and goals for achieving extramural support is outlined the extent of departmental and university support provided to these junior faculty is substantial clear and tangible evidence of institutional commitment has been documented and sufficient and adequate space and equipment resources for the conduct of the proposed studies exists.

project_terms:
Area;Arts;Biomedical Research;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Defect;Development;Discipline;Discipline of Nursing;Engineering;Equipment;Extramural Activities;Faculty;Fostering;Funding;Goals;Grant;Institution;Medicine;Mentors;Molecular;Numbers;Purpose;Research;Research Personnel;Research Proposals;Resources;School Dentistry;Science;Scientist;Series;Signal Transduction;Source;United States National Institutes of Health;Universities;base;career;college;expectation;member;programs;success


application_id: 7720442
project_number: 5P20RR015592-09
project_title: HORMONE REGULATION OF CARDIAC INJURY
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6570
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The central hypothesis of this proposal is that HDL-associated sex hormones (estrogen and testosterone) regulate the activity of cardiac myocyte constitutive nitric oxide synthase which subsequently affects the extent of ischemic injury.

Epidemiological studies demonstrate that women are less prone to ischemic heart disease than men.  The mechanisms responsible the differences in ischemic injury observed between men and women are not know although the current focus is on sex hormones in particular estrogen and testosterone.  A large number of studies have implicated estrogen-induced stimulation of constitutive nitric oxide synthase (cNOS) as providing protection against ischemic injury of cardiac myocytes.  The role of testosterone is unclear with reports of protection against ischemic injury and reports of testosterone promoting ischemic injury.  The majority of the studies on estrogen and testosterone do not distinguish between effects mediated by the endothelium in hearts and cardiac myocytes.  One of the novel aspects of the proposed studies is that the preliminary data indicate that estrogen and testosterone have direct effects on cardiac myocytes independent of the endothelium.  Another novel aspect of the proposed studies is that it is estrogen or testosterone associated with HDL that is responsible for the generation of nitric oxide in cardiac myocytes and protection/promotion of ischemic injury.  The molecular mechanism whereby estrogen limits ischemic injury and testosterone increases ischemic injury will be tested in two Aims.

Aim 1:  To determine the mechanism whereby HDL-associated estrogen stimulates the production of nitric oxide and limits ischemic injury.  The preliminary studies suggest that estrogen receptor alpha and caveolin-1 form a complex that stimulates cNOS via AMP kinase.  Cardiac myocytes isolated from wild type mice caveolin-1 null mice or estrogen receptor alpha null mice will be used along with dominant negative adenoviral constructs agonist/antagonists and enzyme assays to dissect the mechanism(s).  In addition wild type mice SR-BI null mice caveolin-1 null mice and estrogen receptor alpha null mice along with ovariectomies and ovariectomies/estrogen replacement will be used to determine the effect on ischemic injury.  

Aim 2:  To determine the mechanism whereby HDL-associated testosterone decreases the generation of nitric oxide and increases ischemic injury.  The preliminary studies demonstrate that HDL-associated testosterone decreases the generation of nitric oxide without affecting the cellular levels of cNOS.  Isolated cardiac myocytes will be used to examine several possible mechanisms for the HDL-testosterone mediated inhibition of cNOS such as altered caveolin binding to cNOS depletion of caveolae cholesterol re-localization of cNOS and modification of cNOS and/or caveolin-1.  Additional studies will determine if the androgen receptor and/or testosterone uptake are involved in this process.  Wild type mice SR-BI null mice and caveolin-1 null mice along with orchidectomies and orchidectomies/testosterone replacement will be used to determine the effect on ischemic injury.

project_terms:
Affect;Agonist;Androgen Receptor;Binding (Molecular Function);Biological Assay;Cardiac;Caveolae;Caveolins;Cholesterol;Complex;Computer Retrieval of Information on Scientific Projects Database;Data;Dominant-Negative Mutation;Endothelium;Enzyme Inhibitor Drugs;Epidemiologic Studies;Estrogen Receptor alpha;Estrogen Replacements;Estrogens;Funding;Generations;Gonadal Steroid Hormones;Grant;Heart;High Density Lipoproteins;Injury;Institution;Mediating;Mice Knockout;Modification;Molecular;Myocardial Ischemia;Myocytes Cardiac;Nitric Oxide;Nitric Oxide Synthase;Numbers;Orchiectomy;Ovariectomy;Process;Production;Reporting;Research;Research Personnel;Resources;Role;Source;Testing;Testosterone;United States National Institutes of Health;Wild Type Mouse;Woman;adenylate kinase;alpha caveolin;caveolin 1;hormone regulation;men;novel;uptake


application_id: 7720440
project_number: 5P20RR015592-09
project_title: HORMONE ACTIONS ON BEHAVIOR: CLINICAL NEUROPHARMACOLOGY
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6568
contact_pi_person_id: 1858700
contact_pi: KELLY, THOMAS J.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Gonadal neurosteroids are important modulators of behavior and have been shown to impact a range of clinically significant conditions including sexual behavior sleep cognition drug and alcohol abuse affective disorders pain sensitivity epileptic seizure disorders and stress reactivity.  Recent molecular and cellular studies as well as data from whole animal behavioral models indicate that gonadal neurosteroids influence behavior through the direct regulation of neuronal activity as well as the modulation of classical neurotransmitter function through a variety of both genonic and nongenomic mechanisms.  To date the effects of estrogen and progesterone on neurotransmitter function in humans have received almost no attention.  We and others have successfully used drug discrimination and functional neuroimaging methodologies to examine the manner in which psychoactive drugs alter classical neurotransmitter function (i.e. clinical neuropharmacological effects of drugs) as well as the neuroanatomical locations of these effects.  This basic science project will be among the first to apply these methodologies within the same individuals to examine the manner and anatomical locations in which estrogen and progesterone modulate clinical neurotransmitter function in humans. One series of studies will examine the effects of estradiol on dopaminergic activity.  It is hypothesized that estradiol will enhance dopamine function selectively in women.  A second series of studies will examine the neuropharmacological effects of progesterone.  It is hypothesized that progesterone and its metabolites will engender direct interoceptive effects via modulation of multiple receptor sites including GABA alpha and NMDA in both men and women.  This information will be invaluable for expanding our understanding of the neurobiological basis of gender differences in mood and behavior regulation.  These studies will have important applied significance in helping future development of gender-specific medications having selective effects at steroidal receptor sites and/or tailored to work in combination with endogenous neurosteroids. It is also likely that these studies will inform and enhance ongoing efforts to develop and evaluate steroid-based medications.  Finally this project will promote the mentoring development and promotion of our junior and early career colleagues' academic interests in the clinical neurobiology of women's health.

project_terms:
Alcohol abuse;Animals;Attention;Basic Science;Behavior;Behavioral Model;Clinical;Cognition;Computer Retrieval of Information on Scientific Projects Database;Condition;Data;Development;Dopamine;Epilepsy;Estradiol;Estrogens;Funding;Future;Gender;Grant;Hormones;Human;Individual;Institution;Location;Mentors;Methodology;Molecular;Mood Disorders;Moods;N-Methylaspartate;Neurobiology;Neurons;Neuropharmacology;Neurotransmitters;Pain;Pharmaceutical Preparations;Progesterone;Psychotropic Drugs;Range;Regulation;Research;Research Personnel;Resources;Series;Sex Behavior;Sex Characteristics;Site;Sleep;Source;Steroids;Stress Disorders Traumatic;United States National Institutes of Health;Woman;Women's Health;Work;base;behavior influence;career;clinically significant;drug discrimination;gamma-Aminobutyric Acid;interest;men;neuroimaging;non-genomic;receptor


application_id: 7720439
project_number: 5P20RR015592-09
project_title: ESTRADIOL INTERACTIONS WITH THE PROTEASOME IN HIV REGULATION
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6567
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.      The overall goal of this proposal is to test the hypothesis that estrogen can decrease HIV viral load by decreasing viral replication.  As AIDS is now the third leading cause of death among women ages 25-44 understanding the role that female sex hormones might play in the physiology of HIV-1 infection is especially critical.  Many manifestations of HIV differ in women including that women generally have lower HIV viral loads compared to men at similar stages of disease and have attenuated or absent disease progression during pregnancy.  Conversely while studies suggest that women may be more vulnerable to certain AIDS-related illnesses such as HIV dementia and lipodystrophy there is data strongly suggesting that an estrogen deficient state can be associated with HIV infection.  Evaluated as a whole this clinical evidence indicates that female hormones such as estrogen could act to maintain low viral titers and suggest that maintenance of serum estradiol levels could decrease the incidence of AIDS-related syndromes.  While the mechanisms whereby estrogen modulates HIV infection are still very poorly understood data from our labs show that estrogen attenuates Tat-induceed transcription at the long-term repeat (LTR) domain of the HIV-1 promoter.  These studies are thus designed to use novel molecular pharmacological and proteomic tools to determine the mechanisms whereby estrogen modulates HIV replication with specific emphasis on the role of the multicatalytic proteasome as a convergence point for estrogen and Tat in HIV regulation.  The specific aims are to 1: To test the hypothesis that estrogen has specific negative effects on Tat-induced LTR activation; 2: To test the hypothesis that the effects of estrogen on the HIV-1 LTR are proteasome dependent; and 3: To determine the full proteomic mechanisms whereby estrogen modulates the HIV-1 LTR.  Realization of these goals could lead to identification of novel and pertinent protein regulators of HIV-1 replication the manipulation of which might allow for more precise control over HIV infection in humans.

project_terms:
AIDS Dementia Complex;Acquired Immunodeficiency Syndrome;Age;Attenuated;Cause of Death;Clinical;Computer Retrieval of Information on Scientific Projects Database;Data;Disease;Disease Progression;Estradiol;Estrogens;Female;Funding;Goals;Gonadal Steroid Hormones;Grant;HIV;HIV Infections;HIV-1;Hormones;Human;Incidence;Infection;Institution;Lead;Lipodystrophy;Maintenance;Molecular;Physiology;Play;Pregnancy;Promotor (Genetics);Proteins;Proteomics;Regulation;Research;Research Personnel;Resources;Role;Serum;Source;Staging;Syndrome;Testing;Transcription Genetic;United States National Institutes of Health;Viral;Viral Load result;Woman;Women's Role;design;men;multicatalytic endopeptidase complex;novel;tool


application_id: 7720438
project_number: 5P20RR015592-09
project_title: EFFECTS OF ESTRADIOL & ANTIDEPRESSANTS IN HIPPOCAMPAL NEUROGENESIS
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6566
contact_pi_person_id: 1891759
contact_pi: JENNES, LOTHAR H
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Depressive disorders are a major health issue in the United States and cause severe social and economic problems. Currently most of these disorders are treated with Selective Serotonin Reuptake Inhibitors (SSRIs) which cause an increase in serotonin levels in the synaptic cleft. How this increased availability of serotonin causes beneficial effects is not clear however it appears that it stimulates the synthesis of Brain-Derived Neurotrophic Factor (BDNF) which in turn enhances neurogenesis in the dentate gyrus of the hippocampus. It is thought that the formation of new connectivities of these neurons is at least in part responsible for successful treatment of depression. Thus one goal is to identify the sites of actions as well as the mechanisms by which SSRIs cause an enhancement of BDNF levels in the hippocampus thereby stimulating neurogenesis. Many studies have shown that the frequency of depressive incidences increases in post-menopausal women and estrogen reduces depressive symptoms. Thus a second goal is to identify the estrogen-sensitive neurons that project to the hippocampus and are regulated by serotonin and to reveal the mechanisms by which estrogen reduces the frequency and severity of depressive episodes. 

Aim 1: test the hypothesis that SSRIs and estrogen act on medial septal-diagonal band cholinergic neurons the prefrontal cortex as well as directly on the hippocampus to enhance BDNF synthesis and neurogenesis in an additive or synergistic fashion.
Aim 2: test the hypothesis that medial septal-diagonal band cholinergic neurons and cortical GABAergic neurons are necessary for estradiol and SSRIs to stimulate BDNF synthesis and neurogenesis in the hippocampus. 
Aim 3: test the hypothesis that the transcript-specific BDNF promoters and the untranslated regions 
regulate the expression localization and function of BDNF.

project_terms:
Antidepressive Agents;Brain-Derived Neurotrophic Factor;Computer Retrieval of Information on Scientific Projects Database;Depressive disorder;Disease;Economics;Estradiol;Estrogens;Frequencies (time pattern);Funding;Goals;Grant;Health;Hippocampus (Brain);Incidence;Institution;Medial;Mental Depression;Neurons;Parahippocampal Gyrus;Postmenopause;Prefrontal Cortex;Promotor (Genetics);Research;Research Personnel;Resources;Selective Serotonin Reuptake Inhibitor;Serotonin;Severities;Site;Source;Structure of dentate gyrus;Synaptic Cleft;Testing;Thinking function;Transcript;United States;United States National Institutes of Health;Untranslated Regions;Woman;cholinergic neuron;depressive symptoms;neurogenesis;social


application_id: 7720437
project_number: 5P20RR015592-09
project_title: HORMONE MEDIATED REGULATION OF OVARIAN FUNCTION
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6565
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This project explores estrogen action on the ovary and the mammary gland.  Studies conducted during the past funding period have explored the changes in 1) the ovarian matrix metalloproteinases 2) ovarian gene expression and 3) a class of nuclear hormone receptors the peroxisome proliferator-activated receptors (PPARs) in mammary gland function.  All four of the investigators associated with this project have made significant progress towards their individual experiments as well as towards establishing preliminary data for the competitive renewal of this Project.  Dr. Misung Jo is continuing to examine the functional significance of a novel gene Runx1 in late follicle development.  The localization pattern of Runx1 expression and the mechanism(s) of Runx1 expression continue to shed light on the functional role this protein plays in follicular development and ovulation.  Preliminary experiments with silencing RNA have suggested that Runx1 may mediate the LH induced increase in progesterone production.  Experiments by Dr. Michael Kilgore have continued to investigate the signal crosstalk between the estrogen receptor beta (ERb) and the peroxisome proliferator-activated receptor gamma (PPARg).  Preliminary data indicates that crosstalk between these receptors results in gene-specific changes with a number of genes being upregulated while other genes are downregulated as seen by DNA microarray.  Ongoing studies are examining the significance of these changes in gene expression on cellular proliferation and migration.  Finally a series of breeding experiments by Dr. Jay Ko have been in progress to generate tissue-specific knockouts of the estrogen receptor (ER) isoforms. These ongoing studies are creating mice which lack ERa or ERb in the oocyte the granulosa cell or the theca cells.  To date oocyte-specific estrogen receptor knockout have been generated which lack ERa.  These mice exhibit a reduced ovulatory capacity although they are fertile.  The impact of estrogen action on the theca and granulosa cell layers of the follicle will be explored as these mice become available.  In Dr. Curry's laboratory the role and timing of expression of the matrix metalloproteinase-19 and its inhibitors in ovarian development and ovulation continues to be unraveled.  These studies demonstrate the importance of tissue remodeling in regulating ovarian function and fertility.  Therefore all the projects have made significant progress in developing the necessary tools to address the goals of each project and are in an excellent position to provide convincing data for the competitive renewal of the COBRE project as well as compete for extramural support.

project_terms:
Address;Breeding;Cell Proliferation;Centers of Research Excellence;Class;Computer Retrieval of Information on Scientific Projects Database;DNA Microarray Chip;DNA Microarray format;Data;Development;Estrogen Receptor beta;Estrogen Receptors;Estrogens;Exhibits;Extramural Activities;Fertility;Funding;Gelatinase A;Gene Expression;Genes;Goals;Grant;Hormones;Individual;Institution;Knock-out;Laboratories;Light;Mammary gland;Mediating;Mus;Nuclear Hormone Receptors;Numbers;Oocytes;Ovarian;Ovary;Ovulation;PPAR gamma;Pattern;Peroxisome Proliferator-Activated Receptors;Play;Positioning Attribute;Production;Progesterone;Protein Isoforms;Proteins;RNA Interference;Regulation;Research;Research Personnel;Resources;Role;Series;Signal Transduction;Source;Time;Tissues;United States National Institutes of Health;granulosa cell;inhibitor/antagonist;matrix metalloproteinase 19;migration;novel;receptor;research study;theca cell;tool


application_id: 7720436
project_number: 5P20RR015592-09
project_title: KY COBRE: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2008-05-02
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2008-03-01
project_end_date: 2009-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 6564
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator. The Administrative Core will facilitate the research and training of the COBRE-WH scholars by:

1.  providing the organizational and administrative structure that insures optimal dissemination of information among COBRE-WH investigators 

2.  insuring that the junior faculty obtain state-of-the-art broad-based training in a mentoring and stimulating environment that enhances their prospects of successfully establishing independent NIH-funded research careers

3.  supporting critical Cores to promote optimal sharing of techniques and approaches 
           
The Administrative Core has and will continue to support shared-use Cores to insure COBRE-WH investigators utilize state-of-the-art methods.  We have chosen to focus our funds and attention on the same four core facilities:  (A) the Animal Core (B) the Imaging Core (C) the Molecular and Cellular Core and (D) the Biostatistics Consulting Core.

4.  funding new pilot projects in promising areas of research that complement the goals of the COBREWH to increase the critical mass of investigators with expertise and experience in women?s health research and

5.  working with the Associate Dean for Research of the College of Medicine the Senior Associate Vice President for Research and departmental Chairs to increase the pool of faculty involved in women's health research by hiring new faculty members.

project_terms:
Animals;Area;Arts;Attention;Biometry;Complement;Computer Retrieval of Information on Scientific Projects Database;Consult;Core Facility;Environment;Faculty;Funding;Goals;Grant;Image;Information Dissemination;Institution;Medicine;Mentors;Methods;Molecular;Pilot Projects;Research;Research Personnel;Research Training;Resources;Source;Structure;Techniques;Training;United States National Institutes of Health;Women's Health;Work;base;career;college;experience;member


application_id: 7720381
project_number: 5P20RR015576-09
project_title: ROLE OF ESTROGEN AND PROGESTERONE IN SCI PAIN
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6509
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.   Chronic central pain develops in the majority of spinal cord injury (SCI) patients following complete and partial injuries including at level allodynia (pain to touch in dermatomes at and just above the level of injury).  Using a recently developed electrophysiological rat model (in vivo) for investigating the effects of chronic SCI on responses in supraspinal neurons new data from our lab was obtained which indicates that the development of at level allodynia is dramatically reduced after SCI in female rats with normal hormonal cycles compared to males/ovariectomized females.  This raises the possibility that progesterone and/or estrogen could play therapeutic roles for SCI-induced pain.  We also have evidence supporting the hypothesis that at level allodynia if and when it develops may result from damage to descending pathways in the dorsolateral quadrant in combination with sparing of at least a portion of ascending tract(s) in the ventrolateral quadrant that transmit to higher centers the information from dermatomes just above the level of injury.  Moreover preliminary data indicate that the allodynia when it develops may be exacerbated by circulating progesterone and/or estrogen which is clearly seen in the responsiveness of brainstem neurons.  This exacerbation is consistent with findings for numerous conditions with cycle related changes in pain thresholds in humans. Thus the development and perpetuation of at level allodynia will be examined relative to experimental variations of hormonal status and variations in specific patterns of damage/sparing.  The underlying mechanism may include changes in the responses of neurons in the thalamus (an important region involved in the processing of inputs that ultimately lead to pain) which will be compared to the concomitant behavioral signs that accompany these changes (i.e. allodynia).  Thus a unique feature of this proposal is the multidisciplinary approach that is taken i.e. using electrophysiological behavioral and anatomical measures for each animal.  The proposed research will examine the underlying mechanisms related to ovarian hormones that prevent the development and contribute to the perpetuation of this clinically-relevant at level allodynia.  Therefore these studies will lead to a better understanding of the neural mechanisms underlying SCI pain and will identify ovarian hormones as targets that can readily be modulated to prevent and treat SCI-related pain.  This is very important since current drug therapies and surgical interventions are inadequate.

project_terms:
Animals;Behavioral;Brain Stem;Chronic;Computer Retrieval of Information on Scientific Projects Database;Condition;Data;Development;Estrogens;Female;Funding;Grant;Hormonal;Human;Information Centers;Injury;Institution;Lead;Measures;Neurons;Operative Surgical Procedures;Ovarian hormone;Pain;Pain Threshold;Pathway interactions;Pattern;Pharmacotherapy;Play;Process;Progesterone;Rattus;Relative (related person);Research;Research Personnel;Resources;Role;Source;Spinal cord injury;Spinal cord injury patients;Thalamic structure;Therapeutic;Touch sensation;United States National Institutes of Health;Variant;allodynia;central pain;clinically relevant;in vivo Model;interdisciplinary approach;male;neuromechanism;prevent;response;spinal cord injury pain


application_id: 7720380
project_number: 5P20RR015576-09
project_title: ROLE OF HSP 25 IN THE ASTROCYTE RESPONSE AND RECOVERY FROM SPINAL CORD INJURY
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6508
contact_pi_person_id: 6155708
contact_pi: GOZAL, EVELYNE
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Spinal cord injury (SCI) and subsequent secondary cell death partially involves an ischemic component. Oligodendrocytes and astrocytes survival is critical to maintain cellular interactions in the white matter and limit secondary injury damage. The purpose of this proposal is to study heat shock proteins (hsps) induction and interactions in hypoxia/ischemia-exposed oligodendrocytes and astrocytes and identify molecules and signaling pathways associated with higher tolerance to ischemia. Hsps induced by various stresses are involved in protein refolding and repair and have been implicated in cellular ischemic tolerance in brain and in spinal cord. We will test the hypothesis that after SCI induction of hsp expression modulates glial cell survival signaling pathways to preserve oligodendrocyte / astrocyte integrity and interactions with neurons. The specific aims of this proposal are: 1. To examine the expression profile of heat shock proteins induced in hypoxic/ischemic oligodendrocytes and astrocytes in culture and in contused spinal cord. 2. To determine the effect of hsp on oligodendrocytes and astrocytes survival to hypoxia/ ischemic injury and after SCI. 3. To determine the mechanism(s) of hsp-related cell protection and the role of hsp binding proteins in hypoxia/ ischemia survival pathways and in cell death after SCI. Using embryonic oligodendrocyte precursors (OPCs) differentiated to either oligodendrocytes or astrocytes and exposed to hypoxia/ischemia we will assess heat shock proteins expression in a cellular model and correlate the levels of hsp expression with cell survival. In addition we will characterize the profile of hsps induced by SCI in rodent spinal cord. The effect of hsp gene overexpression or silencing on oligodendrocytes/astrocytes survival to cellular hypoxia/ ischemia and on SCI-induced delayed injury will be determined as well as the effect of experimental hsp induction in the whole animal on secondary injury-induced damage after SCI. Finally we will use proteomic approaches to identify protein-protein interactions with hsps induced by hypoxia/ischemia in oligodendro- cytes and in astrocytes and in differentially damaged areas of the spinal cord after SCI. Thus we will characterize signaling pathways underlying cellular differential sensitivity to hypoxia/ischemia and identify potential intervention targets in SCI. These studies will identify novel therapeutic approaches to preserve oligodendroglial support in injured spinal cord inhibit apoptosis and reduce delayed white matter injury.

project_terms:
Animals;Apoptosis;Area;Astrocytes;Binding Proteins;Brain;Cell Death;Cell Survival;Cell model;Computer Retrieval of Information on Scientific Projects Database;Cytoprotection;Embryo;Funding;Genes;Grant;Heat shock proteins;Hypoxia;Hypoxia-Ischemia Brain;Injury;Institution;Intervention;Ischemia;Molecular Profiling;Neuroglia;Neurons;Oligodendroglia;Pathway interactions;Protein Overexpression;Proteins;Proteomics;Purpose;Recovery;Research;Research Personnel;Resources;Rodent;Role;Signal Pathway;Source;Spinal Cord;Spinal cord injury;Stress;Testing;United States National Institutes of Health;novel therapeutics;oligodendrocyte precursor;protein expression;protein protein interaction;repaired;response;white matter;white matter injury


application_id: 7720379
project_number: 5P20RR015576-09
project_title: REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6507
contact_pi_person_id: 8141627
contact_pi: CAO, QI LIN
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Demyelination contributes to the dysfunction after the traumatical spinal cord injury (SCI) in both humans and experimental animals. We hypothesize that remyelination of demyelinated but otherwise intact axons will facilitate the functional recovery. Our preliminary data showed that the combination of oligodendrocyte precursor cells (OPCs) transplantation and administration of D15A a novel neurotrophin with both NT3 and BDNF activities77 partially restored electrophysiological and behavioral function after contusive SCI. However many transplanted OPCs remained undifferentiated. Preliminary data also showed up-regulation of Notch signaling after SCI and activation of Notch signaling inhibited oligodendrocyte differentiation of OPCs in vitro. We propose that combination of blocking inhibitory Notch signaling increasing the expression of oligodendrocyte differentiation growth factor D15A and delivery of growth factor(s) known to potentiate myelination will further promote remyelination from engrafted OPCs and leads to greater functional recovery. We will test these strategies in a novel clinically relevant model of rat contusive SCI whose injury severity can be adjusted to cause enough loss of myelin and/or axons to result in specific behavioral and electrophysiological deficits but also sufficient sparing of demyelinated axons to enable remyelination. Objective and sensitive electrophysiological and behavioral tests will be used to examine if the increased remyelination will enhance functional recovery in this contusive SCI model. Collectively these experiments will provide a foundation to identify myelin-based therapies for SCI. There are three specific aims.
Aim 1: To test if the combination of blocking inhibitory Notch signaling and increasing the expression of D15A in transplanted OPCs will lead to enhanced remyelination and functional recovery after acute SCI. This will identify the mechanism through which engrafted OPCs differentiate into oligodendrocytes in the adult injured spinal cord.
Aim 2: To test if increasing the expression of growth factors that potentiate oligodendrocyte maturation and myelination will further promote remyelination from the grafted D15A+Notch- OPCs and facilitate functional recovery after acute SCI. This will provide important insight into mechanisms controlling the maturation and remyelination by oligodendrocytes in the injured spinal cord. 
Aim 3: To test if the optimal combinatory strategies established in acute SCI promote remyelination and functional recovery in the chronically injured spinal cord. This will identify the strategy to promote functional remyelination in the chronically injured spinal cord.

