# projects

application_id: 7980247
project_number: 1R15AA019795-01
project_title: Acute effects of alcohol and energy drinks on behavioral control
administering_ic: NIAAA
award_notice_date: 2010-07-14
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: AA
serial_number: 019795
program_official: WITT, ELLEN
project_start_date: 2010-08-01
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1 RPIA-K (09)]
contact_pi_person_id: 10253421
contact_pi: MARCZINSKI, CECILE A.
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Underage and binge drinking (i.e. drinking to intoxication) are serious public health problems. Despite substantial efforts to change this health risk behavior current levels of binge drinking in young people in the U.S. appear to be relatively unchanged from year 2000 levels. The constancy of underage and binge drinking behavior in young people despite increased attention to this crisis begs the question of what unexamined factors may be contributing to the problem. One possible variable that may be contributing to excessive drinking in young people is the new trend of consuming of alcohol mixed with energy drinks (AmED). Despite a dramatic increase in the use of AmED in young people little laboratory research has examined how these drinks alter objective and subjective measures of intoxication. The working hypothesis of this proposal is that the consumption of AmED may be riskier than alcohol consumption alone. Mixing alcohol with another beverage with strong stimulant properties may decrease self-perceptions of intoxication and may increase the reinforcing properties of alcohol. In addition the acute effects of alcohol impair impulse control and this impairment may not be counteracted by co-administration of a stimulant. The proposed research will examine the acute effects of alcohol energy drinks AmED or a placebo beverage in social drinkers. The effects of these beverages will be determined by performance on tasks that measure neurocognitive control mechanisms and the subjective effects of alcohol. The specific aims of the proposed research are: 1) to determine whether the consumption of AmED alters neurocognitive and subjective measures of intoxication compared to the consumption of alcohol alone 2) to establish whether the consumption of AmED enhances priming of the motivation to drink alcohol compared with the consumption of alcohol alone and 3) to examine whether the consumption of AmED enhances tolerance to alcohol compared to a similar history of the consumption of alcohol or energy drinks alone. The results of these studies should elucidate whether the consumption of AmED increases alcohol consumption and may be escalating binge drinking in young people. Consistent with AREA program objectives the funding of this application will also expand undergraduate student research in human psychopharmacology and better enable students from Kentucky a state traditionally underrepresented in biomedical sciences to successfully advance in biomedical graduate programs.  
  
PUBLIC HEALTH RELEVANCE: Underage and binge drinking (i.e. drinking to intoxication) are serious public health problems leading to a significant number of accidents injuries unsafe sexual activities and deaths. The goal of this project is to understand if the consumption of alcohol mixed with energy drinks (AmED) increases alcohol consumption and escalates binge drinking in young people to a greater degree than if alcohol is consumed alone. This research will provide information about how AmED consumption may be increasing the risks of alcohol consumption by leading a drinker to perceive that he or she is less intoxicated and thus can consume more alcohol.

project_terms:
Academic Research Enhancement Awards;Accidents;Acute;Alcohol consumption;Alcohol dependence;Alcohols;American Psychiatric Association;Attention;Behavior;Behavior Control;Beverages;Brain;Caffeine;Cessation of life;Consumption;Development;Dose;Funding;Future;Goals;Grant;Health;Heavy Drinking;Human;Impairment;Individual;Injury;Institution;Intoxication;Kentucky;Laboratories;Laboratory Research;Lead;Measures;Motivation;Neurocognitive;Perception;Performance;Pharmaceutical Preparations;Placebos;Plants;Property;Psychopharmacology;Recording of previous events;Research;Risk;Risk Behaviors;Science;Self Perception;Sex Behavior;Students;Testing;Training;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Universities;Work;alcohol effect;alcohol response;base;behavior change;binge drinking;drinking;drinking behavior;experience;high risk drinking;high school;preference;problem drinker;programs;public health medicine (field);public health relevance;reinforcer;response;social;trend;university student

public_health_relevance:
Project NarrativeUnderage and binge drinking (i.e. drinking to intoxication) are serious public health problems leading to asignificant number of accidents injuries unsafe sexual activities and deaths. The goal of this project is tounderstand if the consumption of alcohol mixed with energy drinks (AmED) increases alcohol consumptionand escalates binge drinking in young people to a greater degree than if alcohol is consumed alone. Thisresearch will provide information about how AmED consumption may be increasing the risks of alcoholconsumption by leading a drinker to perceive that he or she is less intoxicated and thus can consume morealcohol.