project_terms:
Acute;Adult;Animals;Axon;Behavioral;Brain-Derived Neurotrophic Factor;Cell Transplantation;Computer Retrieval of Information on Scientific Projects Database;Data;Demyelinations;Differentiation and Growth;Foundations;Functional disorder;Funding;Grant;Growth Factor;Human;In Vitro;Injury;Institution;Lead;Modeling;Myelin;NTF3 gene;Neurotrophin 3;Oligodendroglia;Rattus;Recovery of Function;Repair of spinal cord;Research;Research Personnel;Resources;Severities;Signal Transduction;Source;Spinal cord injury;Testing;Transcriptional Activation;Transplantation;Undifferentiated;United States National Institutes of Health;Up-Regulation (Physiology);base;behavior test;clinically relevant;insight;myelination;neurotrophic factor;notch protein;novel;oligodendrocyte precursor;precursor cell;research study


application_id: 7720378
project_number: 5P20RR015576-09
project_title: GSK3B AS A TARGET FOR PRO-NEURONAL SURVIVAL IN CNS NEURONS
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6506
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.During the previous budget period we revealed that contrary to the initial hypothesis ERK does not seem to directly regulate GSK3beta activity. Therefore we decided to change direction of the project. Endoplasmic reticulum (ER) dysfunction occurs as a result of oxidative damage to the ER or accumulation of misfolded proteins in that compartment leading to ER stress. ER stress induces an evolutionary conserved unfolded protein response that provides tools to restore the normal ER function. Also ER stress may lead to cell death. The ER stress is an important player in several neurological disease including chronic neurodegenerative conditions or stroke. However its contribution to the pathology that evolves after traumatic spinal cord injury (SCI) is unknown at present. We propose to test the hypothesis that after SCI ER stress contributes to demyelination by inducing death of oligodendrocytes and oligodendrocyte precursor cells. The specific aims include (i) analysis of ER stress marker expression after contusion SCI (ii) analysis of SCI outcome in mouse mutants deficient in ER stress response pathways (iii) identification of endogenous ER stress defenses in cultured oligodendrocytes (iv) identification of anti-ER stress interventions for oligodendrocyte protection and improvement of ER stress outcome.

project_terms:
Budgets;Cell Death;Cessation of life;Chronic;Computer Retrieval of Information on Scientific Projects Database;Condition;Contusions;Demyelinations;Endoplasmic Reticulum;Functional disorder;Funding;Grant;Institution;Intervention;Lead;Mice Mutant Strains;Nerve Degeneration;Neurons;Oligodendroglia;Outcome;Pathology;Pathway interactions;Proteins;Research;Research Personnel;Resources;Source;Spinal cord injury;Stress;Testing;United States National Institutes of Health;biological adaptation to stress;nervous system disorder;neuronal survival;oligodendrocyte precursor;precursor cell;protein misfolding;response;stroke;tool


application_id: 7720377
project_number: 5P20RR015576-09
project_title: COBRE: UL: CELL INSTRINSIC MECHANISMS REGULATING SENSORY AXON REGENERATION
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6505
contact_pi_person_id: 7936903
contact_pi: SHIELDS, CHRISTOPHER B
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Our specific aims have changed based on new data that we obtained.  After consulting with the Program Director we will test the hypothesis that intrinsic mechanisms for axon growth is programmed in the developmental stage and turned off after CNS maturation. We are attempting to rejuvenate this mechanism by modulation of Id2 and SnoN transcription factors that may promote axonal regeneration after SCI.  As a result of the data outlined below this work has been submitted to the NIH as an R01 Feb 08. 
Aim 1: Determine the role of Id2 in neurite sprouting from DRG neurons as well as axon regeneration in the dorsal columns following a T8 dorsal hemisection.   
Aim 2: Determine the role of SnoN in neurite sprouting and axon regeneration following T8 dorsal hemisection.  
Aim 3: Explore combinatorial strategies using CSPG digestion and MPI blocking to maximize axon regeneration and functional recovery following SCI.

project_terms:
Cells;Computer Retrieval of Information on Scientific Projects Database;Consult;Data;Development;Digestion;Dorsal;Funding;Grant;Institution;Neurites;Neurons;Recovery of Function;Research;Research Personnel;Resources;Role;SLPI protein human;Sensory;Source;Staging;Testing;United States National Institutes of Health;Work;axon growth;axon regeneration;base;combinatorial;dorsal column;programs;transcription factor


application_id: 7720376
project_number: 5P20RR015576-09
project_title: COBRE: UL: MICROSCOPY CORE: CORE E
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6504
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The purpose of CORE E:  Microscopy is to provide all projects with the personnel facilities resources and supplies to perform florescent microscopy using both an upright Nikon TiE and confocal microscopes.   Assistance and the expertise will be available for developing specialized microscopy procedures.

project_terms:
Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Funding;Grant;Human Resources;Institution;Microscope;Microscopy;Procedures;Purpose;Research;Research Personnel;Resources;Source;United States National Institutes of Health


application_id: 7720375
project_number: 5P20RR015576-09
project_title: COBRE: MECHANISMS OF PLASTICITY & REPAIR AFTER SCI D: BEHAV & ELECTROPHYS CORE
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6503
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The purpose of the Electrophysiology and Behavior CORE (CORE D) is to provide a battery of standard tests to assess the function of animals and their spinal cords after injury and treatment and to facilitate the development of more specialized tests that may be needed for the COBRE projects.  The CORE will provide the following tests:  1. Transcranial magnetic motor evoked potentials (tcMMEPs) to assess action potential conduction in descending axons located in the ventrolateral funiculus in rats and mice.  2. Somatosensory evoked potentials (SSEPs) to assess ascending primary sensory pathways (rats only). 3. Magnetic interenlargement reflexes (MIERs) to assess conduction in ascending propriospinal axons located in the lateral white matter (rats only). 4. Open Field Locomotor Scale (BBB) to assess hindlimb function during overground locomotioin in rats and the Basso Mouse Scale (BMS) for mice. 5. Grid-walking test and horizontal ladder tests to assess sensorimotor function. 6. The Louisville Swimming Scale (LSS; rats only) to assess hindlimb function during swimming. 7. Hindlimb kinematics during overground locomotion and swimming for rats and mice using joint angle limb excursion and step cycle duration as primary measures. 8. The Hargreave's test to assess thermal hyperalgesia. 9. Electro von Frey hairs to assess mechano-hypersensitivity after injury.  In addition the CORE will pursue the development of novel electrophysiological and behavioral assessment tools as needed by specific projects within the COBRE laboratires.

project_terms:
Action Potentials;Animals;Axon;Behavior;Behavior assessment;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Development;Electrophysiology (science);Evoked Potentials Motor;Funding;Grant;Hair;Hindlimb;Hypersensitivity;Injury;Institution;Joints;Lateral;Limb structure;Locomotion;Magnetism;Measures;Mus;Pathway interactions;Purpose;Rattus;Reflex action;Research;Research Personnel;Resources;Sensorimotor functions;Sensory;Somatosensory Evoked Potentials;Source;Spinal Cord;Standards of Weights and Measures;Swimming;Testing;Thermal Hyperalgesias;United States National Institutes of Health;Walking;kinematics;novel;repaired;tool;white matter


application_id: 7720374
project_number: 5P20RR015576-09
project_title: COBRE: UL: MECHANISMS OF PLASTICITY AND REPAIR AFTER SCI/ C: SURGICAL CORE
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6502
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The purpose of Core C will be to significantly reduce variability in all Projects of the proposal by providing the expertise personnel facilities equipment and supplies required to reproducibly perform their surgery and veterinary care procedures.  The standardized surgery procedures will include producing contusion and laceration types of spinal cord cord injuries in adult rats and mice plus cell transplantation injection neuroanatomical tracing cranial electrode implantation euthanasia perfusion fixation and tissue dissection.  The standardized daily veterinary care procedures are designed to significantly reduce morbidity and mortality.  They will include treating wounds expressing bladders preventing urinary tract and other infections plus providing supplemental fluids and nutrition.

project_terms:
Adult;Bladder;Caring;Cell Transplantation;Cephalic;Computer Retrieval of Information on Scientific Projects Database;Contusions;Daily;Dissection;Electrodes;Equipment and Supplies;Euthanasia;Funding;Grant;Human Resources;Infection;Injection of therapeutic agent;Injury;Institution;Laceration;Liquid substance;Morbidity - disease rate;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Perfusion;Procedures;Purpose;Rattus;Research;Research Personnel;Resources;Science of nutrition;Source;Spinal Cord;Surgery Veterinary;Tissue Fixation;United States National Institutes of Health;Urinary tract;design;implantation;prevent;repaired


application_id: 7720373
project_number: 5P20RR015576-09
project_title: COBRE: CELL CULTURE AND MOLECULAR BIOLOGY: CORE B
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6501
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.CORE B:  Cell and Molecular Biology CORE

   CORE B shall meet all of the cell culture molecular biology and fluorescence-activated cell sorting (FACS) needs of the COBRE PIs who are not routinely using these methods in their own laboratories.
   CORE B can provide stem and/or lineage restricted precursor cells derived from embryonic cortex or spinal cord.  These can be from fetuses that constitutively express endogenous labels such as green fluorescent protein (GFP) or human placental alkaline phosphatase (hPLP) or they can be exogenous labeled or induced to express transgenes as described below.
   CORE B can provide retroviral adenoviral and lentiviral vectors that express whatever cDNA the Investigators' need.  In addition we have regulatable retroviruses (TetON and TetOFF) that are responsive to doxycyline both in vitro and in vivo.
   CORE B has developed lentiviruses that express siRNA cassettes that we can target any mRNA that the COBRE Investigators' want silenced.
   CORE B has also developed RNAse protection assays that can be modified to all Investigators' needs.
   CORE B can provide expertise in quantiative real time PCR to assess mRNA levels for any gene of interest.

All of these reagents have been characterized by the CORE prior to their dispersal to the COBRE PIs to ensure quality control.

project_terms:
Alkaline Phosphatase;B-Lymphocytes;Biological Assay;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Cultured Cells;DNA Complementary;Embryo;Ensure;Fetus;Fluorescence-Activated Cell Sorting;Funding;Genes;Grant;Green Fluorescent Proteins;Human;In Vitro;Institution;Label;Laboratories;Lentivirus Vector;Methods;Molecular Biology;Polymerase Chain Reaction;Quality Control;RNA Messenger;RNA Small Interfering;Reagent;Research;Research Personnel;Resources;Retroviridae;Source;Spinal Cord;Subfamily lentivirinae;Time;Transgenes;United States National Institutes of Health;in vivo;interest;precursor cell;stem


application_id: 7720372
project_number: 5P20RR015576-09
project_title: COBRE: UL: MECHANISMS OF PLASTICITY AND REPAIR AFTER SCI: A ADMIN CORE
administering_ic: NCRR
award_notice_date: 2008-06-06
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2008-06-01
project_end_date: 2009-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 6500
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Core A will be responsible for the overall administration of this COBRE. Core A will coordinate all meetings between Principal Investigators and the Internal (IAC) and External (EAC) Advisory Committees as well as weekly seminar series and Visiting Lecturer Series.  Drs. Whittemore Hagg and Xu will serve as mentors for each of the Projects and each individual having primary or secondary oversight for 2-4 Projects.  CORE A will provide fiscal oversight of all Projects and CORES and also provide expertise in statistical analysis and experimental design for all Projects.

project_terms:
Advisory Committees;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Experimental Designs;Funding;Grant;Individual;Institution;Mentors;Principal Investigator;Research;Research Personnel;Resources;Series;Source;United States National Institutes of Health;Visit;lecturer;repaired


application_id: 7720148
project_number: 5P20RR016481-08
project_title: DRUG DELIVERY TO THE BRAIN USING NOVEL NANOMATERIALS
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6276
contact_pi_person_id: 8564296
contact_pi: HAIK, KRISTI LYNN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Dendrimers are highly customizable polymers that act as basic building blocks allowing specific nanostructures to be built. The purpose of this project is to design dendrimers that cross the blood brain barrier (BBB) for potential use in drug delivery.  The aims of this project are to synthesize and charaterize novel poly(lysine) dendrimers and poly(amidoamine) (PAMAM) dendrimers each with a biotin label or dansyl chloride label and surface groups including anandamide (a compound that may aid the dendrimer in crossing the BBB).  Additionally we will investigate dendrimer penetration into model lipid bilayers using attenuated total reflection infrared spectroscopy; characterize the fundamental interactions of dendrimer nanostructures at a solid/solution interface using scanning probe microscopy; measure the passage of dendrimers across a cell co-culture of brain endothelial cells and astrocytes and through the rat BBB using ultra performance liquid chromatography
  (UPLC) and HPLC.  Collectively these studies will provide valuable information on the use of dendrimers in applications such as drug delivery and chemical sensing.  This far we have sunthesized all G4 and G5 PAMAM dendrimer conjugates and submitted a manuscript to Journal of Nanomaterials (with undergraduate student co-authors).  In the paper UPLC analysis was utilized for the first time as a methodology for monitoring PAMAM dendrimer surface transformations (biotin) and product quality.  Currently we are testing of passage of various dendrimers across the in vitro BBB model.  Faculty Mentor Robert Yokel will share his in vivo method of testing nanoparticle passage across a rat BBB in the next 2 weeks as PI Martines will travel to UK to perfect this technique.  An NIH R15 grant proposal and SOMAS (Support of Mentors and their Students in the Neurosciences) grant proposal are currently in review.  Two internal grant proposals were awarded.  Manuscripts are also in prepar ation for the characteriztion and in vitro and in vivo studies.  PI Martines traveled to Magdeburg Germany to establish a collaboration with the University of Madgeburg Medical School where new nanoparticles (with potential of treating glioma) and a new in vivo model will be shared trip supported by NKU Research Foundation grant.

project_terms:
Astrocytes;Attenuated;Award;Biotin;Blood - brain barrier anatomy;Brain;Cells;Chemicals;Chloride Ion;Chlorides;Chromatography High Pressure Liquid;Coculture Techniques;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Dendrimers;Drug Delivery Systems;Endothelial Cells;Faculty;Foundations;Funding;Germany;Glioma;Grant;Grants Applications;In Vitro;Institution;Journals;Label;Lipid Bilayers;Liquid Chromatography;Lysine;Manuscripts;Measures;Mentors;Methodology;Methods;Microscopy Scanning Probe;Modeling;Monitor;Nanostructures;Neurosciences;Paper;Penetration;Performance;Polymers;Pre-Par;Purpose;Rattus;Research;Research Personnel;Resources;Schools Medical;Source;Students;Surface;Techniques;Testing;Time;Travel;United States National Institutes of Health;Universities;Week;anandamide;design;in vivo;in vivo Model;infrared spectroscopy;nanomaterials;nanoparticle;novel;solid solution


application_id: 7720147
project_number: 5P20RR016481-08
project_title: BIOINFORMATIC ANALYSIS OF ACCELERATED SEQUENCE EVOLUTION OF SPECIFIC EUBACTERIA
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6275
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The two specific aims of this effort are to identify and quantitate the level of sequence variation among a set of four rapidly evolving RNA polymerase (RNAP) genes that constitute targets for antibiotic therapy and to identify highly conserved structural motifs in the four RNAP core complex subunit proteins that could be suitable candidates for new antibiotic development.  RNA polymerase subunits normally evolve at comparatively slow rates but in one family of flowering plants the Geraniaceae the cyanobacterial-type RNAP in chloroplasts are evolving at a much higher rate. Nucleotide and deduced-amino acid sequence analysis of full length and partial (ca. 1 kb) genomic sequences of 8 a (rpoA) 19 beta (rpoB) 16 beta (rpoC1) and one beta (rpoC2) subunit genes from several species of the genus Pelargonium revealed a gradient of sequence evolution with rpoA (encoding an assembly or scaffolding protein) evolving most rapidly followed by rpoC1  rpoC2 and rpoB 
 (encoding subunits involved in catalysis and contact between the RNAP and the DNA template).  These genes appear to be the most rapidly evolving RNAP genes yet sequenced.  Remarkably there is as much sequence divergence between rpo genes in this genus of plants (representing about 20 million years of evolution) as between rpo genes from distantly-related groups of eubacteria representing at least 2 billion years of evolution.  As such the rpo genes from these organisms might represent a natural experiment in saturation mutagenesis and may help define immutable portions of the RNAP structure.  Several core motifs in all genes were found to be highly conserved and may represent suitable targets for smart drug design against the eubacterial RNAP homologues.

project_terms:
Angiosperms;Antibiotic Therapy;Antibiotics;Bioinformatics;Catalysis;Chloroplasts;Computer Retrieval of Information on Scientific Projects Database;DNA;DNA-Directed RNA Polymerase;Development;Eubacterium;Evolution;Family;Funding;Genes;Genomics;Geraniaceae;Grant;Homologous Gene;Institution;Length;Mutagenesis;Natural experiment;Nucleotides;Organism;Pelargonium;Plants;Polymerase Gene;Protein Complex Subunit;Rate;Research;Research Personnel;Resources;Scaffolding Protein;Sequence Analysis Protein;Source;Structure;United States National Institutes of Health;Variant;design;sigma factor KatF protein Bacteria


application_id: 7720146
project_number: 5P20RR016481-08
project_title: PROTEIN STRUCTURAL REFINEMENT USING COARSE-GRAINED MODELS OVER HIGH PERF COMPUT
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6274
contact_pi_person_id: 9259622
contact_pi: WU, DI
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator. Protein structures can be determined through either experimental methods such as X-ray crystallography and Nuclear Magnetic Resonance (NMR) technology or theoretical methods such as protein folding and homology modeling. However many of determine protein structures are usually not as accurate as desired. Therefore their applications have been severely limited in important fields and structure refinement is always important and critical. In recent decades the number of high resolution protein structures determined and deposited in PDB database is increasing which makes it possible to conduct statistical analysis in the structural database. In this project we propose a knowledge-based approach for protein structure refinement. From 2007-2008 we have finished the following work. Besides studying distance distributions of pair wise inter-atomic distances we have studied side chain torsion angles Cb-Ca-Ca-Cb and many of them have significant distributions. The statistical analysis is essentially the most important step in this project and also we have developed a user-friendly web service for protein structure modeling community ( www.wku.edu/~di.wu/psd ) so that such geometric prosperities with statistical analysis can be accessible and useful for refinement and analysis of protein models.  A related report is in preparation and will be presented in bioinformatics related conferences. We have also developed a computational approach for structure refinement. Additional statistical potentials derived from distributions of distances and dihedral angles can be incorporated into the empirical energy function. We applied such idea specifically on X-ray structures with disorder regions and results have shown that such regions can be greatly refined with employing additional statistical potentials.  Using obtained results we have submitted a NIH R15 grant proposal for the project of protein structure refinement. We also plan to finish
  a few things from 2008-2009 including conducting a large number of samples in modeling disorder regions of crystal structures and employing torsion angle derived potentials in NMR structure refinement and crystal structure refinement. A more detailed report will be prepared and submitted for publication elsewhere in the future.

project_terms:
Bioinformatics;Cereals;Communities;Computer Retrieval of Information on Scientific Projects Database;Crystallography X-Ray;Databases;Deposition;Disease;Disease model;Funding;Future;Grant;Grants Applications;Homology Modeling;Institution;Internet;Methods;Modeling;Nuclear Magnetic Resonance;Numbers;Preparation;Protein Analysis;Publications;Reporting;Research;Research Personnel;Resolution;Resources;Roentgen Rays;Sampling;Services;Side;Source;Structural Protein;Structure;Technology;Torsion (malposition);United States National Institutes of Health;Work;desire;knowledge base;protein folding;protein structure;symposium;user-friendly


application_id: 7720145
project_number: 5P20RR016481-08
project_title: TARGETING SODIUM-PROTON EXCHANGE TO TREAT BRAIN CANCER
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6273
contact_pi_person_id: 9359085
contact_pi: PALANDOKEN, HASAN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.More than 200000 people in the United States are diagnosed with a primary or metastatic brain tumor annually.  The life expectancy for these individuals is approximately 9-12 months from the time of diagnosis.  This poor prognosis is due to the ineffectiveness of existing therapies (e.g. chemotherapy and radiotherapy) against brain cancer where the problem is the inability to differentiate cancer cells from healthy cells.  Currently there is no curative therapy for brain cancer.  Thus the field is in great need for cancer cell-selective therapies.  This proposal outlines a target-specific approach to treating brain cancer that could lead to a curative therapy.  Relative to healthy brain tissue the heightened metabolism of brain cancer cells (e.g. malignant gliomas) increases their reliance the ion transport proteins specifically sodium-proton (NHE) exchangers.  The inhibition of these cell surface proteins disrupts the intricate pH and ion balances within ca ncer cells to a much greater extent than in normal cells and this leads to glioma cell death.  Consequently NHE is an excellent molecular target for brain cancer therapy.  We will synthesize potent inhibitors in a prodrug form.  As the prodrugs encounter extracellular enzymes from gliomas at the tumor site they will release inhibitors that bind to NHE to cause glioma death.  These inhibitors also are expected to assist with the regional management of tumor swelling and increased intracranial pressure often associated with brain cancer.  The proposed project seeks to demonstrate a prodrug approach for cell surface ion exchange inhibition as a selective therapy for brain cancer.

project_terms:
Binding (Molecular Function);Brain Neoplasms;Carrier Proteins;Cell Death;Cell surface;Cells;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Diagnosis;Enzymes;Equilibrium;Forecast of outcome;Funding;Glioma;Grant;Individual;Institution;Intracranial Hypertension;Ion Exchange;Ion Transport;Ions;Lead;Life Expectancy;Malignant Glioma;Malignant neoplasm of brain;Metabolism;Molecular Target;Normal Cell;Prodrugs;Proteins Cell Surface;Protons;Radiation therapy;Relative (related person);Reliance;Research;Research Personnel;Resources;Site;Sodium;Source;Swelling;Time;United States;United States National Institutes of Health;brain tissue;cancer cell;cancer therapy;chemotherapy;extracellular;inhibitor/antagonist;tumor


application_id: 7720144
project_number: 5P20RR016481-08
project_title: SEX SPECIFIC PARENTAL ROLES AND THEIR MODULATION VIA NEUROPEPTIDES
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6272
contact_pi_person_id: 7550029
contact_pi: SANTANGELO, NICHOLAS
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.A long term goal of this project is to determine the role of neuropeptides in male and female parental care. Parental care is modulated via the mammalian neuropeptides arginine vasopressin (AVP) and oxytocin (OT). However due the paucity of biparental mammals which are also viable experimental species it remains unclear the role each hormone actually plays in specific behaviors within each sex where males and females have distinct parental roles. The social ecology of systems tested is typically overlooked and it is plausible that the interaction between these neuropeptides is dependant on the degree to which parental care roles are shared or divided between the parents. The well known behavioral model the convict cichlid Archocentrus nigrofasiatum is a species that exhibits just such a division of labor between parents in care. An added benefit of using teleosts is that fish provide a pliable laboratory system with complex social structures. The teleost homologue of AVP and OT is arginine vasotocin (AVT) and isotocin (IT) respectively and they are known to modulate similar social behaviors as in mammalian systems. Using exogenous injections and behavioral analysis I will explore the modulation of sex differences in parental care. My specific aims are as follows:  1) To explore the relationship between social ecology (i.e. a biparental species that exhibits a stark division of labor) and neuropeptide AVT on a) male parental aggression and male parental care abilities and b) female parental aggression and direct care abilities. 2) to explore the neuropeptide IT a) the parental aggression and parental care abilities of males and b) female parental aggression and direct care abilities. The outcome of these experiments will determine the future studies which will explore the potential of these hormones to modulate biparental care through interacting with each other.

project_terms:
Aggressive behavior;Argipressin;Behavior;Behavioral;Behavioral Model;Caring;Cichlids;Complex;Computer Retrieval of Information on Scientific Projects Database;Ecology;Exhibits;Female;Fishes;Funding;Future;Goals;Grant;Homologous Gene;Hormones;Injection of therapeutic agent;Institution;Laboratories;Mammals;Neuropeptides;Outcome;Oxytocin;Parents;Play;Research;Research Personnel;Resources;Role;Sex Characteristics;Social Behavior;Source;Structure;System;Testing;United States National Institutes of Health;Vasotocin;convict;male;parental role;research study;sex;social;teleost


application_id: 7720143
project_number: 5P20RR016481-08
project_title: ALPHA-ACTIN REMODELING IN THE A7R5 SMOOTH MUSCLE CELL
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6271
contact_pi_person_id: 2017035
contact_pi: FULTZ, MICHAEL J
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.It has become increasingly clear that there are additional mechanisms additional to the sliding filament theory that contribute to the contractile properties of smooth muscle.  Ourselves and others have proposed that remodelling of the cytoskeleton may explain the uniqie contractile properties exhibited by smooth muscle.  The goal of this project is to determine the relationship of changes in organization of the cytoskeleton in the contracting A7r5 cell line to its contractile properties as well as contractile properties of vascular smooth muscle.

project_terms:
Cell Line;Computer Retrieval of Information on Scientific Projects Database;Contracts;Cytoskeleton;Exhibits;Filament;Funding;Goals;Grant;Institution;Muscle Smooth Vascular;Myocytes Smooth Muscle;Property;Research;Research Personnel;Resources;Slide;Smooth muscle (tissue);Source;United States National Institutes of Health;alpha Actin;theories


application_id: 7720142
project_number: 5P20RR016481-08
project_title: PHOTORECEPTORS INVOLVED IN CHLAMYDOMONAS REINHARDTII CIRCADIAN ENTRAINMENT
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6270
contact_pi_person_id: 8234056
contact_pi: JACOBSHAGEN, SIGRID
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The long-term objectives of the proposed research are to elucidate the biochemical mechanisms underlying the circadian clock in Chlamydomonas reinhardtii. This unicellular eukaryotic green alga serves as a model system for a number of cell processes in animals and plants. Understanding its circadian clock will contribute to an understanding of circadian clock evolution and thus also help to better understand the circadian clock in humans. The strategy of achieving the long-term objectives is to identify the photoreceptor(s) responsible for adjusting the circadian clock to the daily light/dark cycles. If successful the photoreceptors can be used as a handle to investigate the signal transduction chain(s) that convey the information to the central oscillator and possibly the components of the oscillator itself. C. reinhardtii provides an advantage over other model organisms such as Arabidopsis thaliana because it contains only a limited number of photoreceptors. They fall into three classes: cryptochromes rhodopsins and ototropins. Phototropins are blue-light photoreceptors found in higher plants and green algae (Briggs and Christie 2002). Whether phototropins are involved in lightentrainment of the circadian clock is not completely understood yet. Cryptochromes on the other hand are blue-light photoreceptors that were shown to be involved in clock entrainment in higher plants and insects (Cashmore 2003). They are also found in mammals but serve as components of the pacemaker that creates the circadian oscillation in this group of organisms. In fungi as exemplified by Neurospora crassa cryptochrome seems not to be involved in the circadian clock.

project_terms:
Algae Green;Animal Model;Animals;Biochemical;Biological Models;Cell physiology;Chlamydomonas reinhardtii;Circadian Rhythms;Class;Computer Retrieval of Information on Scientific Projects Database;Cress Mouse-ear;Daily;Evolution;Funding;Grant;Hand;Human;Insecta;Institution;Mammals;Neurospora crassa;Numbers;Organism;Pacemakers;Photoreceptors;Plants;Research;Research Personnel;Resources;Rhodopsin;Signal Transduction;Source;United States National Institutes of Health;Vascular Plant;circadian pacemaker;cryptochrome;falls;fungus


application_id: 7720141
project_number: 5P20RR016481-08
project_title: ANALYSIS OF 25-DIALKYL HYDROQUINONES AS NOVEL ENZYME INHIBITORS
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6269
contact_pi_person_id: 8527958
contact_pi: PAULA, STEFAN FRANZ
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The overall goal of the proposed research is to initiate the development of novel inhibitors of the enzyme sarco-endoplasmic reticulum calcium ATPase (SERCA) using a combination of experimental and computational techniques. Not only are SERCA inhibitors powerful tools for the study of the enzyme's function but they are also believed to be of potential medicinal value for cancer chemotherapy.

project_terms:
Ca(2+)-Transporting ATPase;Chemotherapy-Oncologic Procedure;Computational Technique;Computer Retrieval of Information on Scientific Projects Database;Development;Endoplasmic Reticulum;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Funding;Goals;Grant;Hydroquinones;Institution;Research;Research Personnel;Resources;Source;United States National Institutes of Health;hydroquinone;inhibitor/antagonist;novel;tool


application_id: 7720140
project_number: 5P20RR016481-08
project_title: STRUCTURAL AND FUNCTIONAL RECOVERY OF AUDITORY HAIR CELLS IN ZEBRAFISH
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6268
contact_pi_person_id: 2128827
contact_pi: SMITH, MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Auditory hair cells are the sensory cells that transduce acoustical signals into neural ones in vertebrates thus providing the ability to hear.  In mammals when these terminally-differentiated cells are damaged or lost the result is permanent loss of hearing since lost mammalian hair cells do not regenerate. In fish and birds damaged auditory sensory epithelia have the capability of regenerating new hair cells resulting in  recovery of hearing. Recent studies show that goldfish exhibit both structural (hair cells) and functional (hearing) recovery following noise exposure. To fully understand what normal cellular processes lead to regeneration in fishes knowledge of how specific genes mediate hair cell growth (proliferation and transdifferentiation) and apoptosis is essential.

project_terms:
Apoptosis;Auditory;Birds;Cell physiology;Computer Retrieval of Information on Scientific Projects Database;Epithelium;Exhibits;Fishes;Funding;Genes;Goldfish;Grant;Hair Cells;Hearing;Institution;Knowledge;Lead;Mammals;Mediating;Natural regeneration;Noise;Recovery;Recovery of Function;Research;Research Personnel;Resources;Sensory;Signal Transduction;Source;United States National Institutes of Health;Vertebrates;Zebrafish;cell growth;cell injury;cellular transduction;hearing impairment;relating to nervous system;transdifferentiation


application_id: 7720139
project_number: 5P20RR016481-08
project_title: WKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6267
contact_pi_person_id: 7326029
contact_pi: DAVIS, CHERYL D
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.As Lead Faculty Representative my role in Western Kentucky University's (WKU) INBRE program is primarily administrative.  During this budget year I served as WKUs representative on the KBRIN/INBRE steering committee and participated in numerous grant-related initiatives at WKU.

project_terms:
Budgets;Computer Retrieval of Information on Scientific Projects Database;Faculty;Funding;Grant;Institution;Kentucky;Lead;Research;Research Personnel;Resources;Role;Source;United States National Institutes of Health;Universities;programs


application_id: 7720138
project_number: 5P20RR016481-08
project_title: BEHAVIOR AND MECHANISM IN ACUTE AMPHETAMINE WITHDRAWAL
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6266
contact_pi_person_id: 1885629
contact_pi: WHITE, WESLEY O
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Rats are hypoactive 20 hours after receiving a moderate dose of amphetamine. This hypo-activity may indicate the presence of an acute withdrawal state and of a low-grade depression. The purpose of the research is to develop an animal model of acute withdrawal and to use it to investigate mechanisms and treatments. Methods. In the past year we have continued to develop behavioral procedures designed to provide converging evidence for the presence of acute withdrawal 20 hours after amphetamine treatment: We assessed working for food (appetitive behavior) and consuming food (consummatory behavior) at different times following amphetamine treatment. In order to evaluate whether amphetamine produces longer-term hypoactivity by initially activating dopamine receptors we continued to look at the ability of pre-treatment with dopamine receptor antagonists to block amphetamine-induced hypoactivity. In order to identify molecular events that might mediate amphetamine's effects we used real-time PCR to look at changes in gene expression (prodynorphin D1 receptor D2 receptor) in several brain regions at different times following treatment.

project_terms:
Acute;Amphetamines;Animal Model;Appetitive Behavior;Behavior;Behavioral;Brain region;Computer Retrieval of Information on Scientific Projects Database;Consummatory Behavior;Dopamine Antagonists;Dopamine D1 Receptor;Dopamine D2 Receptor;Dopamine Receptor;Dose;Event;Food;Funding;Gene Expression;Grant;Hour;Institution;Mediating;Mental Depression;Methods;Molecular;Polymerase Chain Reaction;Procedures;Purpose;Rattus;Research;Research Personnel;Resources;Source;Time;United States National Institutes of Health;Withdrawal;Work;design;prodynorphin


application_id: 7720137
project_number: 5P20RR016481-08
project_title: A BUTTERFLY TRANSPOSON MUTAGENESIS SCREEN FOR THE STUDY OF WINGLESS SIGNAL
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6265
contact_pi_person_id: 7015251
contact_pi: MARCUS, JEFFREY
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.My laboratory is developing techniques for genetic mapping and germ-line transformation in the buckeye butterfly Junonia (Precis) coenia.  We are using these techniques to introduce a transposon carrying either an enhancer trap construct or a stable source of transposase into the different strains of butterflies and to use these strains to conduct a genome-wide enhancer trap mutagenesis screen.

project_terms:
Butterflies;Castanea dentata;Chromosome Mapping;Computer Retrieval of Information on Scientific Projects Database;Enhancers;Funding;Genome;Germ Lines;Grant;Institution;Laboratories;Mutagenesis;Research;Research Personnel;Resources;Signal Transduction;Source;Techniques;Transposase;United States National Institutes of Health


application_id: 7720136
project_number: 5P20RR016481-08
project_title: RNA-BASED MECHANISMS OF TRANSCRIPTION ELONGATION CONTROL
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6264
contact_pi_person_id: 8534212
contact_pi: KING, RODNEY ALLEN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The goal of this proposal is to build research capacity in the state of Kentucky by establishing a research program that is competitive at the RO1 level of federal funding.  The project is designed to understand mechanisms of transcription elongation control and their evolution.

project_terms:
Computer Retrieval of Information on Scientific Projects Database;Evolution;Funding;Goals;Grant;Institution;Kentucky;Research;Research Personnel;Resources;Source;Transcription Elongation;United States National Institutes of Health;base;design;programs


application_id: 7720135
project_number: 5P20RR016481-08
project_title: NKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6263
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Introduction: This application requests funding for lead faculty activities at Northern Kentucky University (NKU). The lead faculty will coordinate KY-BRIN activities within NKU and between NKU and other KY-BRIN organizations recruit new faculty into the BRIN program and support faculty and undergraduate research in the biomedical sciences. A part-time database/website administrator will also be hired. This person will develop and maintain databases pertinent to KY-BRIN research at NKU and a website that will provide information about the KY-BRIN program at NKU. This website will also serve as a resource for KY-BRIN researchers and students at NKU. The funding of this application will help strengthen the presence of the BRIN program at NKU and increase the awareness and involvement of NKU faculty and students in biomedical research. 

Methods: Provide release time and compensatory salary to PI to implement the goals listed above as well as recruit and maintain a qualified individual for the database/website administrator.

project_terms:
Administrator;Awareness;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Databases;Faculty;Funding;Goals;Grant;Individual;Institution;Kentucky;Lead;Methods;Persons;Qualifying;Recruitment Activity;Request for Applications;Research;Research Personnel;Resources;Science;Source;Students;Time;United States National Institutes of Health;Universities;Wages;programs


application_id: 7720134
project_number: 5P20RR016481-08
project_title: MOLECULAR MECHANISMS OF ESTROGEN-REGULATED BONE RESORPTION
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6262
contact_pi_person_id: 8475908
contact_pi: DEMOSS, DARRIN LEE
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The primary objective of this project is to enhance our understanding of the mechanisms of increased bone resorption which accompanies estrogen deficiency.  Bone resorption parameters have been compared between control females six months of age ovariectomized females (OVX) females receiving hormone replacement therapy (HRT) and females receiving a calcium channel antagonists (Diltiazem Nifedipine Verapamil) or females receiving a combination of the two agents.

project_terms:
Age-Months;Bone Resorption;Calcium Channel;Computer Retrieval of Information on Scientific Projects Database;Diltiazem;Estrogens;Female;Funding;Grant;Hormone replacement therapy;Institution;Molecular;Nifedipine;Research;Research Personnel;Resources;Source;United States National Institutes of Health;Verapamil


application_id: 7720133
project_number: 5P20RR016481-08
project_title: CHARACTERIZATION OF PUTATIVE MAGNESIUM TRANSPORTING P-TYPE ATPASES
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6261
contact_pi_person_id: 6945317
contact_pi: SCHULTHEIS, PATRICK JOHN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Introduction: P-type ATPases comprise a large superfamily of proteins present in both prokaryotes and eukaryotes that transport inorganic cations and possibly other substrates across cell membranes. Based on phylogenetic studies they have been classified into 5 subfamilies termed P1-P5 which group according to sequence similarities transmembrane organization and substrate specificity. The most poorly understood P-type ATPases are those of the P5 subfamily which are expressed only in eukaryotes. The overall goal of the current proposal is to obtain basic information about the P5-ATPases in mice that will be essential for an eventual understanding of their cell biological and physiological functions. The aims of the current proposal are to 1) isolate full-length cDNA clones for each of the family members and determine their tissue distribution and membrane location 2) overexpress the novel P-type ATPases in the appropriate cell lines in order to assess their i
 on specificity and 3) determine their cellular and physiological roles in vivo using RNA interference (RNAi) and gene targeting technologies.

project_terms:
ATP phosphohydrolase;Biological;Cations;Cell Line;Cell membrane;Cells;Computer Retrieval of Information on Scientific Projects Database;DNA Complementary;Drug or chemical Tissue Distribution;Eukaryota;Eukaryotic Cell;Family member;Funding;Gene Targeting;Goals;Grant;Institution;Length;Location;Magnesium;Membrane;Mus;Phylogenetic Analysis;Physiological;Prokaryotic Cells;Protein Overexpression;Proteins;RNA Interference;Research;Research Personnel;Resources;Role;Source;Specificity;Substrate Specificity;Technology;United States National Institutes of Health;base;in vivo;novel


application_id: 7720132
project_number: 5P20RR016481-08
project_title: MECHANISMS OF TRANSCRIPTIONAL COORDINATION AMONG PHOSPHORYLASE KINASE GENES
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6260
contact_pi_person_id: 6773495
contact_pi: RICE, NANCY AYERS
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Phosphorylase kinase (PhK) is a key regulatory enzyme involved in the glycogenolytic pathway catalyzing the activation by phosphorylation of phosphorylase. The hexadecameric enzyme with subunit composition (alphabetagammadelta)4 serves to integrate hormonal metabolic and neural signals leading to the breakdown of glycogen stores in muscle and liver. Each subunit of PhK is encoded by a separate gene and multiple tissue specific isoforms exist for all of the subunits. While much work has been done to elucidate the biochemical regulation of PhK catalysis little information regarding transcriptional regulation of this complex oligomer is available. Our work seeks to elucidate those elements responsible for the temporal and spatial regulation of PhK gene expression by providing for the identification and functional analysis of all human alpha beta and gamma promoters.

project_terms:
Biochemical;Catalysis;Complex;Computer Retrieval of Information on Scientific Projects Database;Elements;Enzymes;Funding;Gene Expression;Genes;Glycogen;Glycogen Phosphorylase Muscle Form;Grant;Hormonal;Human;Institution;Liver;Metabolic;Muscle;Pathway interactions;Phosphorylase Kinase;Phosphorylases;Phosphorylation;Promotor (Genetics);Protein Isoforms;Regulation;Research;Research Personnel;Resources;Signal Transduction;Source;Tissues;Transcriptional Regulation;United States National Institutes of Health;Work;relating to nervous system


application_id: 7720131
project_number: 5P20RR016481-08
project_title: GENETIC & METABOLIC ADAPTATION BY SALMONELLA TO THE NATURAL ENVIRONMENT
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6259
contact_pi_person_id: 7614787
contact_pi: BARTON, HAZEL A
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Salmonella is generally considered a low-frequency commensal and low-grade pathogen with very limited ability to survive long term in the environment outside of a host organism. Recent work has identified a constellation of interactive metabolic functions shared by all Salmonellae but absent from its nearest relative E. coli.  The constellation of Salmonella-specific functions includes de novo synthesis of cobalamin (B12) use of B12 in degradation of ethanolamine and propanediol anaerobic respiration of tetrathionate to thiosulfate (ttr genes) and subsequent reduction to sulfite (phs genes) and sulfide (asr genes).  All these functions would be used when Salmonella grows anaerobically on ethanolamine or propanediol in the presence of reducible sulfur compounds.  Under these conditions Salmonella forms granules of mineral sulfur which it (but not E. coli) can later reduce by a process that requires the phs genes.  While these functions may be important to pathogenesis we think it more likely that they suggest a significant lifestyle for Salmonella in particular soil environments.  Our work has been geared to understanding whether there is an environmental niche for Salmonella and the potential impact that such an ecological niche will have on our understanding of the pathogenesis of this organism.

project_terms:
Cobalamin;Computer Retrieval of Information on Scientific Projects Database;Condition;Cytoplasmic Granules;Environment;Escherichia coli;Ethanolamines;Frequencies (time pattern);Funding;Genes;Genetic;Grant;Institution;Life Style;Metabolic;Minerals;Organism;Pathogenesis;Process;Propylene Glycols;Relative (related person);Research;Research Personnel;Resources;Respiration;Salmonella;Soil;Source;Sulfides;Sulfites;Sulfur;Sulfur Compounds;Thinking function;United States National Institutes of Health;Work;ethanolamine;pathogen


application_id: 7720130
project_number: 5P20RR016481-08
project_title: ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6258
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Introduction: Deformations and functional alterations of the hippocampus a brain regions important in learning and memory have been reported in disorders such as schizophrenia and Alzheimer?s disease that are commonly treated with antipsychotic drugs. However it is unknown whether antipsychotic drugs can ameliorate the behavioral consequence of hippocampal dysfunction or conversely if hippocampal damage can undermine the behavioral and molecular pharmacology of antipsychotic drugs. The purpose of this project is to address these issues by using a rat model of excitotoxic hippocampal damage. 

Methods: The first aim of the grant has been to determine if and how acute or chronic antipsychotic drug treatment can reverse or reduce the effects of hippocampal damage on locomotor activity and spatial working memory. The second aim of the grant has been to determine if the effects of antipsychotic drug treatment on global gene expression are altered by hippocampal damage. The third aim has been to determine if and how hippocampal lesions alter the induction of transcription factors and other proteins by antipsychotic drug treatment. 

Results: Between July 2005 and February 2006 we have focused our research on two proteins that serve as receptors for antipsychotic drugs the histamine3 (H3) and alpha2 (?2) adrenergic receptors. Our studies have found that antagonists for the former receptor can moderately improve spatial memory in rats with hippocampal damage while agonists for the latter site do not improve spatial memory in such animals. These data served as the basis for an R15 application submitted in 2005 by the P.I.. (The application received a score of 199 and was not funded). We have also characterized the effects of hippocampal lesions on global gene expression in the prefrontal cortex using microarray technology. A number of genes related to synaptic function were found to be altered in the prefrontal cortex of lesioned animals. We will continue these lines of research as well as study the effects of antipsychotic drugs on gene and protein expression in the frontal cortex and other brain regions.

project_terms:
Acute;Address;Adrenergic Receptor;Agonist;Alzheimer's Disease;Animals;Antipsychotic Agents;Behavioral;Brain region;Chronic;Computer Retrieval of Information on Scientific Projects Database;Data;Disease;Drug effect disorder;Functional disorder;Funding;Gene Expression;Gene Proteins;Genes;Grant;Hippocampus (Brain);Institution;Learning;Lesion;Memory;Memory Short-Term;Methods;Microarray Analysis;Modeling;Molecular;Motor Activity;Numbers;Pharmacology;Prefrontal Cortex;Proteins;Purpose;Rattus;Reporting;Research;Research Personnel;Resources;Schizophrenia;Score;Site;Source;United States National Institutes of Health;base;frontal lobe;improved;protein expression;receptor;synaptic function;transcription factor


application_id: 7720127
project_number: 5P20RR016481-08
project_title: KBRIN -MOREHEAD STATE UNIVERSITY
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6255
contact_pi_person_id: 9258139
contact_pi: MATTINGLY, BRUCE A
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The major of objective of this project is to increase biomedical research infrastructure and capacity at MSU. The specific aims are: 1) to increase biomedical NIH grant applications and funding; and 2) to increase the number of undergraduate students pursuing careers in biomedical research.

project_terms:
Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Funding;Grant;Grants Applications;Institution;Numbers;Research;Research Infrastructure;Research Personnel;Resources;Source;Students;United States National Institutes of Health;Universities;career


application_id: 7720126
project_number: 5P20RR016481-08
project_title: BRIN: UL: GENOMICS CORE
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6254
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The shared centralized research core facility is designed to provide sequencing and gene-micro-array services to the University of Louisville and its KBRIN/INBRE affiliated institutions.

project_terms:
Computer Retrieval of Information on Scientific Projects Database;Core Facility;Funding;Genes;Grant;Institution;Research;Research Personnel;Resources;Services;Source;United States National Institutes of Health;Universities;design


application_id: 7720125
project_number: 5P20RR016481-08
project_title: BIOINFORMATICS CORE
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6253
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This is a network-distributed core with assets contributed by and shared among the KBRIN-affiliated institutions. The resources include hardware software and human resources.