application_id: 7978208
project_number: 1R03HD066012-01
project_title: The role of Core Binding Factors (CBFs) in the periovulatory process
administering_ic: NICHD
award_notice_date: 2010-08-09
opportunity_number: PA-09-163
application_type: 1
activity_code: R03
ic: HD
serial_number: 066012
program_official: TAYMANS, SUSAN
project_start_date: 2010-08-12
project_end_date: 2012-07-31
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The preovulatory gonadotropin surge initiates the final process of follicular maturation that culminates in ovulation of an expanded cumulus-oocyte complex (COC) and formation of the corpus luteum (CL). One essential step elicited by the gonadotropin surge required for successful follicular maturation is the expression of specific transcription factors. However our knowledge of the identity and regulatory actions of LH-induced key transcription factors remains very limited. Recent studies from our laboratory and others shed light on a small family of nuclear transcription factor Core binding factor (CBF) as a key transcriptional regulator involved in periovulatory processes. CBF is composed of two subunits; DNA binding alpha-subunit encoded by one of Runx1 Runx2 and Runx3 genes and non-DNA binding beta-subunit CBF2. To be functional RUNX proteins need to be dimerized with CBF2. Our preliminary data showed the rapid induction of CBF components (Runx1 Runx2 and CBF2) by the LH surge in periovulatory follicles. Using an in vitro model we further demonstrated that CBFs (RUNX1/CBF2 and RUNX2/CBF2) regulate the expression of periovulatory genes that are known to be critical for COC expansion ovulation and luteinization. Moreover our pilot study revealed that inhibition of RUNX activity blocked COC expansion in vitro. Based on these novel findings we hypothesized that CBFs are key transcriptional regulators necessary for successful COC expansion ovulation and luteinization.  Homozygous null mutation of genes for CBF components in mice results in early lethality and consequently fails to define the function of CBFs in the ovary. The additional challenge in demonstrating the physiological importance of CBFs in vivo is the overlapping expression of Runx1 and Runx2 and their functional redundancy in periovulatory follicles. To circumvent this problem we propose to establish a novel transgenic mouse model in which CBFs are inactivated specifically in ovarian cells. This will be accomplished by deleting CBF2 in ovarian cells using Cre-lox technology. Since CBF2 is a binding partner for both RUNX1 and RUNX2 targeted deletion of CBF2 abrogates the activity of all CBFs (RUNX1/CBF2 and RUNX2/CBF2). Using this transgenic mouse model we will test the hypothesis that targeted inactivation of CBFs results in defective COC expansion ovulation and luteinization by examining the ovarian phenotype of this mutant mouse (Specific Aim #1). Using this mutant mouse ovary we will identify the genes downstream of CBFs in periovulatory follicular cells and begin to delineate the transcriptional regulatory pathways necessary for the final stage of periovulatory follicle development (Specific Aim #2).  These studies will establish a genetically modified animal model not only to define the in vivo ovarian function of CBFs but also to identify the transcriptional regulatory machinery that controls the periovulatory process. Information derived from this proposal will provide new insight into the mechanism(s) involved in COC expansion ovulation and CL formation. Gaining a thorough understanding of cellular/molecular mechanisms of the periovulatory process will lead to better diagnostic evaluation of ovarian pathology and facilitate the physiological manipulation of these processes to either promote or inhibit fertility.  
  