Dr. Eric Rouchka a faculty member in CECS. His background and training is in computer sciences and genomics (sequencing). Dr. Rouchka serves as the KBRIN Bioinformatics Lead at the University of Louisville.
A University of Louisville Bioinformatics Research Group (CECS SOM and SPH faculty and students meet every other week; anyone interested in bioinformatics should attend). The group has developed a Web site which lists Bioinformatics Research Group personnel and projects. The BRG are developing new tools for the development of data banks for genomics data mining image analysis and for gene-array analysis.

project_terms:
Bioinformatics;Computer Retrieval of Information on Scientific Projects Database;Computer software;Databases;Faculty;Funding;Genes;Genomics;Grant;Human Resources;Image Analysis;Institution;Internet;Lead;Research;Research Personnel;Resources;Site;Source;Students;Training;United States National Institutes of Health;Universities;Week;computer science;data mining;interest;member;tool development


application_id: 7720124
project_number: 5P20RR016481-08
project_title: BRIN:KENTUCKY BRIN MENTORING & TRAINING CORE
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6252
contact_pi_person_id: 2101814
contact_pi: RAWLS, JOHN M
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The functions of this core are to promote education and research training in the biomedical sciences provide mentored research opportunities for undergraduate students and to provide support for collaborative research for faculty. The long-term objectives of these activities are to encourage and prepare students to enter careers in biomedical research and to build faculty research capacity in biomedical research.

project_terms:
Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Educational aspects;Faculty;Funding;Grant;Institution;Kentucky;Mentors;Research;Research Personnel;Research Training;Resources;Science;Source;Students;Training;United States National Institutes of Health;career


application_id: 7720123
project_number: 5P20RR016481-08
project_title: BRIN: UL: KENTUCKY BRIN ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2008-05-18
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2008-05-01
project_end_date: 2009-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 6251
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The administrative core provides a leadership role in the development and support of KBRIN activities and provides logistical support for KBRIN committees and activities. This project year that included an External Advisory Committee Meeting at Morehead in May and the University of Louisville in December along with multiple Steering Committee Meetings. The core also hosted and coordinated the University of Louisville Summer Research Program the 2007 Kentucky Academy of Science Meeting that was held at UofL and the Bioinformatics Summit at Lake Barkley State Park. Dr. Mukhopyay is our Internal Evaluator and Newsletter Editor. The KBRIN administrative office works with the Grants Management Office at the University of Louisville for the development of subcontracts to KBRIN affiliates and the subsequent invoicing.

project_terms:
Academy;Advisory Committees;Bioinformatics;Computer Retrieval of Information on Scientific Projects Database;Development;Funding;Grant;Institution;Kentucky;Leadership;Newsletter;Office Management;Office of Management;Research;Research Personnel;Resources;Role;Science;Source;United States National Institutes of Health;Universities;Work;programs


application_id: 7714790
project_number: 1R15CA133844-01A2
project_title: Development of Statistical Methods for Analyzing Proteomic Cancer Data
administering_ic: NCI
award_notice_date: 2009-06-08
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: CA
serial_number: 133844
suffix: A2
program_official: LI, JERRY
project_start_date: 2009-07-01
project_end_date: 2013-06-30
study_section: Biostatistical Methods and Research Design Study Section[BMRD]
contact_pi_person_id: 1859011
contact_pi: DATTA, SUSMITA
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): High dimensional proteomics spectra generated by Mass spectrometry instruments potentially can identify more sensitive and specific biomarker for complex diseases like cancer. However the lack of sophisticated methods of automated analysis of mass spectra makes it difficult to interpret the spectral data in an efficient manner. Although there are some quantitative works in this area in recent years very few have developed algorithms with the underlined knowledge of chemistry in mind. Overall goal of this project is to develop novel and improved statistical methods for analyzing high dimensional proteomic data. In particular this proposal focuses on 1) separating the true isotopic peaks from chemical noise in a mass spectrum using statistical modeling and hypotheses tests 2) comprehensive evaluation and aggregate ranking of a number of classification techniques to classify the case and control samples using proteomic profiles of the detected peaks and construction of an adaptive classifier which is expected to perform better than individual classifiers under an ensemble of performance measures and 3) construction of a protein- protein association network from the truly classifying peaks in a case-control study. We will incorporate the knowledge of the isotopic composition of a molecule of protein and fit a mixture of location shifted Poisson distributions to the isotopic pattern to the polypeptide spectrum. Our expectation is that our proposed methodology in three different aspects of biomarker identification study will result in better understanding of the underlined biological system and will translate into more sensitive and specific proteomic biomarker useful to treat cancer in future. Moreover the proposed methodologies are general enough to be adapted to other high dimensional biological data generated from genomes proteomes and metabolomes. The results from this study will expose the graduate students of the department of Bioinformatics and Biostatistics and many other students in the interdisciplinary PhD program at the university in the area of statistical proteomics. PUBLIC HEALTH RELEVANCE: Our proposed research will help identifying sensitive and specific proteomic biomarkers for complex diseases like cancer. This research will enhance the capacity of understanding the molecular basis of cancer in general. Moreover identification of the interrelationship between different proteins and peptides responsible for the disease may eventually result into clinical interventions custom made for every individual patient.

project_terms:
Algorithms;Area;Base Ratios;Bioinformatics;Biological;Biometry;Case-Control Studies;Chemicals;Chemistry;Classification;Clinical;Collection;Complex;Custom;Data;Development;Disease;Doctor of Philosophy;Engineering;Entropy;Evaluation;Future;Genome;Goals;Individual;Intervention;Knowledge;Least-Squares Analysis;Liquid substance;Location;MALDI-TOF Mass Spectrometry;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Methodology;Methods;Mind;Modeling;Molecular;National Cancer Institute;Noise;Pathway Analysis;Patients;Pattern;Peptides;Performance;Poisson Distribution;Protein Engineering;Proteins;Proteome;Proteomics;Research;Sampling;Serum;Statistical Methods;Statistical Models;Students;Techniques;Testing;Time;Training;Translating;Universities;Work;base;biological systems;biomarker;cancer proteomics;case control;expectation;graduate student;improved;instrument;novel;polypeptide;programs;protein protein interaction;public health relevance;research study;surface enhanced laser desorption ionization

public_health_relevance:
Our proposed research will help identifying sensitive and specific proteomic biomarkersfor complex diseases like cancer. This research will enhance the capacity of understandingthe molecular basis of cancer in general. Moreover identification of the interrelationshipbetween different proteins and peptides responsible for the disease may eventually resultinto clinical interventions custom made for every individual patient.


application_id: 7714488
project_number: 1R01MH086784-01
project_title: Building a Selective Inhibitory Control Tone in Autism: An rTMS Study
administering_ic: NIMH
award_notice_date: 2009-06-18
opportunity_number: RFA-GM-09-008
application_type: 1
activity_code: R01
ic: MH
serial_number: 086784
program_official: GILOTTY, LISA
project_start_date: 2009-07-01
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZMH1 ERB-L (05)]
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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:
Autism is a pervasive developmental disorder of childhood characterized by deficits in social interaction language and stereotyped behaviors and restricted range of interests. Recent studies on postmortem tissue suggest that autism is associated with cortical cytoarchitectural abnormalities. In brief reports on independent populations have shown a reduction in the neuropil space at the periphery of the minicolumn. This is the compartment where lateral inhibition sharpens the borders of minicolumns and increases their definition. The primary source of for this inhibitory effect is derived from axon bundles of double-bouquet cells. The axons of double bouquet cells arrange themselves in essentially repeatable patterns varying between 15 ?m and 30 ?m wide perpendicular to the cortical surface. This grant attempts to preferentially strengthen the inhibitory surround of minicolumns by taking advantage of the geometry of double bouquet cells. We will use the principle of induction to induce electrical currents in double bouquet cells by applying a coil of wire energized by a capacitor (Transcranial Magnetic Stimulator or TMS) to provide a magnetic field orthogonal to the plane of the coil. Slow or low frequency TMS will enhance interneuron inhibition which in turn will enhance spatial contrast needed to optimize functional discrimination in minicolumnar units. The trial will recruit 70 autistic patients and 30 controls matched for age sex IQ and socio-economic class. Outcome measures will include behavioral and electrophysiological measures. Overall our project will link behavioral clinical and neurophysiological (qEEG ERP) responses during cognitive tests and TMS treatment outcomes with an underlying neuropathology model (minicolumnar pathology and lateral inhibition deficits) derived from investigations in our laboratory. The results of the proposed study will help understand the specific social communication and cognitive deficits associated with developmental abnormalities of functions within cortical circuitry and thereby contribute to understanding the brain substrates of behavioral dysfunctions typical for autism. The proposal represents a new development in combining TMS with functional outcome measures (cognitive ERP EEG) using TMS as a theory-guided psychiatric therapy in autism.

project_terms:
Age;Applications Grants;Asperger Syndrome;Autistic Disorder;Autopsy;Axon;Behavioral;Brain;Cells;Clinical;Cognitive;Cognitive deficits;Development;Discrimination (Psychology);Economics;Electroencephalography;Environment;Frequencies (time pattern);Functional disorder;Grant;Interneurons;Intervention;Investigation;Laboratories;Language;Lateral;Link;Magnetism;Measures;Modeling;Neuropil;Outcome Measure;Pathology;Patients;Pattern;Persons;Pervasive Child Development Disorders;Population;Psychiatric therapeutic procedure;Recruitment Activity;Reporting;Rett Syndrome;Sensory Process;Social Interaction;Source;Stereotyped Behavior;Surface;Symptoms;Testing;Therapeutic Intervention;Thinking function;Tissues;Transcranial magnetic stimulation;Treatment outcome;functional outcomes;interest;magnetic field;neuropathology;neurophysiology;response;sex;social communication;theories

public_health_relevance:
Relevance In this grant proposal we describe a potential therapeutic intervention for autism using transcranialmagnetic stimulation (TMS). Therapy would not change a person's way of thinking but is aimed at specificsymptoms related to processing sensory information from the environment which have proven disabling insome patients. The intervention if proven effective for autism would also be of value to patients with Aspergersyndrome or Rett syndrome.


application_id: 7713904
project_number: 1R01DA027068-01
project_title: Efficacy of Extended Release Tramadol for Treating Prescription Opioid Withdrawal
administering_ic: NIDA
award_notice_date: 2009-08-06
opportunity_number: RFA-DA-09-005
application_type: 1
activity_code: R01
ic: DA
serial_number: 027068
program_official: BOUGH, KRISTOPHER J
project_start_date: 2009-08-15
project_end_date: 2012-05-31
study_section: Special Emphasis Panel[ZDA1 EXL-T (06)]
contact_pi_person_id: 8887956
contact_pi: LOFWALL, MICHELLE RENEE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Approximately 1.7 million people in the United States met diagnostic criteria for prescription opioid abuse or dependence in 2007 and more than 2 million people initiated misuse of these medications in the last three years of the National Survey of Drug Use and Health. Given that opioid addiction is known to be chronic and relapsing and cause individual and societal public health problems (individual morbidity and mortality increased transmission of infectious diseases and crime) more efficacious treatment options for this disorder are needed. Currently approved maintenance medications for opioid dependence while efficacious have been hampered by limited patient acceptance (naltrexone) limited availability (methadone) and concerns about diversion (methadone and buprenorphine). Tramadol an atypical analgesic with opioid agonist activity that is uncontrolled by the Controlled Substances Act has reduced abuse potential relative to other full mu- opioid agonists and may be an effective treatment for opioid dependence. This two-week randomized placebo-controlled inpatient study has two phases each with one primary aim. Phase 1 (Days 1-7) will evaluate the withdrawal suppression efficacy of extended release (ER) tramadol for treatment of short-acting prescription opioid withdrawal. Phase 2 (Days 8-14) will assess the characteristics and severity of withdrawal from acute cessation of ER tramadol dosing and will provide further information about the strength of opioid agonist effects and dependence potential produced by tramadol. Persons age 18-55 years old with a positive observed opioid urine specimen self-report of use of a short-acting opioid at least 21 out of the last 30 days meeting diagnostic criteria for prescription opioid dependence (otherwise healthy) will be eligible for inpatient admission to the residential research unit. After the first overnight stay (to ensure a period of opioid abstinence) participants showing observable signs of opioid withdrawal will be randomized to one of three double-blind treatments: placebo or ER tramadol (400 or 800 mg daily given as two divided doses of matched capsules). Stratification will occur based on three levels of objective opioid withdrawal severity (low medium and high) as assessed by trained staff immediately prior to randomization. Twelve subjects will be needed to complete each treatment arm (n=36). Tramadol doses will be escalated over the first 24 hours to decrease chance of side effects. Ancillary medications are available to all groups to treat breakthrough withdrawal. Primary outcome measures include the participant-rated Opioid Adjectives Questionnaire Withdrawal Scale and amount of ancillary medication used for breakthrough opioid withdrawal during each Phase of the study. Numerous secondary outcome measures will be collected. The data gathered from this study will provide novel and important information regarding the dose-related withdrawal suppression efficacy of ER tramadol and determine whether tramadol produces a withdrawal syndrome after acute cessation. These results will be used to determine if a larger-scale evaluation of tramadol for prescription opioid dependence is warranted.  
  
PUBLIC HEALTH RELEVANCE: Prescription opioid addiction is a growing public health problem and more pharmacologic treatments are needed because current approved medications have had limited patient acceptance (naltrexone) limited availability (methadone) and concerns about misuse and diversion (methadone and buprenorphine). Tramadol is a currently approved medication used to treat moderate-severe pain and initial studies demonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal without producing euphoric effects. This study will determine whether two different doses of extended release tramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longer taken.

project_terms:
12 year old;Abstinence;Acute;Admission activity;Adverse effects;Age;Agonist;Analgesics;Buprenorphine;Cessation of life;Characteristics;Chronic;Cognition;Cognitive;Communicable Diseases;Crime;Data;Dependence;Diabetes Mellitus;Diagnostic;Disease;Dose;Double-Blind Method;Drug usage;Enrollment;Ensure;Evaluation;FDA approved;Health;Hepatic;Heroin;Hour;Hypertension;Illicit Drugs;Individual;Inpatients;Intravenous;Kentucky;Licensing;Life;Mainstreaming (Education);Maintenance;Measures;Medical;Methadone;Moods;Morbidity - disease rate;Morphine;Mortality Vital Statistics;Naltrexone;Opiate Addiction;Opioid;Oral;Outcome Measure;Pain;Parents;Participant;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Phase;Physical Dependence;Pilot Projects;Placebo Control;Placebos;Population;Provider;Questionnaires;Randomized;Randomized Controlled Trials;Relapse;Relative (related person);Reporting;Research;Route;Safety;Schedule;Screening procedure;Severities;Societies;Specimen;Stratification;Substance Withdrawal Syndrome;Surveys;Syndrome;Task Performances;Time;Training;Tramadol;United States;Universities;Upper arm;Urine;Variant;Withdrawal;addiction;base;capsule (pharmacologic);design;disease transmission;drug craving;effective therapy;epidemiologic data;meetings;monoamine;novel;opioid abuse;opioid withdrawal;primary outcome;public health medicine (field);public health relevance;reuptake;secondary outcome;volunteer

public_health_relevance:
PROJECT NARRATIVEPrescription opioid addiction is a growing public health problem and more pharmacologic treatments areneeded because current approved medications have had limited patient acceptance (naltrexone) limitedavailability (methadone) and concerns about misuse and diversion (methadone and buprenorphine).Tramadol is a currently approved medication used to treat moderate-severe pain and initial studiesdemonstrate that it may be useful for treatment of the uncomfortable syndrome of opioid withdrawal withoutproducing euphoric effects. This study will determine whether two different doses of extended releasetramadol can treat opioid withdrawal and whether tramadol itself produces withdrawal after it is no longertaken.


application_id: 7713556
project_number: 1R01DA027031-01
project_title: New Neural Targets for Opioid Use Disorders: Human Studies
administering_ic: NIDA
award_notice_date: 2009-08-14
opportunity_number: RFA-DA-09-005
application_type: 1
activity_code: R01
ic: DA
serial_number: 027031
program_official: BOUGH, KRISTOPHER J
project_start_date: 2009-08-15
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZDA1 EXL-T (06)]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Opioid abuse and dependence are growing public health problems in the United States. While rates of heroin use have remained fairly stable over the past several years abuse and dependence on prescription opioids have shown sharp increases over the past decade. In 2006 (SAMHSA 2007b) it was estimated that approximately one million people were prescription opioid-dependent (based upon DSM-IV criteria) adding to the current one million people estimated by the Office of National Drug Control Policy to be addicted to heroin. While there are existing pharmacotherapies approved for the treatment of opioid dependence in the United States the most efficacious (buprenorphine and methadone) are restricted in use to specified practice conditions thus limiting their availability to patients. Substance P a neurokinin peptide is widely distributed throughout human brain and its receptors are highly expressed in brain regions involved in affect and reward. Recent evidence suggests that inactivation of substance P receptors (NK1) either through genetic deletion or pharmacological blockade significantly attenuates the rewarding effects of opioids in an array of non-human laboratory models. We hypothesize that pretreatment with a substance P receptor antagonist may reduce the direct pharmacodynamic actions of mu opioid agonists related to their abuse liability and rewarding effects in humans. Aprepitant is a NK1 receptor antagonist used clinically for its anti-emetic action. The proposed studies will enroll healthy adult male and female volunteers with histories of illicit opioid use. Two inpatient experiments will be conducted that incorporate double-blind placebo-controlled randomized within-subject designs and include careful evaluation of full dose-effect and time action curves on multi-dimensional outcomes. Experiment 1 will examine the effects of acute doses of aprepitant alone and in combination with acute doses of oral oxycodone and intranasal oxycodone in non-dependent opioid abusers (n=10). Pharmacodynamic outcomes will include subject- and observer-rated measures related to abuse potential psychomotor performance and physiological indices. Experiment 2 will examine the effects of chronic dosing with aprepitant and test its ability at steady state to alter the reinforcing effects of intranasal oxycodone (n=10). A progressive ratio self-administration procedure will be employed in this study to examine directly opioid reinforcement. Additionally the pharmacodynamic interactions after repeated dosing of aprepitant with oxycodone on an array of measures will be examined during the sample sessions. Thus these studies will provide new information on the safety of NK1 antagonist treatment under both acute and chronic dosing conditions and on its potential efficacy to alter the abuse liability and reinforcing properties of oxycodone. These studies are responsive to the RFA (DA-06-002) as they will provide proof-of-concept data and assess the utility of a novel CNS target the substance P receptor by evaluating the potential efficacy of an NK1 receptor antagonist aprepitant to reduce the abuse liability and reinforcing effects of opioids in humans.  
  
PUBLIC HEALTH RELEVANCE: This project will test the hypothesis that blockade of substance P receptors in human brain may reduce the effects of opioids related to their abuse. The substance P system has not been examined as a potential target for the development of treatments for opioid abuse and dependence. Thus these studies conducted in healthy humans will provide fundamental information regarding the potential for this system as a target for development of new treatment agents for opioid use disorders.

project_terms:
Acute;Adult;Affect;Agonist;American;Amygdaloid structure;Analgesics;Antiemetics;Anxiety;Attenuated;Behavior;Brain;Brain region;Buprenorphine;Chronic;Clinical;Clinical Research;Compliance behavior;DSM-IV;Data;Dependence;Development;Disease;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug usage;Effectiveness;Enrollment;Evaluation;Female;Genetic;Health;Heroin;Hippocampus (Brain);Human;Individual;Inpatients;Knowledge;Laboratories;Laboratory Study;Location;Marketing;Measures;Mediation;Methadone;Modeling;Naltrexone;Names;Narcotic Antagonists;Nausea and Vomiting;Neuraxis;Nociception;Nucleus Accumbens;Opiate Addiction;Opioid;Oral;Outcome;Oxycodone;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Physical Dependence;Physiological;Pilot Projects;Placebo Control;Policies;Population;Procedures;Property;Psychological reinforcement;Psychomotor Performance;Publications;Randomized;Receptors Opioid mu;Recording of previous events;Reporting;Rewards;Role;Route;Safety;Sampling;Self Administration;Series;Stress;Substance P;Substance P Receptor;Substance-Related Disorders;Surveys;System;Testing;Time;To specify;United States;United States Dept. of Health and Human Services;United States Substance Abuse and Mental Health Services Administration;aprepitant;base;chemotherapy;chronic pain;design;government documents;indexing;male;novel;opioid abuse;public health medicine (field);public health relevance;receptor;relating to nervous system;research study;therapy development;volunteer

public_health_relevance:
The major benefits of these studies are scientific and clinical ones related to the knowledge gained concerning development of potential new pharmacotherapies for the treatment of opioid use disorders. These studies will provide important fundamental information on the role of the substance P system in modulating opioid effects in humans. This knowledge may be relevant to the development of novel pharmacotherapies for the treatment of opioid dependence. This knowledge may also be relevant to the development of novel analgesics as well as to understanding a potential mechanism for the modulation of opioid tolerance and opioid physical dependence in individuals who require ongoing treatment with opioids including chronic pain patients.


application_id: 7713537
project_number: 5R01NS055228-03
project_title: Multiple circadian oscillators: Regulation of a neuroendocrine rhythm
administering_ic: NINDS
award_notice_date: 2009-11-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 055228
program_official: MITLER, MERRILL
project_start_date: 2007-12-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-D(02)M]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: LEGAN, SANDRA J.
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Exciting recent studies have demonstrated autonomous circadian oscillators in many regions outside of the suprachiasmatic nucleus (SCN) the site of the mammalian master circadian pacemaker. The existence of multiple oscillators had been postulated for decades as a basis for the desynchrony of overt circadian rhythms that occurs during shift work jet lag and depression. These extra-SCN oscillators have been studied mainly in vitro using tissues explanted from males; thus the physiological role of these oscillators is not yet known especially in females. We propose to investigate the regulation of circadian rhythms in clock gene expression in vivo in female neuroendocrine cells the gonadotropin releasing hormone (GnRH) neurons because they have an easily measured physiologically important output the preovulatory luteinizing hormone (LH) surge. Although the LH surge depends on the SCN the GnRH neurons themselves express the circadian clock gene Per1. Furthermore immortalized GnRH neurons GT1-7 cells exhibit circadian rhythms of clock gene expression in vitro. Disruption of these molecular circadian rhythms in GT1-7 cells alters their pattern of GnRH secretion suggesting that molecular circadian clocks are necessary for the  
secretory function of GnRH neurons. This proposal aims to study the regulation and function of a circadian molecular oscillation in native GnRH neurons in female hamsters. The specific aims are to investigate:  
  
Aim 1) the role of circadian phase advances in control of the LH surge Aim 2) the role of SCN GABA-A receptors in control of the LH surge Aim 3) the role of circadian clock genes in the SCN in control of the LH surge Aim 4) the role of vasopressin as an output signal from the SCN regulating GnRH neurons and Aim 5) the expression of PER1 in endogenous GnRH neurons and its role in the LH surge. These studies will exploit the GnRH neurons as a model system with an essential physiological role and easily measured output in order to elucidate the regulation and function of an extra-SCN brain oscillator in vivo.   
  
Understanding multiple oscillators is important for the amelioration of internal desynchrony of circadian rhythms that occurs during shift work and jet lag. Also by studying females the findings of this project may be relevant to the disruptions in circadian hormone rhythms seen in women with affective disorders.This project seeks to understand the regulation and interaction of multiple circadian oscillators that regulate circadian neuroendocrine rhythms. Understanding multiple circadian oscillators is important for amelioration of circadian rhythms desynchrony which occurs during shift work jet lag aging and depression and increases the risk of obesity cardiovascular disease cognitive deficits and depression.  
  
Because this project focuses on females the findings will also be relevant to disruptions in circadian hormone rhythms seen in women with affective disorders such as pre-menstrual dysphoric syndrome post-partum depression and postmenopausal depression.

project_terms:
Acute;Address;Affect;Affective;Age;Animals;Area;Barbiturates;Biological Assay;Biological Models;Blood specimen;Brain;Budgets;Calendar;Cardiovascular Diseases;Categories;Cells;Circadian Rhythms;Cognitive deficits;Critiques;Data;Distal;Effectiveness;Estradiol;Exhibits;Female;GABA-A Receptor;Gene Expression;Genes;Gonadotropin Hormone Releasing Hormone;Hamsters;Hormones;Immunohistochemistry;In Vitro;Injection of therapeutic agent;Jet Lag Syndrome;Lead;Lesion;Luteinizing Hormone;Measurement;Measures;Medial;Mental Depression;Messenger RNA;Microdialysis;Molecular;Mood Disorders;Neuroendocrine Cell;Neurons;Neuropeptides;Neurosciences;Neurosecretory Systems;Norepinephrine;Outcome;Output;Pattern;Peptides;Phase;Phenobarbital;Physiological;Postmenopause;Postpartum Depression;Preoptic Areas;Principal Investigator;Proteins;Protocols documentation;Published Comment;Rattus;Recovery;Regulation;Role;Signal Transduction;Site;Synapses;Syndrome;Third ventricle structure;Time;Tissues;Translating;Vasopressins;Wages;Woman;barbituric acid salt;base;circadian pacemaker;cost;design;in vivo;mRNA Expression;male;neurotransmitter release;obesity risk;organum vasculosum of the lamina terminalis;prevent;professor;programs;research study;shift work;suprachiasmatic nucleus


application_id: 7708574
project_number: 7R56NS045954-07
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
project_terms: Pain;Spinal;transmission process
administering_ic: NINDS
award_notice_date: 2008-11-26
opportunity_number: PA-07-282
application_type: 7
activity_code: R56
ic: NS
serial_number: 045954
program_official: PORTER, LINDA L
project_start_date: 2002-09-10
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-IFCN-K(02)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Our work indicates that intrathecal administration of NPY acts in a dose- and NPY receptor-dependent mannerto reduce the mechanical and thermal hypersensitivity associated with inflammation or nerve injury. Theobjective of the present application is to establish NPY as an intrinsic pain modulator and to identify themechanisms underlying NPY-mediated inhibition of inflammatory or neuropathic pain. The central hypothesis isthat tissue or nerve injury sensitizes the dorsal horn to the pain inhibitory actions of NPY receptor signaling.Our approach involves transgenic biochemical and anatomical methods to determine: the anti-allodynicactions of intrinsic NPY (Aim 1); the effect of injury on the efficacy of NPY receptor stimulation (Aim 2); theeffect of NPY on the release of substance P (Aim 3A); and the effect of NPY on activity of spinal neurons thatexpress the NPY Y1 receptor (Aim 3B). Our long-term goal is to establish the therapeutic potential of NPYreceptor agonists for chronic pain.AIM #1 tests the hypothesis that intrinsic NPY reduces allodynia. To address the contribution ofendogenous NPY to chronic pain Aim #1 will utilize transgenic mice (NPYtet) that contain a doxycycline (Dox)-regulated cassette (tetracycline trans-activator tTA) at the promotor region of the npy locus. We describe dataindicating that inducible NPY depletion increases behavioral signs of tactile and cold allodynia in the sparednerve injury (SNI) model of neuropathic pain. These data lead us to determine the effect of conditional NPYknockdown on the induction maintenance and reinstatement of chronic pain. We predict that NPY depletionwill speed the development increase the intensity and extend the duration of the allodynia induced by nerveinjury or adjuvant-induced inflammation.AIM #2 tests the hypothesis that injury increases NPY receptor signaling in the dorsal horn. Todetermine whether injury increases NPY receptor-G protein coupling we will evaluate Y1- and Y2-agoniststimulatedGTP?S binding after inflammation nerve injury or sham surgery in NPYtet mice. Because receptorexpression levels must be taken into account when assessing the efficacy of NPY receptor stimulation we willalso measure Y1 and Y2 expression after inflammation nerve injury or sham surgery.AIM #3 will test the hypothesis that NPY inhibits spinal pronociceptive neurotransmission. Y1 receptorsdecorate presynaptic terminals in the dorsal horn. Based on our preliminary results we predict that intrathecalNPY will dose- and receptor-dependently reduce the injury-induced release of SP (using microdialysis andinjury-induced NK1 receptor internalization). Because Y1 receptors also label spinal neurons we will test forpostsynaptic actions of NPY. We will determine the effect of intrathecal NPY on SP-induced nociceptivebehavior and NK1 receptor internalization. Our preliminary data with the selective neurotoxin NPY-saporinsuggest that Y1-expressing cells in the dorsal horn facilitate pain transmission. We predict that the activity ofthis population of spinal neurons will be decreased by NPY administration and increased by NPY knockdown.


application_id: 7708382
project_number: 1R01CA150947-01
project_title: Mechanisms of Immune Modulation Mediated by Yeast-derived Particulate Beta-Glucan
administering_ic: NCI
award_notice_date: 2009-07-23
opportunity_number: RFA-AT-08-003
application_type: 1
activity_code: R01
ic: CA
serial_number: 150947
program_official: KIM, YOUNG S
project_start_date: 2009-09-28
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZAT1 SM (13)]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The use of -glucans in complementary and alternative medicine (CAM) has prevailed for centuries in traditional Asian medicine. However their clinical use against malignancies in Western medicine has experienced an oscillating success due to a lack of understanding in their exact mechanisms of action. We have previously demonstrated that soluble yeast -glucan of low molecular weight is capable of binding to the lectin site of complement receptor 3 (CR3 CD11b/CD18) and priming CR3+ effector cells for cytotoxicity of iC3b-opsonized tumor cells. The work presented here shows that particulate yeast -glucan has more unique features than soluble -glucan. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of action for particulate -glucan in tumor immunotherapy.   
Preliminary studies demonstrated that particulate -glucan not soluble -glucan stimulated macrophages and dendritic cells (DCs) for activation and proinflammatory cytokine production. Furthermore orally administered particulate -glucan stimulated DCs that captured apoptotic tumor cells for activation and maturation leading to the enhanced anti-tumor CD4 and CD8 T cell responses. Strikingly oral particulate -glucan treatment altered the tumor microenvironment toward Th1 response. Particulate -glucan was also shown to activate the complement system via an alternative pathway leading to C5a deposition on tumors. These preliminary data provide a strong basis for the current study.   
Aim 1 will dissect which signaling pathway(s) may be critical for particulate -glucan-mediated DC activation and cytokine release. Toll-like receptor pathway MyD-88- and TRIF-deficient mice CR3-deficient mice and dectin-1 pathway dectin-1- and CARD9-deficient mice will be used to address this issue. In addition T cell differentiation (Th1 Th2 and Th17) in the presence of particulate yeast -glucan stimulated DCs will be examined both in vitro and in vivo. Aim 2 will test the hypothesis that particulate -glucan modulates suppressive cells existing in the tumor microenvironment thereby promoting Th1 response. The function of myeloid-derived suppressive cells (MDSCs) dynamic interaction between regulatory T cells (Treg) and Th17 cells cross-talk between MDSCs and tumor-infiltrating macrophages will be examined. Lewis lung carcinoma transfected with surrogate antigen ovalbumin and tumor-associated antigen MUC1 will be used as the model systems to address those issues. Aim 3 will test the hypothesis that particulate -glucan stimulated complement activation may be partially contributed to the enhanced anti-tumor T cell responses. Furthermore the requirement for C3a and/or C5a and their receptors C3aR and C5aR as modulators of anti-tumor T cell responses will be determined. Further knowledge of the mechanisms involved in these effects of particulate -glucan will be of great value in the design of effective clinical applications.  
  