PUBLIC HEALTH RELEVANCE: The overall goal of the proposed study is to investigate how the LH surge induces the release of a mature egg from the ovary and corpus luteum formation which are essential steps for female fertility. The current proposal focuses on determining the function of a small family of transcription factors Core binding factors (CBFs) as key LH-induced mediators in these processes. Such knowledge can be applied for promoting and inhibiting these critical facets of ovarian physiology thereby allowing us to better manage fertility infertility and ovarian-based disorders.

project_terms:
Animal Model;Binding (Molecular Function);Cells;Complex;Core-Binding Factor;DNA Binding;Data;Development;Diagnostic;Disease;Evaluation;Family;Female;Fertility;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetically Modified Animals;Genotype;Goals;Gonadotropins;Human;In Vitro;Infertility;Knockout Mice;Knowledge;Laboratories;Lead;Light;Luteinization;Mediator of activation protein;Molecular;Mus;Mutant Strains Mice;Nuclear Family;Oocytes;Ovarian;Ovary;Ovulation;Pathology;Phenotype;Physiological;Physiology;Pilot Projects;Play;Process;RUNX1 gene;Regulatory Pathway;Rodent;Role;Staging;Technology;Testing;Time;Transgenic Mice;Up-Regulation (Physiology);base;corpus luteum;egg;in vitro Model;in vivo;insight;mouse model;novel;null mutation;public health relevance;runx proteins;transcription factor

public_health_relevance:
Project Narrative The overall goal of the proposed study is to investigate how the LH surge induces the releaseof a mature egg from the ovary and corpus luteum formation which are essential steps for femalefertility. The current proposal focuses on determining the function of a small family of transcriptionfactors Core binding factors (CBFs) as key LH-induced mediators in these processes. Suchknowledge can be applied for promoting and inhibiting these critical facets of ovarian physiologythereby allowing us to better manage fertility infertility and ovarian-based disorders.


application_id: 7962823
project_number: 7R01DK048498-15
project_title: Surgical Studies of Functional Gene Expression
administering_ic: NIDDK
award_notice_date: 2009-10-26
application_type: 7
activity_code: R01
ic: DK
serial_number: 048498
program_official: MAY, MICHAEL K
project_start_date: 1996-03-15
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1-SBIB-G(02)M]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa is in a constant state of renewal characterized by active proliferation of stem cells localized in the crypts progression of these cells up the crypt-villus axis with cessation of proliferation and subsequent differentiation and apoptosis. A delicate and precise balance of proliferation differentiation -- apoptosis must exist in the gut mucosa to maintain normal intestinal homeostasis. The major focus of our collaborative group has been the analysis of mechanisms regulating intestinal proliferation differentiation and apoptosis. With support of this grant we have made great strides in our better understanding of the molecular mechanisms contributing to intestinal cell differentiation and apoptosis. We have shown that the phosphatidylinositol-3 kinase (PI3K) pathway plays an important role in intestinal differentiation and proliferation; inhibition of PI3K by chemical inhibitors or overexpression of PTEN a tumor suppressor enhanced enterocyte differentiation. Furthermore PI3K inhibition leads to upregulation of the apoptosis-related protein TRAIL which is localized to the differentiated cells of the colon and small bowel; overexpression of PTEN in prostate cancer cells induces TRAIL expression through activation of the FOXO family of forkhead transcription factors. Recently our studies have identified a novel interaction between PI3K/Akt and NF-_B via transcriptional regulation of PTEN. Based on our findings the central hypothesis of this proposal is that intestinal cell differentiation is regulated by signaling mechanisms involving the PI3K/Akt/PTEN and NF-kB pathways acting on downstream effectors (eg FOXO and TRAIL proteins); novel interactions between these pathways exist that further add to the complex but highly regimented regulation of intestinal homeostasis. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) to further delineate the role of the PI3K/Akt/GSK-3 pathway in gut differentiation 2) to define novel mechanisms of PTEN regulation in the intestine and 3) to examine downstream targets of the PI3K/PTEN pathway in the intestine. The studies in this current proposal are direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the process of normal intestinal differentiation and apoptosis. Delineating the cellular factors and signaling pathways regulating gut differentiation is crucial to our understanding of not only normal gut development and maturation but also aberrant gut growth.