Public Health Relevance: This study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rational design of immunotherapeutic protocols usable in clinical trials.

project_terms:
Address;Adjuvant;Affinity;Anti-Infective Agents;Antibodies;Antigens;Apoptotic;Asians;Bacteria;Barley (Food);Binding (Molecular Function);Biological Models;Biological Process;Biological Response Modifiers;Bone Marrow;C3bi;CD4 Positive T Lymphocytes;CD8B1 gene;Cell Differentiation process;Cell Maturation;Cells;Clinical;Clinical Trials;Complement;Complement 3a;Complement 5a;Complement Activation;Complementary and alternative medicine;Data;Dendritic Cells;Dendritic cell activation;Deposition;Effector Cell;Frequencies (time pattern);Glucans;Glucose;Helper-Inducer T-Lymphocyte;Host Defense Mechanism;Human;ITGAM gene;Immune response;Immunity;Immunotherapeutic agent;Immunotherapy;In Vitro;Individual;Infection;Integrins;Interleukin-12;Knowledge;Lactosylceramides;Lectin;Lewis Lung Carcinoma;Ligands;Link;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Medicine;Modeling;Molecular Mechanisms of Action;Molecular Weight;Mucin-1 Staining Method;Mus;Myelogenous;Myeloid Cells;Oral;Ovalbumin;Particulate;Pathway interactions;Production;Protocols documentation;Reporting;Side;Signal Pathway;Site;Solubility;Structure;System;T-Lymphocyte;Testing;Toll-Like Receptor Pathway;Treatment Efficacy;Tumor Antigens;Vertebral column;Work;Xenograft procedure;Yeasts;activation product;base;beta-Glucans;clinical application;cytokine;cytotoxic;cytotoxicity;dectin 1;design;experience;fungus;immunoregulation;in vivo;interest;macrophage;microbial;neoplastic cell;polyglucosan;public health relevance;receptor;response;scavenger receptor;success;tool;tumor


application_id: 7707895
project_number: 1R21AG034279-01
project_title: Contribution of altered muscle hemodynamics to fatigability in older persons with
administering_ic: NIA
award_notice_date: 2009-09-11
opportunity_number: PA-08-162
application_type: 1
activity_code: R21
ic: AG
serial_number: 034279
program_official: ELDADAH, BASIL A
project_start_date: 2009-09-15
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1 CFS-D (01)]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: CROFFORD, LESLIE J
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  Fibromyalgia (FM) is a clinical state of widespread musculoskeletal pain with multiple tender points that is most common in postmenopausal women. Fatigue particularly post-exertional is an additional hallmark of the syndrome. FM likely has no single etiology and may have neuroendocrine neurologic immune and musculoskeletal components. Fatigue and fatigability also contribute directly to functional dependence and activity limitations that impact quality of life among the aged. Although associated with co-morbidities fatigue in the elderly is often not associated with an identified medical cause. The relationship among fatigue associated with FM fatigue associated with disease and exacerbation of fatigue symptoms with age are unexplored. The goal of this pilot study is to identify defects in muscle physiology of older FM patients as well as older healthy but fatigable individuals which may contribute to this symptom. Older normal healthy women and women who are healthy but prove most fatiguable during testing as well as older women diagnosed with FM will be studied. Aim 1 will test the hypothesis that decreased blood flow and reduced muscle oxygenation contribute directly to pain and post exercise fatigue. Using novel noninvasive near-infrared diffuse optical spectroscopies muscle blood flow and oxygen saturation will be quantified before during and after an acute bout of exercise. To identify mechanisms underlying reduced tissue oxygenation muscle microvasculature will be analyzed in Aim 2. Vascular density and endothelial function will be assessed in muscle biopsies by immunofluorescent detection of endothelial cell antigens and detection of endothelial alkaline phosphatase and non-invasively with the flow-mediated dilatation (FMD) test and optical probe. Aim 3 will test the hypothesis that the long term consequence of reduced muscle oxygenation may be compromised mitochondrial function. Assays of mitochondrial oxidative phosphorylation from muscle biopsies will be performed including respiration rates and complex I-IV activities. Aberrant accumulation of mitochondrial metabolites may alter muscle vasodilatory properties further reducing oxygen availability contributing to the pain and fatigue of FM as well as fatigue in the elderly.  PUBLIC HEALTH RELEVANCE: Fibromyalgia is increasingly common in postmenopausal women. As FM is commonly associated with pain fatigue sleep disturbances depression psychological and mood disorders and cognitive deficiencies individuals with FM may suffer from temporary to permanent debilitation. This project will explore the role of altered muscle physiology as a contributor to the pain and fatigue experienced by fibromyalgic patients as well as older healthy women experiencing fatigue.

project_terms:
Acute;Age;Alkaline Phosphatase;Antigens;Area;Behavioral;Biological Assay;Biomedical Engineering;Biopsy;Blood Vessels;Blood flow;Clinical;Cognitive;Complex;Defect;Dependence;Detection;Diagnosis;Diffuse;Dilatation - action;Disease;Elderly;Endothelial Cells;Etiology;Exercise;Exertion;Fatigue;Fibromyalgia;Foundations;Future;Gerontology;Goals;Grant;Immune;Individual;Interdisciplinary Study;Intervention;Mediating;Medical;Mitochondria;Mood Disorders;Morbidity - disease rate;Muscle;Muscle Fibers;Musculoskeletal;Musculoskeletal Pain;NIH Program Announcements;Neurologic;Neurosecretory Systems;Optics;Outcome;Oxidative Phosphorylation;Oxygen;Pain;Patients;Physicians;Physiological;Physiology;Pilot Projects;Postmenopause;Property;Quality of life;Research Personnel;Respiration;Role;Scientist;Sleep disturbances;Spectrum Analysis;Symptoms;Syndrome;Techniques;Testing;Woman;aged;base;clinically significant;combat fatigue;density;depression;experience;hemodynamics;novel;older women;psychologic;psychosocial;public health relevance;response;tissue oxygenation

public_health_relevance:
Project NarrativeFibromyalgia is increasingly common in postmenopausal women. As FM is commonly associated with painfatigue sleep disturbances depression psychological and mood disorders and cognitive deficienciesindividuals with FM may suffer from temporary to permanent debilitation. This project will explore the role ofaltered muscle physiology as a contributor to the pain and fatigue experienced by fibromyalgic patients as wellas older healthy women experiencing fatigue.


application_id: 7707250
project_number: 1R21CA140919-01
project_title: Targeted CSN5 inhibition in Pancreatic Cancer
administering_ic: NCI
award_notice_date: 2009-06-02
opportunity_number: PA-08-208
application_type: 1
activity_code: R21
ic: CA
serial_number: 140919
program_official: FORRY, SUZANNE L
project_start_date: 2009-06-02
project_end_date: 2010-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 1959966
contact_pi: ZUNDEL, WAYNE S
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Protein turnover in pancreatic tumors is much higher than in normal tissues due to both unchecked proliferation and ongoing adaptive pressures. Coincident with this normal controls on both protein synthesis and degradation are often found deregulated. Recently the development of small molecules that block proteosomal degradation have been found to be efficacious in a number of cancers but surprisingly not in pancreatic cancer. Perhaps the reason for this is the dismal half-life of these drugs/metabolites in patients thus limiting drug efficacy to predominantly hematological malignancies. Therefore inhibitors that possess better pharmacologic characteristics are needed. It is feared however that increased half-life of drugs targeting the 26S proteosome will have greater systemic toxicity in a variety of potentially sensitive organs. Therefore an ideal protein degradation antagonist would have good pharmacologic properties and would not target global protein degradation but instead would selectively target the degradation of proteins that are key for tumor growth or therapeutic resistance. Recently a large multi-subunit complex termed the COP9 Signalosome (CSN) that regulates cullin-dependent degradation of proteins has become of interest in tumor biology as cullins regulate multiple oncogenic pathways. Theoretically by therapeutically targeting such a "node" a large portion of the oncogenic network could be deregulated without many of the anticipated side effects generated by drugs that directly target the 26S proteosome. Recently we have developed multiple lead compounds against the catalytic portion (CSN5) of the COP9 Signalosome (CSN). Specifically targeting CSN5 genetically or pharmacologically results in deneddylation of cullins stabilization of their substrates cell cycle arrest and severely compromised clonogenic growth in pancreatic adenocarcinoma cells. The same treatment in normal cells results in delayed proliferation but virtually no changes in clonogenic potential suggesting that this is a viable therapeutic paradigm. Goal: We will further examine the anti-tumorigenic effects of CSN disruption using genetic and pharmacologic testing of CSN5 both in vitro and in murine models of human lung cancers. These experiments will serve as a basis for pre-clinical trials and optimization of further therapeutics. PUBLIC HEALTH RELEVANCE: The COP9 Signalosome (CSN) controls the stability and function of Cullin-dependent ubiquitin E3 ligases. These ligases in turn control the stability of proteins in multiple oncogenic pathways. Using structure-based modeling we have recently developed multiple lead CSN5 antagonists possessing specific activity toward the CSN and having significant effects on clonogenic growth. This proposal seeks to further characterize these inhibitors both in vitro and in vivo as a prelude to evaluating their efficacy in clinical trials.

project_terms:
26S proteasome;Adenocarcinoma Cell;Adverse effects;Affect;Biological Assay;Cancer cell line;Catalytic Domain;Cell Cycle Arrest;Cell Death Inhibition;Cells;Characteristics;Clinical Trials;Complex;Cullin Proteins;Cyclin D1;Development;Distant Metastasis;Dose;Drug Delivery Systems;Effectiveness;Epidermal Growth Factor Receptor;Fright;Genetic;Goals;Growth;Half-Life;Hematologic Neoplasms;Homology Modeling;Human;In Vitro;Inhibition of Apoptosis;Lead;Ligase;MADH4 gene;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Modeling;Mus;Normal Cell;Normal tissue morphology;Oncogenic;Organ;Pancreatic Adenocarcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Property;Protein Biosynthesis;Proteins;Proteolysis;Resistance;Specificity;Structure;TP53 gene;Testing;Therapeutic;Toxic effect;Transgenic Model;Tumor Biology;Tumor Pathology;Ubiquitin;base;cancer cell;drug efficacy;in vivo;inhibitor/antagonist;interest;mouse model;overexpression;pancreatic neoplasm;preclinical study;pressure;prevent;protein complex;protein degradation;protein expression;public health relevance;research study;response;small molecule;tumor;tumor growth;tumor initiation;tumorigenic;ubiquitin-protein ligase

public_health_relevance:
PROJECT NARRATIVEThe COP9 Signalosome (CSN) controls the stability and function of Cullin-dependentubiquitin E3 ligases. These ligases in turn control the stability of proteins in multipleoncogenic pathways. Using structure-based modeling we have recently developedmultiple lead CSN5 antagonists possessing specific activity toward the CSN and havingsignificant effects on clonogenic growth. This proposal seeks to further characterizethese inhibitors both in vitro and in vivo as a prelude to evaluating their efficacy in clinicaltrials.


application_id: 7706840
project_number: 1R21AI083528-01
project_title: Host defense against influenza virus in the lungs of neonatal mice
administering_ic: NIAID
award_notice_date: 2009-08-14
opportunity_number: RFA-AI-08-020
application_type: 1
activity_code: R21
ic: AI
serial_number: 083528
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2009-08-15
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZAI1 PTM-I (M2)]
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: Y
project_abstract:
DESCRIPTION (provided by applicant):   
  
Infants are particularly susceptible to respiratory infections which have been attributed to an immature and naive immune system that is characterized by suboptimal antigen presentation and a T helper cell bias toward Th2-type cytokines. However little is known about how the post-natally developing lungs contribute to susceptibility to pulmonary infection. Immune homeostasis in the lungs is controlled by a number of factors including epithelial cell production of IL-10 and TGFB and expression of CD200/CD200R on epithelial cells and alveolar macrophages respectively. Our data shows elevated levels of TGFB in the lungs of infant mice over the first 3 weeks of life. Moreover we have previously reported that IL-10 mRNA is constitutively expressed in neonatal lungs. We speculate that these anti-inflammatory cytokines increase the threshold of activation of immune cells in the lungs resulting dampening of inflammation in neonatal lungs. We found that unlike adults neonatal mice develop interstitial pneumonia in response to influenza virus infection which corresponds to differential expression of chemokines compared to adult mice. The goal of this project is to determine mechanisms that contribute to the differences in T cell migration that may result in the greater susceptibility to virus in neonatal mice. We will address the following hypothesis: The neonatal lung environment alters T cell responses to infection leading to interstitial pneumonia and a worse outcome than in adults. Two aims are proposed: 1) To determine whether neonatal T cells and/or the neonatal lung environment are responsible for development of interstitial pneumonia in response to influenza virus; and 2) To determine the mechanisms responsible for the migration of T cells into the neonatal interstitial spaces but not alveolar spaces. We have chosen to use influenza virus as a models system since influenza virus infection causes more morbidity and mortality than any other infection preventable by vaccination and hospitalization rates among infants with influenza virus rival those of the elderly. Understanding the underlying mucosal immune response to influenza virus in infants is an important step in formulating new treatment strategies for infants. Infants that die from influenza virus have been shown to develop interstitial pneumonia with little infiltration of T cells into the alveolar space. The goal of this project is to understand the processes in post-natally developing lungs that leads to development of interstitial pneumonia in response to infection. Understanding the nature of the failure of the neonatal immune system to control influenza virus is important for generation of new vaccine and treatment strategies.

project_terms:
4 year old;Address;Adoptive Transfer;Adult;Age-Years;Alveolar;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antigen Presentation;Antigen-Presenting Cells;Antigens;Biological Models;CD4 Positive T Lymphocytes;Cell Adhesion Molecules;Cell physiology;Cessation of life;Child;Data;Development;Elderly;Environment;Epigenetic Process;Epithelial Cells;Equilibrium;Failure (biologic function);Generations;Goals;Health;Helper-Inducer T-Lymphocyte;Homeostasis;Hospitalization;Host Defense;Human;Immune;Immune Cell Activation;Immune response;Immune system;Immunohistochemistry;Infant;Infection;Infectious Agent;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Influenza;Influenza virus vaccine;Interleukin-10;Interstitial Pneumonia;Kinetics;Knock-out;Life;Lung;Measures;Messenger RNA;Modification;Morbidity - disease rate;Mortality Vital Statistics;Mucosal Immune Responses;Mus;Nature;Neonatal;Outcome;Predisposition;Process;Production;Protein Array Analysis;Recommendation;Regulation;Reporting;Respiratory Tract Infections;Risk;Signal Transduction;Site;Sterility;T-Lymphocyte;TGFB1 gene;Th1 Cells;Time;Transgenic Mice;Vaccinated;Vaccination;Virus;Virus Diseases;base;cell motility;chemokine;cytokine;influenzavirus;interstitial;lung development;mature animal;migration;neonate;neutralizing antibody;novel vaccines;response;treatment strategy

public_health_relevance:
Infants that die from influenza virus have been shown to develop interstitial pneumonia with littleinfiltration of T cells into the alveolar space. The goal of this project is to understand theprocesses in post-natally developing lungs that leads to development of interstitial pneumonia inresponse to infection. Understanding the nature of the failure of the neonatal immune system tocontrol influenza virus is important for generation of new vaccine and treatment strategies.


application_id: 7701289
project_number: 1R21AT005235-01
project_title: Inhibition of Cholesterol Synthesis by Green and Black Tea
administering_ic: NCCIH
award_notice_date: 2009-06-30
opportunity_number: PA-08-185
application_type: 1
activity_code: R21
ic: AT
serial_number: 005235
program_official: WEBER, WENDY J
project_start_date: 2009-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZAT1 PK (03)]
contact_pi_person_id: 1859126
contact_pi: PORTER, TODD D
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): "Functional foods" herbal and other botanical products and nutritional supplements have gained great popularity among the public as safe and effective means to treat chronic and acute diseases. As hypercholesterolemia is a widespread problem for which there is great interest in alternative medicines the demonstrated ability of black tea to decrease serum cholesterol levels is of particular interest. Similarly green tea has been shown to be hypocholesterolemic in animal studies. The mechanism by which these safe and widely consumed beverages act to lower cholesterol has not yet been elucidated. Although most current evidence indicates that tea polyphenols reduce the absorption of dietary and biliary cholesterol our recent studies with hepatoma cells indicate that green and black tea extracts also decrease cholesterol synthesis via both direct enzyme inhibition and by suppression of HMG-CoA reductase activity. Knowledge of how tea consumption lowers cholesterol levels is essential to understanding the benefits and potential adverse effects of its intake particularly in combination with prescription pharmaceuticals including the statin drugs which similarly inhibit cholesterol synthesis at HMG-CoA reductase. As our current studies indicate that tea extracts cause the activation of AMP-kinase to suppress HMG-CoA reductase activity the objectives of this application are to determine if tea extracts directly activate AMP-kinase or if upstream signaling pathways are involved; and to determine if tea suppresses cholesterol synthesis in vivo. These studies should delineate the intracellular mechanism by which tea compounds suppress cholesterol synthesis and elucidate the extent to which suppression of cholesterol synthesis contributes to the hypocholesterolemic effect of green and black tea. These studies should establish a solid mechanistic understanding of how tea decreases cholesterol synthesis and lowers blood cholesterol levels and given the developing recognition of the role of AMP-kinase in diabetes may also open new pathways to the management of diabetes and "metabolic syndrome".

project_terms:
5'-AMP-activated protein kinase;Acute Disease;Adverse effects;Alternative Medicine;Animals;Antibodies;Beverages;Biliary;Biological Assay;Black Tea;Blood;Botanicals;Cells;Cholesterol;Cholesterol Synthesis Inhibition;Chronic;Consumption;Cyclic AMP-Dependent Protein Kinases;Deacetylase;Diabetes Mellitus;Dietary Supplements;Dose;Enzyme Activation;Enzyme Inhibition;Enzymes;Green tea (dietary);Hepatic;Hydroxymethylglutaryl-CoA reductase;Immunoblotting;Intake;Knowledge;LDL Cholesterol Lipoproteins;Lead;Liver;Measures;Mediating;Metabolic syndrome;Monitor;Mus;Oral;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Phosphorylation;Phosphotransferases;Preparation;Protein Kinase;Research;Resveratrol;Role;STK11 gene;Serum;Signal Pathway;Small Interfering RNA;Solid;Sterols;Tea;Water;absorption;adenylate kinase;diabetes management;functional food;hepatoma cell;hypercholesterolemia;in vivo;interest;knock-down;man;polyphenol;upstream kinase

public_health_relevance:
PROJECT NARRATIVE
Inhibition of Cholesterol Synthesis by Green and Black Tea
"Functional foods" herbal and other botanical products and nutritional supplements have gained great
popularity among the public as safe and effective means to treat chronic and acute diseases. As
hypercholesterolemia is a widespread problem for which there is great interest in alternative medicines the
demonstrated ability of tea to decrease serum cholesterol levels is of particular interest. Preliminary studies
demonstrate that tea decreases cholesterol synthesis by suppressing the activity of a key enzyme in the
biosynthetic pathway; the proposed studies will elucidate the mechanism by which tea effects this suppression
and will determine the extent to which tea suppresses cholesterol synthesis in whole animals after oral
consumption.


application_id: 7700946
project_number: 1R15NS066245-01
project_title: Phenotype analysis of tyrosine hydroxylase neurons in rat and human cortices
administering_ic: NINDS
award_notice_date: 2009-05-15
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: NS
serial_number: 066245
program_official: SIEBER, BETH-ANNE
project_start_date: 2009-05-15
project_end_date: 2012-09-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 1905314
contact_pi: ASMUS, STEPHEN E
other_pis: Not Applicable
congressional_district: 01
department: BIOCHEMISTRY
primary_duns: 077867604
primary_uei: DDJFJ6UEBEF5
duns_number: 077867604
uei: DDJFJ6UEBEF5
fips: US
organization_id: 1295801
organization_name: CENTRE COLLEGE
organization_city: DANVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 404221309
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Understanding the phenotypic diversity of interneurons in the cerebral cortex is critical because interneuron dysfunction has been implicated in neurological disorders. Numerous subgroups of cortical interneurons have been identified. The current proposal extends from my first AREA grant and focuses on an enigmatic subset of interneurons that expresses tyrosine hydroxylase (TH) the rate-limiting catecholaminergic enzyme but no subsequent enzymes in this family. Little is known about cortical TH neurons despite the fact that they are lost in Parkinson's disease and dementia. During postnatal rat development the number of cortical TH-immunoreactive (IR) neurons sharply increases and then decreases. This reduction is not due to cell death but due to a decline in the detectable level of TH in these cells as they acquire their mature phenotype. A subset of these cells colocalizes with the GABA synthetic enzyme GAD and with calretinin present in one of three distinct interneuron subpopulations. The proposed studies address important unresolved questions. First I will immunohistochemically characterize the neurotransmitter phenotype of cortical TH-IR neurons in developing and adult rats. The activity of TH will be determined by examining the phosphorylation of TH at Ser19 31 and 40 where phosphorylation regulates activity. The developmental coexpression of TH with GABA vasoactive intestinal peptide (VIP) and the cholinergic enzyme choline acetyltransferase (ChAT) will be assessed. Second I will characterize the neurochemical phenotype of TH-IR neurons in the adult human cortex. Half of these cells reportedly are GABAergic but few other characteristics have been examined. The activity of TH will be addressed by examining its phosphorylation in human cortical neurons. The coexpression of TH with GABA VIP and ChAT and with the calcium-binding proteins calretinin calbindin and parvalbumin will be assessed. The neurochemical characterization of cortical TH cells in rats and humans will increase our understanding of the function of these cells across species. The proposed studies will provide opportunities for undergraduates at a liberal arts college to engage in clinically-relevant biomedical research encouraging their pursuit of postgraduate training in the biomedical sciences. PUBLIC HEALTH RELEVANCE: Interneurons of the cerebral cortex play a key role in cognitive function and interneuron abnormalities have been implicated in neurological disorders. The proposed studies explore the chemical properties of interneurons that express tyrosine hydroxylase an enzyme that produces the dopamine family of neurotransmitters in the rat and human brain with the goal of better understanding their function and role in disease.

project_terms:
Address;Adult;Arts;Biomedical Research;Brain;Calcium-Binding Proteins;Cell Death;Cell physiology;Cells;Cerebral cortex;Characteristics;Choline O-Acetyltransferase;Development;Disease;Dopamine;Enzymes;Epilepsy;Family;Functional disorder;Funding;Goals;Grant;Human;Interneurons;Label;Metabolism;Morphology;Neuroanatomy;Neurons;Neuropeptides;Neurotransmitters;Parkinson's Dementia;Parvalbumins;Phenotype;Phosphorylation;Physiology;Play;Property;Rattus;Regional Blood Flow;Research Project Grants;Role;Schizophrenia;Science;Signaling Molecule;Students;Subgroup;Tissues;Training;Tyrosine 3-Monooxygenase;Universities;Vasoactive Intestinal Peptide;Work;base;calbindin;calretinin;chemical property;cholinergic;clinically relevant;cognitive function;college;disease phenotype;enzyme activity;experience;gamma-Aminobutyric Acid;information processing;nervous system disorder;neurochemistry;postnatal;public health relevance;success;synthetic enzyme

public_health_relevance:
Interneurons of the cerebral cortex play a key role in cognitive function and interneuronabnormalities have been implicated in neurological disorders. The proposed studiesexplore the chemical properties of interneurons that express tyrosine hydroxylase anenzyme that produces the dopamine family of neurotransmitters in the rat and humanbrain with the goal of better understanding their function and role in disease.


application_id: 7700660
project_number: 5P01HL086670-02
project_title: Administrative Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9003
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Accounting;Adherence (attribute);Budgets;Chemicals;Ensure;Guidelines;Human Resources;Hygiene;Internet;Location;Purpose;Radioactivity;Reports Progress;Resources;Services;Site;Travel;animal care;human subject;programs


application_id: 7700659
project_number: 5P01HL086670-02
project_title: Core C
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8817787
contact_pi: RATERI, DEBRA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Adenoviruses;Bone Marrow Transplantation;Breeding;Caring;Clip;Condition;DNA;Development;Diet;Equipment;Generations;Genotype;Harvest;Hepatocyte;Housing;Infusion procedures;Kinetics;Ligands;Lipoproteins;Location;Macrophages Peritoneal;Maintenance;Methodology;Mus;Plasma;Preparation;Primary Cell Cultures;Procedures;Purpose;Quality Control;Radiolabeled;Reagent;Resources;Services;Standardization;Tail;Tissue Sample;Training;base;macrophage;programs;radiotracer


application_id: 7700658
project_number: 5P01HL086670-02
project_title: Analytical and Preparative Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
2-Mercaptoethanol;Acrylamide;Acrylamides;Acute;Acute-Phase Reaction;Adenovirus Vector;Adenoviruses;Aliquot;Ampholine;Ampholyte Mixtures;Animals;Antibodies;Apolipoproteins;Apolipoproteins A;Argon;Autoradiography;Binding (Molecular Function);Biological Assay;Blood;Blotting Western;Bolus Infusion;Buffers;CETP gene;CETP protein human;COS-7 Cell;Canada;Cardiovascular system;Cells;Cellulose;Centrifugation;Centrifugation Density Gradient;Chemicals;Cholesterol;Chromatography;Chromatography Gel;Collaborations;Collection;Condition;Coupled;Culture Media;Cultured Cells;Cyanogen Bromide;Cytolysis;Diagnostic;Dialysis procedure;Drug or chemical Tissue Distribution;Dyes;Edetic Acid;Exclusion;Fat emulsion;Fatty Acids Nonesterified;Fluorescence;Fluorescent Dyes;Fractionation;Freeze Drying;Freezing;Gases;Gel;Generations;Genes;Geron H14 stem cell line;Glass;Hand;Helper Viruses;High Density Lipoproteins;Human;Hydrolysis;Imagery;In Vitro;Incubated;Individual;Injection of therapeutic agent;Instruction;Iodination reaction;Iodine;Ion-Exchange Chromatography Procedure;Isoelectric Focusing;Kentucky;Label;Ligands;Lipids;Lipoproteins;London;Low-Density Lipoproteins;Lysophospholipids;Manufacturer Name;Mediating;Methods;Methylene Chloride;Modification;Mus;Natural regeneration;Nitrogen;Phase;Phospholipase;Phospholipids;Physical Dialysis;Plaque Assay;Plasma;Preparation;Pressure- physical agent;Procedures;Process;Production;Protein Isoforms;Proteins;Purpose;Pyroxylin;Quality Control;Radioactivity;Radioisotopes;Radiolabeled;Range;Reaction;Recombinant Proteins;Recombinants;Recovery;Research;Resins Plant;Resources;Sampling;Sepharose;Serum;Services;Solid;Speed (motion);Standardization;Sterility;Structure of jugular vein;Superose 12;Tail;Techniques;Temperature;Thick;Time;Triglycerides;Tube;Tyramine;Ultracentrifugation;Universities;Urea;Veins;Very low density lipoprotein;Vial device;Viral;Virion;Virus;Volunteers Human;Week;Wisconsin H14 stem cell line;cholesteryl oleyl ether;citrate carrier;day;defective adenoviral vector;density;evaporation;experience;fast protein liquid chromatography;gel electrophoresis;helper-dependent adenoviral vector;immunoaffinity chromatography;in vivo;interest;iron oxide;mouse model;particle;polyacrylamide gels;programs;radiotracer;reconstitution;research study;scale up;size;sodium sulfate;uptake;vector


application_id: 7700657
project_number: 5P01HL086670-02
project_title: Macrophage Cholesterol Efflux During Inflammation
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
ATP-Binding Cassette Transporters;Acute;Acute-Phase Proteins;Acute-Phase Reaction;Affect;Antiatherogenic;Apolipoprotein E;Apolipoproteins;Apolipoproteins A;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Cell membrane;Cells;Charge;Cholesterol;Cholesterol Ester Transfer Proteins;Data;Development;Equilibrium;Excision;Generations;Helix (Snails);Helix of ear;High Density Lipoproteins;Human;Immunohistochemistry;In Vitro;Inflammation;Inflammatory;Laboratories;Lead;Lipids;Lipoproteins;Mediating;Mediator of activation protein;Modification;Molecular;Mus;Numbers;Pathogenesis;Phase;Phospholipase A2;Phospholipids;Play;Protein Isoforms;Proteins;Rate;Research Personnel;Role;Serum;Serum amyloid A protein;Structure;System;Testing;atherogenesis;extracellular;gain of function;in vivo;loss of function;macrophage;member;particle;prevent;programs;response;reverse cholesterol transport;size;uptake


application_id: 7700656
project_number: 5P01HL086670-02
project_title: Inflammation HDL and class B Scavenger Rectors
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Acute;Acute-Phase Proteins;Acute-Phase Reaction;Affinity;Apolipoproteins;Arterial Fatty Streak;Atherosclerosis;CD36 gene;Cardiovascular Diseases;Catabolism;Cells;Characteristics;Cholesterol;Chronic;Class;Exhibits;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Inflammation;Inflammatory;Inflammatory Response;Lipids;Lipopolysaccharides;Liver;Mediating;Mediator of activation protein;Metabolism;Modification;Mortality Vital Statistics;Pathway interactions;Peripheral;Phase;Phospholipase;Play;Process;Protein Processing Post-Translational;Proteins;Recycling;Research Personnel;Risk;Role;SR-B proteins;Serum amyloid A protein;Structure;Testing;Western World;macrophage;programs;protective effect;receptor;reverse cholesterol transport;therapeutic target;trafficking;uptake


application_id: 7700655
project_number: 5P01HL086670-02
project_title: HDL Structure and Metabolism During Inflammation
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Acute;Adenovirus Vector;Affect;Animal Model;Apolipoproteins;Apolipoproteins A;Atherosclerosis;Binding (Molecular Function);Blood Vessels;Catabolism;Charge;Cholesterol;Cholesterol Ester Transfer Proteins;Chronic;Deposition;Disease;Equilibrium;Generations;Hepatic;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Human;Hydrolysis;Inflammation;Inflammatory;Label;Lipase;Lipids;Lipoproteins;Metabolic;Metabolism;Mice Transgenic;Movement;Myocardial Infarction;Nature;PLA2G2A protein human;Patients;Phase;Phospholipase;Phospholipids;Plasma;Process;Rate;Reaction;Research Personnel;Respiratory Tract Infections;Rheumatoid Arthritis;Serum amyloid A protein;Site;Structure;Surface;Testing;Time;Tissues;Validation;base;cytokine;hepatic lipase;in vivo;metabolic abnormality assessment;particle;programs;size;stroke;uptake;urinary


application_id: 7699623
project_number: 1R01CA140991-01
project_title: Targeting Glucose Metabolism in Cancer
administering_ic: NCI
award_notice_date: 2009-07-09
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 140991
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
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_terms:
6-Phosphofructokinase;A549;Actins;Adenocarcinoma Cell;Age-Months;Anchorage-Independent Growth;Apoptosis;Attenuated;Basement membrane;Binding (Molecular Function);Brain;Breast;Carbon;Cell Fractionation;Cells;Chickens;Citric Acid Cycle;Colon;Cytoplasm;Data;Development;Enzymes;Epithelial Cells;Exons;Family;Freezing;Fructose;Gel;Genes;Genomics;Genus Cola;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Heart;Human;Hypoxia;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;In Vitro;Investigation;Isoenzymes;Knockout Mice;Label;Lactic acid;Lamins;Large T Antigen;Liver;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Measures;Messenger RNA;Metabolic;Metabolism;Mitochondria;Modeling;Mortality Vital Statistics;Mus;Mutation;NADH;Normal tissue morphology;Nude Mice;Oncogenic;Open Reading Frames;Organ;Ovary;Oxygen;Oxygen Consumption;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Placenta;Positron-Emission Tomography;Production;Promotor (Genetics);Protein p53;Proteins;Regulation;Relative (related person);Reporting;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Role;Screening procedure;Shunt Device;Site;Skeletal muscle structure;Small Interfering RNA;Source;Specimen;Subfamily lentivirinae;TP53 gene;Tamoxifen;Telomerase;Testing;Testis;Tissues;Transgenes;Tumor Tissue;Vascularization;Western Blotting;base;cancer cell;cancer type;cell transformation;cellular transduction;design;glucose metabolism;glucose uptake;in vivo;inhibitor/antagonist;mRNA Expression;neoplastic;neoplastic cell;neurotensin mimic 1;novel;overexpression;protein expression;public health relevance;recombinase;small hairpin RNA;small molecule;tumor;tumor growth;vector


application_id: 7699013
project_number: 1R01HL096914-01
project_title: Role of TRPV1 in Airway Hypersensitivity Induced by Inflammation
administering_ic: NHLBI
award_notice_date: 2009-08-31
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 096914
program_official: NOEL, PATRICIA
project_start_date: 2009-09-01
project_end_date: 2011-08-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Airway hypersensitivity characterized by exaggerated sensory and reflexogenic responses to inhaled irritants is a prominent pathophysiological feature of various airway inflammatory diseases (e.g. asthma bronchitis etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and more importantly induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1 a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation.   
  
PUBLIC HEALTH RELEVANCE: In airway inflammatory diseases such as asthma and bronchitis the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel namely TRPV1 plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.

project_terms:
Acute;Afferent Neurons;Allergens;Allergic;Animal Model;Asthma;Breathing;Bronchitis;Bronchoconstriction;C Fiber;Capsaicin;Cations;Chronic;Coughing;Critiques;Development;Disease;Dyspnea;Exhibits;Fever;Human;Hypersensitivity;Inflammation;Inflammatory;Investigation;Ion Channel;Irritants;Lung;Mediating;Mediator of activation protein;Neurons;Ovalbumin;Pathogenesis;Patients;Physiological;Play;Rattus norvegicus;Reaction;Reporting;Research;Research Project Grants;Research Proposals;Respiratory System;Respiratory tract structure;Role;Sensory;Study Section;Symptoms;TRPV channel;Temperature;Testing;Therapeutic;Transducers;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Vanilloid;afferent nerve;airway inflammation;allergic airway inflammation;cytokine;design;insight;irritation;novel;public health relevance;receptor;research study;response;selective expression;sensor

public_health_relevance:
Project Narrative In airway inflammatory diseases such as asthma and bronchitis the respiratorytract becomes overly sensitive to inhaled irritants. This research proposal is designed totest our hypothesis that a specific ion channel namely TRPV1 plays a major role in theexceedingly high excitability of airway sensory nerves caused by allergic inflammation.The results obtained from these studies should bring a new insight into the pathogenesisand therapeutic strategy for alleviating the airway hypersensitivity.


application_id: 7698498
project_number: N01PC54403-13-0-4
project_title: RRSS #10 - Patterns of Care for Diagnosis Year 2007
administering_ic: NCI
project_start_date: 2005-08-01
project_end_date: 2010-07-31
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The objectives of the Patterns of Care Study are to: 1) describe the use of adjuvant therapy which will be verified with the treating physician; 2) characterize the practice patterns in different communities; 3) describe more completely the use of surgery as treatment; 4) compare the patterns of treatment (surgery radiation therapy chemotherapy hormonal therapy) over time and by age and race/ethnicity; 5) describe the effect of co-morbid conditions on treatment and 6) describe treatment by hospital characteristics (i.e. profit vs. not for profit teaching vs. non-teaching bed size etc.) in different geographic areas of the United States. Patterns of Care Studies are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a)(2)(C) adopted November 4 1988) to the National Cancer Institute to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To select the cancers sites the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This year's Pattern's of Care (POC) Study will investigate state-of-the-art therapies for small cell lung cancer acute myeloid leukemia multiple myeloma and hepatocellular carcinoma.


application_id: 7693779
project_number: 5R01MH083621-02
project_title: A Brief Clinic-Based HIV Prevention Program for African American Teen Males
administering_ic: NIMH
award_notice_date: 2009-05-08
opportunity_number: PAR-07-379
application_type: 5
activity_code: R01
ic: MH
serial_number: 083621
program_official: KAMATH, SUSANNAH M A
project_start_date: 2008-09-30
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1-RPHB-K(50)R]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
20 year old;Acquired Immunodeficiency Syndrome;African American;Age-Years;Attention;Biological Assay;Brothers;Caring;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Emergency Situation;Enrollment;Female;Frequencies (time pattern);Funding;Future;Glare;Goals;Gonorrhea;HIV;Health;Health Educators;Hispanics;Incidence;Infection;Instruction;Intervention;Intervention Trial;Kentucky;Laboratories;Life;Low income;Medical Records;Methods;Modeling;Neisseria gonorrhoeae;Newly Diagnosed;Nucleic Acids;Perception;Population;Prevention program;Process;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Resources;Risk;Science;Services;Sex Behavior;Sexual Partners;Specimen;Techniques;Teenagers;Testing;Time;Translating;Translational Research;Translations;Treatment Efficacy;Trichomonas Infections;Trichomonas vaginalis;Uncertainty;United States;Upper arm;Urine;Vagina;Woman;Work;avoid sex;base;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;experience;flexibility;follow up assessment;follow-up;high risk men;improved;innovation;intervention effect;intervention program;male;man;medical specialties;men;neglect;post intervention;prevent;programs;public health medicine (field);public health relevance;research to practice;response;safer sex;sex;sex risk;theories;therapy design;urban area


application_id: 7692946
project_number: 5R01CA139843-02
project_title: MbSOD in chemotherapeutic-Induced Cardiac Injury
administering_ic: NCI
award_notice_date: 2009-07-10
application_type: 5
activity_code: R01
ic: CA
serial_number: 139843
program_official: SONG, MIN-KYUNG H
project_start_date: 2008-09-25
project_end_date: 2013-07-31
study_section: ZCA1-RPRB-O(J1)
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: 2009-08-01
project_terms:
ABCC1 gene;Acute;Adriamycin PFS;Animals;Anthracyclines;Antibodies;Antioxidants;Apoptosis;Biochemical;Biological Assay;Brain;Cancer Patient;Cardiac;Cardiac Myocytes;Cell Death;Cell Fractionation;Cessation of life;Chimeric Proteins;Chronic;Confocal Microscopy;Coupled;Data;Dose-Limiting;Drug Kinetics;Echocardiography;Enzymes;Gene Targeting;Generations;Genes;Genetic Transcription;Goals;Heart;Heart Diseases;Immunoprecipitation;Injury;Intervention;Kinetics;Knock-out;Knockout Mice;Lead;Link;Living Wills;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Messenger RNA;Methods;Mitochondria;Modeling;Morphology;Mus;Nuclear;Oxidation-Reduction;Oxidative Stress;P-Glycoproteins;Pathway interactions;Plasma;Probability;Production;Proteins;Proteomics;Protocols documentation;Quality of life;Reactive Oxygen Species;Role;Signal Transduction;Source;Superoxide Dismutase;Superoxides;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Translations;Treatment Efficacy;Treatment Protocols;Treatment-Related Cancer;Tumor Necrosis Factor-alpha;Wild Type Mouse;adduct;base;cancer therapy;chromatin immunoprecipitation;clinical application;cytokine;improved;in vivo;insight;mimetics;morphometry;novel;overexpression;treatment effect;tumor


application_id: 7692735
project_number: 1R01HL096589-01
project_title: Role of Serum Amyloid A in Atheroscierosis
administering_ic: NHLBI
award_notice_date: 2009-08-31
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 096589
program_official: SRINIVAS, POTHUR R
project_start_date: 2009-09-01
project_end_date: 2011-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Cardiovascular disease is the leading cause of death indeveloped countries. Individuals with obesity metabolic syndrome and/or diabetes are at markedlyincreased risk of atherosclerotic cardiovascular disease although the underlying mechanisms are not fullyunderstood. The retention of atherogenic lipoproteins within the subendothelial space of the arterial wall bytheir interactions with vascular proteoglycans is thought to be a key step in the initiation of atherosclerosisas outlined in the Response to Retention Hypothesis. Obesity the metabolic syndrome and diabetes allare associated with increased levels of inflammatory markers including serum amyloid A (SAA) and SAAlevels are predictive of cardiovascular disease in humans and in animal models. The central hypothesis ofthis grant is that SAA is pro-atherogenic. This hypothesis is based on several key observations: (a) SAA ispresent within atherosclerotic lesions in close association to apolipoproteins and proteoglycans; (b) Werecently demonstrated that SAA alters vascular proteoglycan synthesis in a pro-atherogenic manner; (c)SAA is an apolipoprotein that is capable of binding to proteoglycans and thus may facilitate the retention oflipoproteins on which it is carried; (d) In preliminary studies we demonstrate accelerated atherosclerosis inmice in which SAA is over-expressed. Thus SAA may in fact be a mediator of atherosclerosis by leading toincreased retention of atherogenic lipoproteins by vascular proteoglycans. We will test this hypothesis byevaluating the effect of SAA over-expression on vascular proteoglycan synthesis lipoprotein retention andatherosclerosis development using in vivo methodology. Given the increased SAA levels observed inobesity metabolic syndrome and diabetes we propose that SAA may be a mechanism contributing to theincreased cardiovascular disease in these conditions.Program Director/Principal Investigator (Last First Middle): Tannock Lisa R.

project_terms:
Adenoviruses;Affect;Animal Model;Animals;Apolipoprotein E;Apolipoproteins;Arterial Fatty Streak;Atherosclerosis;Backcrossings;Beer;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Cause of Death;Characteristics;Cholesterol;Data;Developed Countries;Developing Countries;Development;Diabetes Mellitus;Diet;Funding;Goals;Grant;Human;Immunocompetent;Immunodeficient Mouse;Individual;Injection of therapeutic agent;Knockout Mice;Laboratories;Lead;Length;Lipids;Lipoproteins;Measures;Mediating;Mediator of activation protein;Medical;Metabolic syndrome;Methodology;Modeling;Mus;Obesity;Parents;Personal Communication;Plasma;Principal Investigator;Property;Proteoglycan;Risk;Role;Saline;Serum amyloid A protein;Testing;Time;TimeLine;Transgenic Mice;Up-Regulation (Physiology);Viral;Virus;adenoviral-mediated;base;biglycan;feeding;in vivo;inflammatory marker;parent grant;programs;research study;response;trend

public_health_relevance:
Obesity metabolic syndrome and diabetes are all associatedwith high rates of cardiovascular disease and are characterized by modestly but chronically elevated levelsof inflammatory markers including SAA. However it is not currently known if high levels of SAA causeatherosclerosis or merely indicate the amount of atherosclerosis already present. The goal of this proposalis to determine if elevated SAA has a role in causing atherosclerosis which could lead to the identificationof SAA as a new target for medical therapy to decrease atherosclerosis and cardiovascular disease


application_id: 7692308
project_number: 5R01NS061933-02
project_title: A specific microRNA (Mir-107) is a potential therapeutic target in Alzheimer's di
administering_ic: NINDS
award_notice_date: 2009-02-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 061933
program_official: SIEBER, BETH-ANNE
project_start_date: 2008-09-30
project_end_date: 2012-02-28
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Abstract MicroRNAs (miRNAs) are recently-discovered small regulatory RNAs that play fundamental roles in neurobiology. Preliminary results indicate that decreased expression of a particular miRNA miR-107 may contribute to Alzheimer's disease (AD) pathogenesis through a metabolic pathway. These are the first published data pertaining to miRNAs in a specific pathway that may contribute to AD. We will test a specific strategy to target this pathway for AD therapy. Hypothesis #1:  MiR-107 expression is decreased very early in AD which increases BACE1 expression and hence increases the amount of neurotoxic Abeta peptides in AD patients' brains. Hypothesis #2:  Bezafibrate treatment decreases AD-type pathology by increasing levels of miR-107. Specific Aim #1:  Characterize fully the regulation of BACE1 by miRNAs. Sub-Aim a. A novel technique will test directly whether BACE1 mRNA is a miRNA target. This biochemical approach involves co- immunoprecipitation using our monoclonal anti-Argonaute antibody. Sub-Aim b. Tissue culture studies will be performed to evaluate exactly which parts of the BACE1 mRNA 3'UTR constitute miRNA targets. Sub-Aim c. `Knock-in' and `knock-down' techniques will be used to alter miR-107 levels specifically in human cultured cells to determine the effects of miR-107 expression changes on the levels of BACE1 protein C99 polypeptide and A2 peptide. Experiments will be performed initially on H4 and SH-SY5Y cells. Specific Aim #2:  Characterize the impact of miR-107 on glucose metabolism and correlate the expression of miR-107 and other miRNAs with AD pathology in situ Sub-Aim a. Tissue culture studies will be performed to assess how pharmacological treatments that alter metabolism affect miR-107 expression and to evaluate how cellular changes in miR-107 influence the levels of specific metabolic intermediaries. Sub-Aim b. Human brain in situ hybridization will be used to understand how miR-107 expression relates to pathological hallmarks of AD and non-AD dementia. Specific Aim #3:  Evaluate bezafibrate for increasing miR-107 levels and decreasing BACE1 protein and A2 peptide(s) formation in vitro and in vivo. Bezafibrate is an orally-administered well-tolerated medication. Sub-Aim a. Preliminary results in cultured cells demonstrated that bezafibrate causes increased miR-107 expression and also induced down-regulation of BACE1 protein. The specific mechanism of bezafibrate action will be characterized using experiments in which the levels of miR-107 are manipulated. Sub-Aim b. Bezafibrate will be administered to mice - APPNLh/NLh x PS1P264L/P264L humanized APP knock-in mutants - that are an excellent model of AD-type amyloidogenesis (1) to demonstrate in vivo the efficacy of bezafibrate in modulating miR-107 BACE1 A2 levels and AD-type neuropathology. PUBLIC HEALTH RELEVANCE:  MicroRNAs are recently-discovered molecules that serve fundamental functions in the human brain. This research demonstrates for the first time that a particular microRNA may play an important role in Alzheimer's disease. A research program is proposed which exploits this new discovery in order to develop and evaluate a novel therapy for patients at risk for Alzheimer's disease.

project_terms:
3' Untranslated Regions;Affect;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Alzheimer's disease risk;Amyloid beta-Protein;Antibodies;Bezafibrate;Biochemical;Biological Assay;Brain;Cells;Clinical Trials;Co-Immunoprecipitations;Cultured Cells;Data;Dementia;Development;Down-Regulation;Glucose;Human;In Situ;In Situ Hybridization;In Vitro;Knock-in Mouse;Lipids;MK-886;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;MicroRNAs;Mus;Neurobiology;Neuroblastoma;Pathogenesis;Pathologic Processes;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacological Treatment;Play;Proteins;Publishing;Regulation;Research;Research Personnel;Role;Stimulus;Techniques;Testing;Time;Translations;abstracting;amyloidogenesis;base;beta-site APP cleaving enzyme 1;brain tissue;glucose metabolism;in vivo;knock-down;mutant;neuropathology;neurotoxic;novel;polypeptide;programs;relating to nervous system;research study;therapeutic target;tissue culture

public_health_relevance:
Project Narrative MicroRNAs are recently-discovered molecules that serve fundamentalfunctions in the human brain. This research demonstrates for the first time that aparticular microRNA may play an important role in Alzheimer's disease. Aresearch program is proposed which exploits this new discovery in order todevelop and evaluate a novel therapy for patients at risk for Alzheimer's disease.