project_terms:
1-Phosphatidylinositol 3-Kinase;Alkaline Phosphatase;Apoptosis;Brush Border;Cell Cycle;Cell Differentiation process;Cell physiology;Cells;Characteristics;Chemicals;Classification;Colon;Complex;Development;Differentiated Gene;Enterocytes;Enteroendocrine Cell;Enzymes;Epithelial;Epithelial Cells;Equilibrium;Event;Family;Gene Expression;Goblet Cells;Grant;Growth;Growth Factor Receptors;Homeostasis;Intestinal Mucosa;Intestines;Malignant neoplasm of prostate;Molecular;Mucous Membrane;NF-kappa B;Neoplasms;Oligo-16-Glucosidase;Operative Surgical Procedures;PTEN gene;Paneth Cells;Pathway interactions;Pattern;Play;Process;Proliferating;Proteins;Regulation;Role;Signal Pathway;Signal Transduction;Small Intestines;Stem cells;Sucrase;TNF-related apoptosis-inducing ligand;Transcriptional Regulation;Tumor Suppressor Proteins;Up-Regulation (Physiology);Villus;base;cancer cell;cell type;design;forkhead protein;inhibitor/antagonist;novel;overexpression;research study


application_id: 7962760
project_number: 1R21HL104315-01
project_title: MG53 mediated myocardial repair for ischemic heart disease
administering_ic: NHLBI
award_notice_date: 2010-06-17
opportunity_number: PA-09-164
application_type: 1
activity_code: R21
ic: HL
serial_number: 104315
program_official: SCHWARTZ, LISA
project_start_date: 2010-06-17
project_end_date: 2012-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
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):   
Abstract  Ischemic heart disease remains as the single largest leading causes of death in the U.S.A. accounting for more than 1 in 3 deaths per annum. Acute ischemic injury and chronic cardiomyopathy lead to permanent loss of cardiac tissue and ultimately heart failure. Developing novel therapeutic approaches that can directly target the causes of cardiomyocyte death during Ischemia/Reperfusion (IR) injury will have broad translational potential. Our recent findings suggest that MG53 a novel muscle-specific member of the TRIM family of proteins (TRIM72) is essential for repair of muscle damage and also provide a therapeutic target for treatment of cardiovascular diseases. This application focuses on testing our hypothesis that "MG53 is an essential molecule for myocardial repair following ischemia-reperfusion injury and extracellular recombinant MG53 may promote myocardial repair and prevent ischemic heart disease". In specific aim 1 we will examine the mechanism underlying MG53-mediated myocardial repair under conditions of oxidative-stress ischemia or acute injury with isolated cardiomyocytes from neonatal mice. Aim 2 of this proposal will establish the efficacy of recombinant MG53 in protection against IR injury to the heart muscle using the wild type and mg53-/- animal models. Specifically we will determine if the application of MG53 protein prior to or after reperfusion can prevent or attenuate ischemia-reperfusion induced myocardial injury. Fulfillment of the proposed experiments may provide the essential proof-of-principle studies on the feasibility of targeting MG53 in treatment of ischemic heart disease.  
  
PUBLIC HEALTH RELEVANCE:   
Project Narrative  Ischemic heart disease is the most common cause of death in most Western countries. Developing novel therapeutic approaches that can directly target the causes of cardiomyocyte death during Ischemia/reperfusion (IR) injury will have broad translational potential. One pathway with great potential as a therapeutic target in regenerative medicine is the process by which individual cells repair their plasma membrane following injury. We recently found that MG53 is a novel muscle-specific member of the TRIM family of proteins (TRIM72) which contributes to the dynamic membrane repair process in skeletal muscle (1-3). However the role of MG53 in myocardial protection remains unknown. In this application we will conduct experiments to investigate the impacts of MG53 in myocardial repair following Ischemia/reperfusion injury. Initially we will use both wild type and MG53 knockout mice models to investigate the mechanism underlying MG53-mediated repair of membrane damage to cardiomyocytes under conditions of oxidative-stress ischemia or acute injury.  We will also assess the efficacy of recombinant MG53 protein in protection against IR injury to the heart muscle using comprehensive evaluation of myocardial performance including echocardiography immunohistochemistry and confocal microscopy with the wild type and MG53 knockout mice.  The results will provide novel insights into proof-of-principle studies to develop effective protein-based therapies for cardiac repair in patients with cardiovascular diseases.