application_id: 7691134
project_number: 1R01AA018274-01
project_title: Alcohol Tolerance and Behavioral Disinhibition in Humans
administering_ic: NIAAA
award_notice_date: 2009-09-18
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AA
serial_number: 018274
program_official: GRANDISON, LINDSEY
project_start_date: 2009-09-20
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1 BBBP-E (02)]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Alcohol is also well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet little research has examined how such disturbances might reduce self-control over actual alcohol use leading to patterns of abusive drinking (e.g. binge drinking). Moreover despite interest in tolerance as a phenotypic marker for alcohol use disorders little research has sought to determine how differences in alcohol sensitivity and tolerance might characterize populations at-risk for alcohol abuse such as those with externalizing disorders (e.g. ADHD). The proposal is based on the working hypothesis that abuse potential of alcohol is determined by sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in alcohol effects on basic mechanisms involved in the control and regulation of behavior. Studies will investigate: 1) the sensitivity of control mechanisms to the impairing effects of alcohol and their contribution to abuse potential; 2) tolerance development to the impairing effects on mechanisms that control behavior and attention; 3) the contribution of such tolerance to the abuse potential of alcohol; 4) the degree to which the inhibitory and attentional deficits associated with ADHD influence alcohol sensitivity and the development of tolerance; and 5) the degree to which the developmental course of tolerance is affected by concomitant use of stimulant drugs commonly used in the management of ADHD. PUBLIC HEALTH RELEVANCE: Excessive alcohol use contributes to many adverse health consequences (e.g. alcohol poisoning acute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Yet little research has examined how tolerance might increase the risk for alcohol abuse. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in the ability of the drug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this research will provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosate as well as some investigational medications that might operate via neurocognitive control mechanisms.

project_terms:
Accounting;Acute;Acute Alcoholic Hepatitis;Adderall;Address;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Attention;Attention deficit hyperactivity disorder;Attentional deficit;Behavior;Behavior Control;Behavioral;Behavioral Model;Biochemical;Characteristics;Classification;Comb animal structure;Cues;Dependence;Development;Disease;Disinhibition;Dose;Drug usage;Euphoria;Health;Human;Impairment;Informal Social Control;Knowledge;Laboratories;Laboratory Animals;Learning;Liver Cirrhosis;Measures;Methods;Methylphenidate;Modeling;Naltrexone;Neurocognitive;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Play;Populations at Risk;Predisposition;Procedures;Process;Regulation;Reporting;Research;Rewards;Risk;Risk Factors;Role;Self Administration;Self-control as a personality trait;Series;Signal Transduction;Study Section;Techniques;Testing;Training;Treatment Efficacy;Work;acamprosate;alcohol and other drug;alcohol effect;alcohol exposure;alcohol poisoning;alcohol sensitivity;alcohol use disorder;base;binge drinking;disinhibitory psychopathology;drinking;drinking behavior;early onset;interest;programs;public health relevance;response


application_id: 7690572
project_number: 7K02DA019656-03
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NIDA
award_notice_date: 2008-11-17
opportunity_number: PA-00-020
application_type: 7
activity_code: K02
ic: DA
serial_number: 019656
program_official: THOMAS, DAVID A
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The candidate for an Independent Scientist Award (K02) seeks five years of salary support to provide release time to study the role of neuropeptides in mediating inflammatory and neuropathic pain. His integrative approach includes pharmacologic behavioral and molecular studies. The candidate obtained a Ph.D. at UCSD worked with Allan Basbaum at UCSF and is now an Associate Professor of Pharmacology at Tulane University. He has published 28 original articles (25 as first/last author) plus 7 invited reviews and received NRSA FIRST (R29) R21 and R01 grants to study pain and analgesia. His broad career goals include: 1. Extension of his current R01 into a well-conceived long-term research program that yields a new pharmacotherapy for chronic pain (e.g. an NPY receptor agonist); 2. Continued interactions with mentors that will foster his deeper understanding of the physiological cellular and biochemical mechanisms of chronic pain and its inhibition by neuropeptides; and 3. Continued collaborations and training in the utilization of molecular biological viral transfection and conditional transgenic mouse technologies so as to develop precise and targeted approaches to important questions in chronic pain research. Tulane remains rich in educational opportunities for intellectual growth and independence and provides outstanding resources to Dr. Taylor including laboratory space equipment behavioral suites in the vivarium and internal research funding. Tulane considers Dr. Taylor to be an integral part of its strong commitment to research and granted him early tenure in 2004. Contingent upon K02 funding the institution provides assurances that 85% of Dr.Taylor's time will be set aside for research and career development activities. The Research Plan focuses on the overall hypothesis that inflammatory or sensory nerve injury decreases presynaptic and postsynaptic elements of NPY signaling at the dorsal horn thereby facilitating pronociceptive neurotransmission and ultimately increasing allodynia and hyperalgesia. Aim #1 will determine the contribution of Y1 or Y2 receptors to the actions of NPY using new receptor subtype- selective antagonists and deletion mutant mice. Aim #2 will correlate injury-induced changes in behavior with NPY release and Y1 receptor expression. Aim #3 will use microdialysis and immunohistochemistry to determine whether NPY inhibits substance P release and dorsal horn nociresponsive neurons.

project_terms:
Absence of pain sensation;Acute;Address;Affect;Agonist;Amino Acids;Analgesics;Animal Model;Animals;Arthritis;Behavior;Behavioral;Biochemical;Biological;Cell membrane;Cerebrospinal Fluid;Collaborations;Coupled;Cytoplasm;Data;Depth;Development;Doctor of Philosophy;Dose;Elements;Equipment;Fluorescence;Formalin;Fostering;Freund's Adjuvant;Funding;Gene Expression;Genes;Goals;Grant;Growth;Hyperalgesia;Hypersensitivity;Immunohistochemistry;Independent Scientist Award;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Institution;Intrathecal Space;Laboratories;Mechanics;Mediating;Mediator of activation protein;Mentors;Mice Mutant Strains;Mice Transgenic;Microdialysis;Microscopy Confocal;Modeling;Molecular;Morphology;National Research Service Awards;Nerve;Neurons;Neuropathy;Neuropeptide Receptor;Neuropeptide Y Receptor;Neuropeptides;Neurotransmitters;Nociception;Numbers;Pain;Pain Research;Peripheral;Peripheral nerve injury;Persistent pain;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physiological;Posterior Horn Cells;Publishing;Radioimmunoassay;Receptor Activation;Research;Research Design;Research Project Grants;Resources;Role;Signal Transduction;Spinal;Stimulus;Substance P;Sum;Technology;Testing;Time;Training;Transfection;Universities;Viral;Wages;Work;afferent nerve;allodynia;career;chronic pain;dorsal horn;gamma-Aminobutyric Acid;immunoreactivity;in vivo;inflammatory neuropathic pain;inhibitor/antagonist;nerve injury;neuropeptide Y;neuropeptide Y-Y1 receptor;neurotransmission;neurotransmitter release;nociceptive response;painful neuropathy;postsynaptic;presynaptic;professor;programs;receptor;receptor expression;receptor internalization;response;sensory stimulus;transmission process


application_id: 7690071
project_number: 3R42AA016739-02S1
project_title: Hypericum extracts as potential anti-relapse medications in alcoholism
administering_ic: NIAAA
award_notice_date: 2008-09-30
opportunity_number: RFA-AA-06-007
application_type: 3
activity_code: R42
ic: AA
serial_number: 016739
suffix: S1
program_official: FERTIG, JOANNE
project_start_date: 2007-07-20
project_end_date: 2011-06-30
study_section: ZAA1-DD(74)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism is a complex disease and anti-relapse treatments should recognize this. For example depression is a frequent precipitant of relapse (1) and is the most common co-morbid psychiatric disorder in alcoholism. An anti-relapse agent with antidepressant properties might therefore be valuable specifically for this large subpopulation. In this regard the extracts of "St John's Wort" (Hypericum perforatum) that are effective treatments for clinical depression (see 2) also inhibit alcohol consumption in several animal models (e.g. (3). Like antidepressants H perforatum extracts contain serotonin re-uptake inhibitors (SRIs) but (less wellknown) constituents also bind to NMDA receptors (NMDARs) opioid receptors (ORs) GABAA receptors and corticotrophin releasing factor receptors (CRFRs). This is a unique pharmacological spectrum and is potentially valuable because all of these are molecular targets for anti-relapse agents with NMDARs and ORs being the targets for acamprosate and naltrexone respectively. Native Hypericum species and geneticallymodified H perforatum lines share these actions in greater or lesser degree (Preliminary studies) and their relative importance could therefore be assessed using these species or lines. However in this "fast-track" STTR the aim is simply to identify those novel Hypericum extracts that are of most potential value in alcoholism. In phase 1 the focus will be on pharmacological standardization of extracts using molecular and cellular screens developed for evaluation of synthetic anti-relapse medications. In phase 2 evaluation will continue in simple animal screens of alcohol dependence and/or depression and different models of alcohol consumption. The prediction is that some extracts will be more effective than others and that this can be related to the pharmacological activity they contain. The resulting stronger Intellectual Property (compared to known active H perforatum extracts) will make these more commercially attractive as medications for this specific use. In phase 3 the objective (with a major pharmaceutical partner) will be to commercialize extracts or active components as treatments for prevention of relapse in alcoholic patients with co-morbid depression.

project_terms:
Acute;Address;Agonist;Alcohol consumption;Alcohol dependence;Alcoholism;Animal Model;Animals;Antidepressive Agents;Behavioral;Binding (Molecular Function);Characteristics;Complex;Consumption;Crude Extracts;Disease;Dose;Endogenous depression;Evaluation;Fluoxetine;Glutamates;Heavy Drinking;Hypericum;Hypericum perforatum;Intellectual Property;Marketing;Mental Depression;Mental disorders;Metabolism;Modeling;Models Genetic;Molecular;Molecular Mechanisms of Action;Molecular Target;Mus;Mutagenesis;Mutation;N-Methyl-D-Aspartate Receptors;Naltrexone;Natural regeneration;Nerve Degeneration;Opioid Receptor;Opioid Receptor Binding;Oral;Outcome;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plant Extracts;Plants;Population;Property;Rattus;Receptor Inhibition;Receptors Corticotropin;Receptors Corticotropin-Releasing Hormone;Relapse;Relative (related person);Route;Screening procedure;Selective Serotonin Reuptake Inhibitor;Serotonin;Small Business Technology Transfer Research;Standardization;Testing;Therapeutic;Therapeutic Uses;Toxicity Tests;acamprosate;commercialization;deprivation;high throughput screening;inhibitor/antagonist;interest;intraperitoneal;novel;prevent;prevention of later incidences of a disorder;problem drinker;research clinical testing;therapeutic target;transmission process;uptake


application_id: 7689766
project_number: 5R01NS035102-15
project_title: Genotype/Phenotype Correlations in Williams Syndrome
administering_ic: NINDS
award_notice_date: 2009-04-02
application_type: 5
activity_code: R01
ic: NS
serial_number: 035102
program_official: MAMOUNAS, LAURA
project_start_date: 1996-05-17
project_end_date: 2012-03-31
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: 2009-04-01
project_abstract:
DESCRIPTION (provided by applicant): Williams syndrome (WS) is a complex neurodevelopmental disorder characterized by mild to moderate mental retardation (MR) a distinctive personality profile an unusual cognitive profile infantile hypercalcemia dysmorphic facial features and supravalvar aortic stenosis (SVAS). Our research has demonstrated that WS is a contiguous gene disorder resulting from submicroscopic deletions of chromosome 7ql 1.23 including deletion of the elastin gene (causing SVAS connective tissue abnormalities and some facial features of WS) the LIM-kinase 1 gene (contributing to the visuospatial constructive cognitive difficulties of WS) and the GTF21 gene (implicated in the reduced general intellectual ability in WS). In addition we have identified a region of the WS deletion that is likely to include gene(s) that contribute to the WS personality profile. The overall goal of the proposed research is to create a medical and behavioral profile for WS that will then be used to examine genotype/phenotype correlations. We have three specific aims: 1) Ascertain and phenotypically characterize individuals who have WS and individuals who have features that overlap with WS. 2) Identify and characterize the cardinal features of the phenotype of classic WS. The medical phenotype will be characterized based on dysmorphology examination review of medical records and echocardiographic analysis. The neurobehavioral phenotype will be characterized based on psychological tests designed to measure general intelligence including strengths and weaknesses in particular aspects of cognition; specific tests of language memory and visuospatial abilities; and measures of personality temperament and adaptive behavior. 3) Identify genes responsible for specific phenotypic features of WS. Genetic analysis will include defining atypical deletion breakpoints screening genes in the region for mutations in specific populations (e.g.GTF21 mutations in nonspecific MR) determining parent of origin and inversion status to investigate the roles of these variables on the phenotype and testing of candidate genes for involvement in the pathogenesis and phenotypic variability of particular WS features. We expect to identify genes involved in WS personality characteristics and hypercalcemia and to characterize genetic modifying factors. The long term objective is to provide a better understanding of mechanisms underlying cognitive and personality development. The findings will be of immediate use to practitioners who provide educational and therapeutic services to individuals with WS and their families.

project_terms:
Adaptive Behaviors;Affect;Aortic Valve Stenosis;Behavior;Behavioral;Biological Assay;Candidate Disease Gene;Cardiovascular Surgical Procedures;Characteristics;Chromosome Deletion;Chromosomes;Clinical;Cognition;Cognitive;Complex;Connective Tissue;Correlation Studies;Development;Disease;Dysmorphology;Echocardiography;Elastin;Equilibrium;Face;Family;Fluorescent in Situ Hybridization;Foundations;Gene Deletion;Gene Expression;Gene-Modified;General Population;Genes;Genetic;Genotype;Goals;Grant;Hypercalcemia;Hypertension;Individual;Infantile hypercalcemia;Intelligence;LIM Domain Kinase 1;Language Tests;Lead;Location;Maps;Measurement;Measures;Medical;Medical Records;Memory;Mental Retardation;Moderate Mental Retardation;Modification;Mutation;Neurodevelopmental Disorder;Other Genetics;Parents;Pathogenesis;Personality;Personality Development;Phenotype;Physiology;Play;Point Mutation;Population;Psychological Tests;Reporting;Research;Role;Sampling;Screening procedure;Services;Temperament;Testing;Therapeutic;Visuospatial;Williams Syndrome;base;chromosome mutation;design;genetic analysis;insight;instrument;interest;neurobehavioral;research study;success;trait


application_id: 7689186
project_number: 5R42HL074579-03
project_title: Stem Cell Graft Engineering to Treat Sickle Cell Disease
administering_ic: NHLBI
award_notice_date: 2009-09-03
opportunity_number: PA-07-281
application_type: 5
activity_code: R42
ic: HL
serial_number: 074579
program_official: MITCHELL, PHYLLIS
project_start_date: 2004-09-23
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-HEME-D(10)B]
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: 2009-09-20
budget_end_date: 2012-08-31
project_abstract:
DESCRIPTION (provided by applicant): Sickle Cell Disease (SCD) is a genetic abnormality of red blood cells (RBC) that affects over 70000 people in the United States or approximately 1 in every 500 African-Americans. With current therapies the mortality in the United States is 50% by age 40. SCD is a chronic debilitating disease associated with frequent painful crises acute chest syndrome stroke and renal failure. As a result patients require frequent hospitalizations and experience absenteeism from work. The only cure for SCD to date is hematopoietic stem cell transplant (HSCT). However at present the morbidity and mortality associated with ablative HSCT has limited the widespread application of this approach. Moreover the requirement for a matched donor has limited HSCT to only 17% of candidates. We have developed an approach to engineer a bone marrow graft to avoid the major complications of HSCT: graft-versus-host reactivity (GVHD); graft failure; and the need for perfect matching. Our approach is superior to current therapies because it involves a proprietary process that enriches for patented facilitating cells (FC) and stem cells but removes GVHD-producing cells. In this proposal we will utilize the FCRx product already demonstrated to be effective for treatment of leukemic patients for treatment of patients with SCD. In phase I we successfully developed a reduced-intensity nonmyeloablative conditioning approach that established e20% donor chimerism in two pediatric sickle cell patients with matched sibling donors. We met our defined end point of engraftment with production of normal RBC functionally curing the disease. Both patients tolerated the conditioning very well and remain chimeric and asymptomatic at 529 and 644 post-transplant. Patient #1 is off all immunosuppression and Patient #2 is on low dose monotherapy and will complete tapering of the drug in December 2007. We will develop and market a quality controlled/quality assured FDA-approved bone marrow product (SCD FCRx) to treat individuals with SCD. Our platform technology will be provided to hospital systems worldwide. Such a treatment approach could be expanded to other blood disorders including thalassemia the most commonly inherited genetic disease in the world. The complementary structure and expertise of the company and the University lends itself nicely to this joint effort. The company will continue to develop and execute a strategy to produce and market the product while the University will conduct the early stage clinical trial and process the marrow in its FACT-accredited cell processing facility. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation is the only curative treatment for sickle cell disease (SCD) and thalassemia. However the widespread application of this approach has been limited by a need for perfect HLA matching and the unacceptable toxicity of conditioning. This Phase II STTR project will apply our proprietary facilitating cell/stem cell processing approach to prepare a product called FCRx for the approximately 80% of SCD patients who do not have a suitably matched sibling donor. We successfully demonstrated our approach to functionally cure SCD in Phase I of this project.

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


application_id: 7689166
project_number: 5R21EY018112-02
project_title: Temporal and Spatial patterns of structural proteins in extraocular muscles
administering_ic: NEI
award_notice_date: 2009-06-26
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: EY
serial_number: 018112
program_official: ARAJ, HOUMAM H
project_start_date: 2008-09-30
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(07)M]
contact_pi_person_id: 7875119
contact_pi: MONCMAN, CAROLE L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Extraocular muscles (EOM) although classified as skeletal muscle are unique in their developmental origin developmental pattern of myosin heavy chain (MyHC) protein isoform expression and patterns of innervation. Interestingly EOM are spared in many of the devastating muscular dystrophies that affect the peripheral skeletal muscle such as Duchenne's and limb girdle muscular dystrophies and on the other hand are specifically targeted in oculopharyngeal muscular dystrophy and myasthenia gravis. The hypothesis driving this proposal is that the unique nature of the myogenesis myofibrillogenesis and maturation of the EOM provide the mechanisms for enhanced plasticity and regenerative properties. The EOM undergo a different developmental path than the somite derived skeletal muscles and therefore are affected by different signaling pathsways. Gene expression profiling of EOM have implicated the presence of both cardiac and skeletal muscle isoforms of myofibrillar and cytoskeletal mRNAs; however with the notable exceptions of MyHC and myomesin there is little biochemical data to substantiate these data. A major goal of this exploratory project as outlined in the specific aims is to evaluate the end products in these signaling pathways in the form of the cytoskeletal myofibrillar and ECM proteins expressed in the developing and adult EOM and compare these protein distributions to prototypic fast muscle (both adult and developing) such as the EDL. We will use biochemical and immunological tools to examine the expression patterns of the myofibrillar cytoskeletal and extracellular matrix of EOMs. This new information on the proteins that integrate the structural support and contractile elements of the developing and mature EOMs will yield insights into how this novel adult phenotype is established and should add to our understanding of how it is disrupted in strabismus.  PUBLIC HEALTH RELEVENCE: The selective sparing of the extraocular muscle in Duchenne's muscular dystrophy demonstrates the unique nature of the extraocular muscle and suggests that important insights into devastating muscular disease can be learned by studying this muscle. Information gained in this analysis may pave the road for the development of new therapeutic treatments for both eye muscle diseases and peripheral skeletal muscle diseases.

project_terms:
Adult;Affect;Age;Automobile Driving;Biochemical;Cardiac;Cardiac Myosins;Characteristics;Child;Collagen;Correlative Study;Cues;Cytoskeletal Proteins;Data;Development;Distal;Dystrophin;Elements;Embryo;Event;Exhibits;Extracellular Matrix;Eye;Fibronectins;Gene Expression Profile;Gene Expression Profiling;Goals;Hand;Immunologic Techniques;Integrins;Laminin;Learning;Light;Limb-Girdle Muscular Dystrophies;Metabolic;Microfilaments;Molecular;Molecular Profiling;Muscle;Muscular Dystrophies;Muscular Dystrophy Duchenne;Myasthenia Gravis;Myofibrillogenesis;Myopathy;Myosin Heavy Chains;Natural regeneration;Nature;Neuromuscular Diseases;Oculopharyngeal Muscular Dystrophy;Operative Surgical Procedures;Pathway interactions;Pattern;Peripheral;Phenotype;Physiological;Property;Protein Isoforms;Proteins;Proteomics;Signal Pathway;Signal Transduction;Skeletal muscle structure;Somites;Strabismus;Structural Protein;System;Tissues;Tropomyosin;Troponin;Utrophin;connectin;coping;embryo tissue;extracellular;fetal;insight;member;myogenesis;myomesin;nebulin;nerve supply;novel;novel therapeutics;oculomotor;orbit muscle;postnatal;protein distribution;public health medicine (field);regenerative;research study;response;response to injury;scaffold;tool;trait


application_id: 7689145
project_number: 5R03CA137801-02
project_title: Prevention of reflux-induced esophageal adenocarcimona by dietary berries
administering_ic: NCI
award_notice_date: 2009-07-17
opportunity_number: PAR-08-055
application_type: 5
activity_code: R03
ic: CA
serial_number: 137801
program_official: SEIFRIED, HAROLD E
project_start_date: 2008-09-19
project_end_date: 2010-08-31
study_section: ZCA1-SRLB-F(O1)
contact_pi_person_id: 7674642
contact_pi: MARTIN, ROBERT C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
  
Esophageal adenocarcinoma (EAC) has the fastest rate of increase among all cancers in America yet there is very little research on the mechanisms and prevention of its development. EAC primarily affects White males and has one of the poorest prognoses among all cancers. Barrett's esophagus (BE) is a pre-cancerous lesion associated with the development of EAC. BE is caused by chronic heartburn which affects more than 19 million Americans every year. Pharmaceutical treatments to cure heartburn do not appear to largely affect EAC incidence. New intervention strategies are urgently needed to address this issue. Commonly available berries such as blueberries (BB) and black raspberries (BRB) are natural chemopreventative agents that can be easily incorporated into the American diet and used for clinical intervention. Moreover dietary BRBs are highly effective in preventing squamous cell carcinoma (SCC) another type of esophageal cancer the incidence of which is declining. We have developed an animal model that mimics the clinical development of EAC. In this model chronic esophageal reflux resembling heartburn is induced in rats using a surgical procedure. More than one-third of the rats develop EAC at the end of 6 months. We can effectively use this model to study the preventive efficacy of dietary berries. Two types of berries have been chosen since they differ widely in their phytochemical profiles. Our objective is to study the efficacy of dietary berries to prevent the development of reflux-induced EAC and to understand the mechanisms by which they do so. To achieve this we plan to provide BB and BRB via the diet to male rats at a dose of 2.5% which is equivalent of consuming one-half cup of dried berries every day. We will surgically-induce chronic reflux. At the end of 6 months the rats that were provided with berry diet will be compared with those that did not receive intervention to evaluate the incidence of tumors. To further understand the mechanisms by which berries may prevent esophageal tumorigenesis we plan to use intermediary monthly time points during the development of EAC to study the biomarkers that are altered. The first set of biomarkers deal with oxidative stress and will determine whether berries can induce cellular antioxidant enzymes such as superoxide dismutase catalase and glutathione peroxidase which ultimately protect the cells from oxidative damage. Lipid peroxidation and oxidative DNA damage will be used as markers of oxidative stress. The second set of biomarkers deal with inflammation associated with BE. Nuclear factor kappa B (NF?B) a transcription factor that controls the expression of several cancer-inducing genes is found to be activated by inflammation in BE. We will evaluate whether berries can prevent this activation. Thus by following a two-part approach we will be able to determine whether berries prevent EAC progression and the mechanisms involved in this prevention.

project_terms:
8-Oxo-2'-Deoxyguanosine;Address;Adenocarcinoma;Adverse effects;Affect;American;Americas;Anastomosis - action;Animal Model;Animals;Antioxidants;Barrett Esophagus;Berry;Biological Assay;Biology;Blueberries;Cancerous;Carcinogens;Cells;Chemoprevention;Chemopreventive Agent;Chronic;Clinical;DNA Damage;Development;Diet;Dietary Supplements;Dose;Enzyme-Linked Immunosorbent Assay;Enzymes;Epithelium;Esophageal;Esophageal Adenocarcinoma;Esophageal carcinoma;Esophageal mucous membrane;Esophagitis;Etiology;Gastroesophageal reflux disease;Genes;Heartburn;Immunoblot Analysis;Incidence;Inflammation;Inflammatory;Intervention;Lesion;Lipid Peroxidation;Longitudinal Studies;Malignant Neoplasms;Malignant Squamous Cell Neoplasm;Malignant neoplasm of esophagus;Manganese Superoxide Dismutase;Measures;Microscopic;Modeling;Molecular;Mortality Vital Statistics;NF-kappa B;National Cancer Institute;Operative Surgical Procedures;Oxidative Stress;Pathway interactions;Peptic Esophagitis;Pharmacologic Substance;Phytochemical;Polymerase Chain Reaction;Prevention;Preventive;Randomized;Raspberries;Rattus;Reflux;Reporting;Research;Squamous cell carcinoma;Staining method;Stains;Stress;Superoxide Dismutase;Survival Rate;Time;Work;base;biomarker;cancer diagnosis;catalase;cyclooxygenase 2;falls;glutathione peroxidase;male;molecular marker;outcome forecast;oxidative DNA damage;oxidative damage;prevent;transcription factor;tumor;tumorigenesis

public_health_relevance:
Project NarrativeBarrett's esophagus (BE) is a pre-cancerous lesion associated with the development of esophagealadenocarcinoma the fastest growing cancer among Americans. We propose to use an animal model of BE tostudy the preventive effects of 2 types of dietary berries (blueberries and black raspberries) on EAC incidence.


application_id: 7689055
project_number: 1R01HL096508-01
project_title: Oxidant Stress: Is it a biomarker of disease progression and response to therapy
administering_ic: NHLBI
award_notice_date: 2009-09-25
opportunity_number: RFA-HL-08-001
application_type: 1
activity_code: R01
ic: HL
serial_number: 096508
program_official: REYNOLDS, HERBERT Y
project_start_date: 2009-09-25
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZHL1 CSR-G (F1)]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
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):   
  
Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans for which no effective treatments are available. Several studies have demonstrated decreased levels of anti- oxidants in patients with IPF and anti-oxidant strategies seem effective in animal models of lung fibrosis. Consequently the use of anti-oxidants for the treatment of IPF has been proposed. However this approach is considered highly controversial because the role of oxidant stress in the pathogenesis of IPF is not clearly established and it is unclear whether currently available anti-oxidant strategies are capable of restoring normal redox potential in IPF patients. The IPF Clinical Research Network (IPFNET) is a multicenter network sponsored by the NIH/NHLBI and created to engage in well-controlled randomized clinical trials that test new therapeutic regimens in the setting of IPF. The PI of this proposal serves on the IPFNET Steering Committee and directs one of the IPFNET centers at Emory. The IPFNET will soon engage in a clinical trial that tests the effectiveness of what has arguably become the standard of care in the management of IPF: the combination of glucocorticoids azathioprine and the anti-oxidant N-acetylcysteine (NAC). This trial the Panther Trial will include three treatment arms: 1) placebo 2) prednisone + azathioprine + NAC and 3) NAC alone. Among other things this trial will determine if NAC (in combination or alone) is beneficial. However despite the focus on anti-oxidant therapy the Panther Trial will not identify subjects with oxidant stress due to limited resources. In other words the redox state of the recruited subjects will not be known and therefore the impact of NAC on this process will not be evaluated. This is important because it is possible that anti-oxidants might be effective in the management of fibrotic lung disorders but only in the subgroup of subjects with an oxidized redox state. If this possibility is not evaluated the IPFNET runs the risk of overlooking a potentially effective therapeutic strategy that might help a significant portion of IPF patients. We hypothesize that NAC may be effective in the treatment of IPF but only in patients with an oxidized redox state caused by deficiencies in endogenous anti-oxidant activity. Specifically we hypothesize that subjects with an oxidized redox potential as determined by oxidation of one or more of the thiol disulfide couples cysteine and cystine (Cys/CySS) and glutathione and glutathione disulfide (GSH/GSSG) will be the ones to benefit from anti-oxidant therapy. To test this we propose to: Aim 1) Measure the Cys/CySS and GSH/GSSG redox potential in plasma obtained from subjects recruited to the three arms of the IPFNET Panther Trial and determine if the redox potential relates to outcome. Aim 2) Determine if NAC can reverse oxidation of the thiol disulfide couples in those with evidence of oxidant stress. PUBLIC HEALTH RELEVANCE: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans and has no effective medical treatment. This project will explore the role of oxidant stress as a biomarker of disease progression and response to therapy in IPF. It will be conducted in conjunction with the PANTHER TRIAL a phase 3 trial sponsored by the IPF Clinical Research Network of the NIH/NHLBI with the purpose of evaluating redox potential in the plasma of recruited patients and determine if this parameter correlates with progression of disease and response to therapy. (End of Abstract)

project_terms:
Acetylcysteine;Address;Affect;Aging;American;Ancillary Study;Animal Model;Antioxidants;Area;Azathioprine;Biological Preservation;Bronchoalveolar Lavage Fluid;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Design;Conduct Clinical Trials;Consensus;Couples;Cysteine;Cystine;Cytotoxic agent;Data Analyses;Disease;Disease Progression;Disulfides;Dose;Double-Blind Method;Effectiveness;Epidemiologist;Fibrosis;Funding;Glucocorticoids;Glutathione;Glutathione Disulfide;Goals;Hamman-Rich syndrome;Heart;Hematological Disease;Immunosuppressive Agents;International;Intervention;Lead;Letters;Lung;Lung diseases;Measures;Medical;Monitor;Outcome;Oxidation-Reduction;Parents;Pathogenesis;Patient Care;Patient Recruitments;Patients;Phase;Phase III Clinical Trials;Physiological;Placebo Control;Placebos;Plasma;Prednisone;Process;Randomized;Randomized Controlled Clinical Trials;Recruitment Activity;Request for Proposals;Research Personnel;Resources;Respiratory physiology;Risk;Role;Running;Sampling;Site;Subgroup;Sulfhydryl Compounds;Testing;Therapeutic;Therapeutic Intervention;Time;TimeLine;Treatment Protocols;Upper arm;Walking;abstracting;antioxidant therapy;base;biomarker;design;effective therapy;human disease;improved;interstitial;lung volume;member;novel therapeutics;oxidant stress;oxidation;primary outcome;prognostic;programs;prospective;public health relevance;response;standard of care;treatment strategy

public_health_relevance:
PROJECT NARRATIVE:Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans andhas no effective medical treatment. This project will explore the role of oxidant stress as a biomarker ofdisease progression and response to therapy in IPF. It will be conducted in conjunction with the PANTHERTRIAL a phase 3 trial sponsored by the IPF Clinical Research Network of the NIH/NHLBI with the purpose ofevaluating redox potential in the plasma of recruited patients and determine if this parameter correlates withprogression of disease and response to therapy.


application_id: 7688782
project_number: 3R24RR016344-08S1
project_title: Genome resources for model amphibians
administering_ic: NCRR
award_notice_date: 2008-09-23
application_type: 3
activity_code: R24
ic: RR
serial_number: 016344
suffix: S1
program_official: O'NEILL, RAYMOND R
project_start_date: 2001-10-01
project_end_date: 2012-03-31
study_section: Comparative Medicine Review Committee[RIRG-C]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3' Untranslated Regions;Acids;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Animals;Area;Base Sequence;Bioinformatics;Biological Markers;Biology;Biomedical Research;Candidate Disease Gene;Chromosome Mapping;Code;Communities;Custom;DNA;DNA Sequence;Data;Databases;Development;Diagnostic;Disease;Embryonic Development;Endocrine disruption;Expressed Sequence Tags;Failure (biologic function);Funding;Future;Genbank;Gene Chips;Generations;Genes;Genetic;Genome;Genomics;Genotype;Goals;Grant;Health;Human;Hypothyroidism;In Situ Hybridization;Internet;Investigation;Laboratories;Maps;Metamorphosis Biological;Methods;Microarray Analysis;Modeling;Molecular;Molecular Probes;Mus;Nucleotides;Numbers;Orthologous Gene;Phenotype;Pigments;Polymerase Chain Reaction;Proteins;Quantitative Trait Loci;Rattus;Renal function;Research;Research Personnel;Resources;Robotics;Salamander;Signal Transduction;Smell Perception;Spinal Cord;Synaptic Transmission;System;Thyroid Hormones;Time;Toxicology;Vision;Xenopus;Zebrafish;base;cardiogenesis;design;limb regeneration;mutant;novel;programs;research study;sex;spinal cord regeneration;tool


application_id: 7687504
project_number: 5R21DA021178-02
project_title: A Web-based Employment Intervention for Drug Court Participants
administering_ic: NIDA
award_notice_date: 2009-07-30
opportunity_number: PA-07-331
application_type: 5
activity_code: R21
ic: DA
serial_number: 021178
program_official: WILEY, TISHA R A
project_start_date: 2008-09-15
project_end_date: 2012-04-30
study_section: Health Services Research Study Section[NIDA-F]
contact_pi_person_id: 8335129
contact_pi: WEBSTER, JOHN MATTHEW
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This twice amended R21 application is submitted by a new investigator and an established research team to conduct a study of a computerized Web-based employment intervention for female and male drug court participants. The innovative project tailors an employment intervention developed for drug court participants and adapts it for use on the Internet. The project places special emphasis on collecting data to identify and examine important gender differences in employment barriers to employment and perceptions of work as well as to understand gender differences in experiences with the Web-based intervention. Although drug treatment is related to desirable employment outcomes women have not fared as well as men on traditional measures of employment success such as employment status and earnings. The majority of employment interventions for drug abusers have not measured or even considered employment barriers and employment needs separately for females and males. After adapting the intervention for the Internet this project will collect data from both female and male drug abusers and identify differences and commonalities between women and men in employment barriers employment needs and other work-related measures. Over the project's two years a sample of 180 unemployed drug court participants will be recruited during a 15 month period (approximately 12 per month) from a drug court with which the investigators have a strong collaborative relationship. Participants who consent to participate will be interviewed about their employment experiences drug use and criminal history. Upon completing the baseline interview participants will be randomized to a control group (drug court as usual) or to the intervention group (Web-based employment intervention in addition to drug court as usual). Participants in the intervention group will complete a five module intervention grounded in a completed randomized controlled trial of an employment intervention which focused on obtaining maintaining and upgrading employment. Follow-up interviews will be conducted at 3 months. The overall aim of this project is to use the findings from a promising randomized controlled trial adapt it for use on the Internet and test its effectiveness on unemployed female and male drug abusers. The specific aims are to: (1) Adapt an existing efficacious employment intervention for unemployed drug court participants for Internet delivery as a Web-based intervention; (2) Evaluate the Web-based intervention's effect on employment outcomes (employment status days worked and earnings) and secondary outcomes (drug use and crime); and (3) Test the moderating effects of gender on the intervention's effect on employment and secondary outcomes.

project_terms:
Abuse Reporting;Address;Alcohol abuse;Area;Attitude;Client;Consent;Control Groups;Crime;Criminal Justice;Data;Dependence;Drug Courts;Drug abuse;Drug abuser;Drug usage;Economics;Effectiveness;Employment;Employment Status;Face;Female;Gender;Group Meetings;Happiness;Health;Income;Internet;Intervention;Intervention Studies;Interview;Investigation;Kentucky;Knowledge;Legal system;Literature;Measures;Methods;Multimedia;NIH Program Announcements;National Institute of Drug Abuse;Online Systems;Outcome;Outcome Study;Participant;Perception;Performance;Persons;Pharmaceutical Preparations;Pilot Projects;Procedures;Randomized;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Recording of previous events;Recruitment Activity;Reporting;Research;Research Design;Research Personnel;Resources;Role;Sampling;Schedule;Sex Characteristics;Stigmata;System;Technology;Testing;Training;Treatment outcome;Unemployment;United States Substance Abuse and Mental Health Services Administration;Walkers;Woman;Work;base;computerized;cost;experience;flexibility;follow-up;group intervention;high risk;innovation;interest;intervention effect;male;men;physical abuse;programs;response;satisfaction;secondary outcome;sex;social;social stigma;success;tool


application_id: 7687440
project_number: 5R01DA025591-02
project_title: GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2009-06-15
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025591
program_official: BOUGH, KRISTOPHER J
project_start_date: 2008-09-15
project_end_date: 2013-02-28
study_section: ZDA1-MXH-H(22)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. ?-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims.  The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference then an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse.  The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information the proposed research will provide basic-science and translational information. First the inclusion of drug self-administration and discrimination measures along with subjective-effect questionnaires will provide information concerning the relationship between the reinforcing discriminative and subjective effects of methamphetamine. Second because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures the proposed research will determine albeit indirectly the extent those findings from preclinical studies generalize to humans. Public Health Relevance: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.

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


application_id: 7687428
project_number: 5F31DA025424-02
project_title: Transdermal Delivery of Hydroxyphenylarachidonylamides
administering_ic: NIDA
award_notice_date: 2009-07-22
application_type: 5
activity_code: F31
ic: DA
serial_number: 025424
program_official: PARK, MOO KWANG
project_start_date: 2008-07-17
project_end_date: 2010-07-16
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 9288396
contact_pi: SWADLEY, COURTNEY LEAH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-17
project_abstract:
DESCRIPTION (provided by applicant):  A patch for transdermal cannabinoid delivery could be therapeutically important in the reduction of chronic pain especially for patients who can't get pain relief from traditional treatments. Addition of a cannabinoid patch to a patient's standard pain-relief regimen could enhance analgesia because this class of drugs works by a different antinociceptive mechanism. Release of endocannabinoids (eCBs) such as anandamide (AEA) occurs in response to injury to relieve pain and inflammation. Inhibitors of eCB degradation mechanisms and transporters such as AM404 have been developed to induce and prolong the effects of the eCBs in situations of injury-induced pain and inflammation. Endocannabinoid and inhibitor compounds are clinically interesting because they initiate therapeutic effects via cannabinoid (CB) receptors without producing the side effects common to traditional cannabinoid agonist compounds such as THC. N-(4- hydroxyphenyl) arachidonoylamide (AM404) has been shown to relieve neuropathic pain and reduce alcohol consumption and anxiety in animals. N-arachidonoyl dopamine (NADA) is an eCB that acts at the CB receptor 1 which is associated with pain and emesis reduction. Transdermal delivery has numerous advantages over other drug delivery methods such as bypassing first-pass metabolism extended controlled drug release and the added ability for patients to self-administer the drug pain-free. NADA and AM404 present a challenge for transdermal delivery because of their high lipophilicity and enzymatic/chemical instability. The goal of this project is to improve the transdermal delivery of the hydroxyphenylarachidonylamides NADA and AM404. We propose to synthesize hydrophilic prodrugs of these compounds to promote their delivery across the skin barrier and possibly increase their stability. The additional phenolic hydroxyl in NADA will allow us to evaluate the effect of disubstituted prodrugs as compared to monosubstituted prodrugs of the AM404 structure. The proposed hydrophilic prodrugs will be useful in investigating quantitative-structure-permeability relationships (QSPR) of transdermal flux used to develop and improve delivery strategies for highly lipophilic compounds. The specific aims for this project are: (1) to study the diffusion and metabolism of NADA and AM404 across the skin barrier (2) to synthesize a series of prodrugs for transdermal flux optimization (3) to measure the penetration/concurrent bioconversion of the prodrugs through human skin in vitro and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo. Correlation of our in vitro data with the in vivo model will aid in developing a QSPR database for transdermal prodrugs.

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


application_id: 7685383
project_number: 5K23DK073750-05
project_title: Evaluation of the Effect of Green Tea Polyphenols on IBD
administering_ic: NIDDK
award_notice_date: 2009-09-15
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DK
serial_number: 073750
program_official: PODSKALNY, JUDITH M,
project_start_date: 2005-09-15
project_end_date: 2011-08-31
study_section: Clinical Research Review Committee[RIRG-G]
contact_pi_person_id: 7368605
contact_pi: DRYDEN, GERALD W
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Interest in green tea as an agent for improving health and treating disease has increased in both the lay and scientific literature. Green tea consists of several components with most research focusing on the  polyphenol fraction. The green tea polyphenols (GrTP) include (-)-epicatechin (EC) (-)-epigallocatechin  (EGC) (-)- epicatechin-3-gatlate (ECG) and (-)-epigallocatechin-3-gallate (EGCG). Of these EGCG  accounts for greater than 40% of the total polyphenol content. Therapeutic and prophylactic benefits have been attributed to the potent anti-oxidant effects of the polyphenols including reducing the risk of cancer. GrTP also have potent anti-inflammatory properties. GrTP have proven to be potent inhibitors of nuclear factor-kappa B (NF-kB) a key regutatory factor in the control of intestinal inflammation. Activation of NF-kB can be induced by a variety of stimulatory factors such as the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1) bacterial endotoxin or oxidative stress. In unstimulated cells NF-kB exists as a heterodimer comprised of p65 and p50 subunits bound to a member of the inhibitor-kB (IkB) family of inhibitory proteins. NF-kB activators induce degradation of IkB by the 26s proteosome by phosphorylation of two serines in the N-terminal regulatory domain of IkB by IkB kinase (IKK). The liberated NF-kB translocates to the nucleus binds specific promoter sequences and induces expression of proinflammatory cytokines. These cytokines are expressed at high levels in chronic inflammatory bowel disease (IBD). IL-1 and TNF-a also activate NF-kB in a positive regulatory loop. This may lead to amplification of the inflammatory response. NF-kB appears to play a significant role in inflammation and is a likely target for anti-inflammatory therapies. Animal models of inflammation improved with GrTP administration. The scientific portion of this proposal intends to evaluate the use of GrTP in humans. Specific aim 1 will confirm that GrTP inhibit NF-kB activation in human peripheral blood monocytes. Specific aim 2 will evaluate the safety and tolerability of GrTP in volunteers with quiescent IBD while defining the pharmacokinetics and pharmacodynamics of GrTP. Specific aim 3 will further evaluate the safety of GrTP in subjects with IBD while providing preliminary data on the efficacy of this therapy in patients with active ulcerative colitis.

project_terms:
26S proteasome;2H-1-Benzopyran-357-triol 2-(34-dihydroxyphenyl)-34-dihydro- (2R-cis)-;Accounting;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Binding (Molecular Function);Cell Nucleus;Cells;Chronic;Data;Disease;Drug Kinetics;Endotoxins;Epigallocatechin Gallate;Evaluation;Family;Genes;Green tea (dietary);Health;Human;I Kappa B-Alpha;In Vitro;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Inflammatory disease of the intestine;Interleukin-1;Interleukin-8;Laboratory Animals;Lead;Literature;N-terminal;NF-kappa B;Oxidative Stress;Patients;Pharmacodynamics;Phosphorylation;Phosphotransferases;Play;Promotor (Genetics);Property;Proteins;Research;Role;Safety;Serine;Stimulus;TNFRSF5 gene;Therapeutic;Treatment Efficacy;Tumor Necrosis Factor-alpha;Ulcerative Colitis;cancer risk;cytokine;epigallocatechin-(4-82-O-7)epicatechin;gallocatechol;human TNFRSF1A protein;improved;inhibitor/antagonist;interest;member;monocyte;p65;peripheral blood;polyphenol;preclinical study;prophylactic;response;tumor necrosis factor alpha receptor;volunteer


application_id: 7684850
project_number: 5R01DK077632-04
project_title: Protective Effects of Stearic Acid on Gestational and Acquired Diabetes Mellitus
administering_ic: NIDDK
award_notice_date: 2009-08-10
opportunity_number: RFA-DK-05-014
application_type: 5
activity_code: R01
ic: DK
serial_number: 077632
program_official: SILVA, CORINNE M
project_start_date: 2006-09-15
project_end_date: 2010-09-14
study_section: ZDK1-GRB-N(O1)S
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: GRAF, GREGORY A
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): Hypothesis. The central hypothesis of this proposal is that CD36 ABCD2 and mitoNEET mediate the protective effects of stearic acid on gestational diabetes and on the acquired diabetes of the progeny. Rationale. The goal of this proposal is to test the novel hypothesis that stearic acid ameliorates gestational diabetes mellitus (GDM) and subsequent diabetes in the progeny of GDM mothers through a triad of CD36 ABCD2 and mitoNEET proteins. We will use the CSTBLKS/J-Lep/*'* mouse that develops GDM around day 16 of gestation. We will examine the mechanisms of stearic acid on CD36 ABCD2 and mitoNEET expression and function in both GDM and on long-term metabolic and cardiovascular outcomes in the progeny of the db/+ dams. Finally we will use individual genetic knockout models for each protein to determine the extent to which each protein mediates the action of stearic acid in both GDM and diabetes of the progeny. The uniqueness and potential clinical relevance of this approach is the mechanistic analysis of a possible means for treatment of both GDM and pursuant diabetes mellitus acquired by the offspring. We propose in vivo studies that can be further dissected by in vitro studies with isolated tissues and cells which will enable us to thoroughly explore the protective mechanism of action of stearic acid. 1. To determine the impact of stearic acid on the development and extent of GDM. Db/+ dams will be used to examine whether stearic acid affects the development of GDM by measuring oral glucose tolerance vascular responsiveness and adipocyte function. The expression and subcellular localization of CD36 ABCD2 and mitoNEET in adipose will be quantified and functionality of the proteins assessed through measurements of fatty acid biochemistry (p-oxidation fatty acid composition and angiotensin II secretion). Similarly we will also examine the effect of stearic acid treatment fed exclusively to the db/+ dams on the extent of diabetes in the offspring. Finally we will thoroughly examine the mechanism of action of stearic acid on fatty acid biochemistry in insulin resistant 3T3-L1 adipocytes. This aim is important because we will mechanistically evaluate a potential palliative intervention for both GDM and the accompanying diabetes of the offspring. 2. To determine the duration which stearic acid improves the diabetic phenotype in db/db mice. Db/db progeny will be treated with stearic acid and the duration and extent of the protective effect investigated. The effect of withdrawal of stearic acid on the lasting benefit of the intervention will also be examined. We will measure blood pressure vascular responsiveness weight and glucose. We will examine the mechanisms of stearic acid action by determining the expression and subcellular location of CD36 ABCD2 and mitoNEET in adipose and assessing function of each protein through measurements of adipose fatty acid biochemistry. This aim is important because it will provide data on the cardiovascular benefit and sustainability of stearic acid intervention. 3. To determine whether the beneficial effects of stearic acid are mediated by CD36 ABCD2 and/or mitoNEET. We will cross mice null for CD36 ABCD2 or mitoNEET with db/+ mice and assess the efficacious effects of stearic acid in ameliorating GDM and the ensuing diabetic phenotype of the double crossed db/db progeny lacking each individual gene. We will measure OGTT vascular responsiveness and adipose fatty acid biochemistry in db/+ dams. Furthermore we will assess the effect of individual gene knockout on the ability of stearic acid to affect the development of diabetes in the db/db mice. This will be accomplished through measurements of weight glucose insulin blood pressure and vascular responsiveness. Mechanistically the effects of gene ablation will be dissected through comprehensive analyses of isolated primary adipose biochemistry. This aim is critical because each double crossed mouse line will provide the definitive mechanistic data regarding the role of each protein in mediating the beneficial effects of stearic acid.

project_terms:
AMP-activated protein kinase kinase;Ablation;Acetyl-CoA Carboxylase;Acyl Coenzyme A;Adipocytes;Adipose tissue;Affect;Angiotensin II;Biochemical;Biochemistry;Blood Pressure;Blood Vessels;CD36 gene;Cardiovascular system;Carnitine;Cartoons;Caveolae;Cells;Coenzyme A;Commit;Data;Development;Diabetes Mellitus;Esterification;Esterified Fatty Acids;Esters;Fatty Acids;Gene Targeting;Genes;Genetic;Gestational Diabetes;Glucose;Goals;In Vitro;Individual;Insulin;Insulin Resistance;Intervention;Knock-out;Knockout Mice;Linoleic Acids;Lipids;Location;Measurement;Measures;Mediating;Membrane Microdomains;Metabolic;Mitochondria;Modeling;Mothers;Mus;Nonesterified Fatty Acids;OGTT;Outcome;Phenotype;Phosphorylation;Pregnancy;Production;Proteins;Research Personnel;Role;Route;Signal Transduction;Stearic Acids;Testing;Thick;Tissues;Transferase;Triad Acrylic Resin;Triglycerides;Upper arm;Weight;Withdrawal;clinically relevant;db/db mouse;diabetes mellitus genetics;diabetic;diacylglycerol O-acyltransferase;fatty acid biosynthesis;fatty acid oxidation;feeding;glucose metabolism;improved;in vivo;in vivo Model;knockout gene;novel;offspring;oral glucose tolerance;oxidation;palliative;peroxisome;programs;protective effect;uptake