project_terms:
Accounting;Acute;Acute myocardial infarction;Adenoviruses;Animal Model;Arteriosclerosis;Attenuated;Blood flow;Cardiac;Cardiac Myocytes;Cardiac Surgery procedures;Cardiomyopathies;Cardiovascular Diseases;Cause of Death;Cell Death;Cell membrane;Cells;Cessation of life;Chronic;Complex;Confocal Microscopy;Coronary Arteriosclerosis;Country;Data;Development;Echocardiography;Escherichia coli;Evaluation;Exploratory/Developmental Grant;Exposure to;Extracellular Space;Faculty;Future;Goals;Heart;Heart Diseases;Heart Injuries;Heart failure;Immunohistochemistry;Individual;Infarction;Injury;Intellectual Property;Ischemia;Knockout Mice;Lead;Mediating;Membrane;Membrane Protein Traffic;Metabolism;Molecular;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Myocardial;Myocardial Ischemia;Myocardium;NIH Program Announcements;Neonatal;Oxidative Stress;Pathway interactions;Patients;Performance;Physiological;Prevention;Process;Proteins;Recombinants;Regenerative Medicine;Reperfusion Injury;Reperfusion Therapy;Research;Research Project Grants;Role;Signal Transduction;Site;Skeletal muscle structure;Staging;Striated Muscles;TRIM Family;Testing;Therapeutic;Therapeutic Intervention;Tissues;Translating;United States National Institutes of Health;Vesicle;abstracting;anaerobic glycolysis;base;caveolin-3;efficacy testing;extracellular;human DYSF protein;human disease;injury and repair;insight;member;mouse model;novel;novel therapeutic intervention;oxidation;percutaneous coronary intervention;post-doctoral training;prevent;public health relevance;repaired;research and development;research study;restoration;sensor;skeletal;therapeutic protein;therapeutic target;thrombolysis

public_health_relevance:
Project Narrative Ischemic heart disease is the most common cause of death in most Western countries.Developing novel therapeutic approaches that can directly target the causes of cardiomyocytedeath during Ischemia/reperfusion (IR) injury will have broad translational potential. Onepathway with great potential as a therapeutic target in regenerative medicine is the process bywhich individual cells repair their plasma membrane following injury. We recently found thatMG53 is a novel muscle-specific member of the TRIM family of proteins (TRIM72) whichcontributes to the dynamic membrane repair process in skeletal muscle (1-3). However the roleof MG53 in myocardial protection remains unknown. In this application we will conductexperiments to investigate the impacts of MG53 in myocardial repair followingIschemia/reperfusion injury. Initially we will use both wild type and MG53 knockout mice modelsto investigate the mechanism underlying MG53-mediated repair of membrane damage tocardiomyocytes under conditions of oxidative-stress ischemia or acute injury.  We will alsoassess the efficacy of recombinant MG53 protein in protection against IR injury to the heartmuscle using comprehensive evaluation of myocardial performance includingechocardiography immunohistochemistry and confocal microscopy with the wild type andMG53 knockout mice.  The results will provide novel insights into proof-of-principle studies todevelop effective protein-based therapies for cardiac repair in patients with cardiovasculardiseases.


application_id: 7962678
project_number: N01PC54403-16-0-5
project_title: RSS#12 - Patterns of Care- Diagnosis Year 2008
administering_ic: NCI
project_start_date: 2005-08-01
project_end_date: 2010-07-31
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. SEER 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 to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This years Patterns of Care (POC) Study will investigate state-of-the-art therapies for prostate cancer chronic lymphocytic leukemia non-Hodgkin lymphoma and gastrointestinal stromal tumors.


application_id: 7960563
project_number: 2P20RR020145-06
project_title: CHRONIC INFLAMMATION AT MUCOSAL SURFACS: INTERVENTION WITH NOVEL ANTIOXIDANTS
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6733
contact_pi_person_id: 7130705
contact_pi: OZ, HELIEH S
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: 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 chronic lesions of inflammatory bowel disease (IBD) and Crohn's disease (CD) have many similarities to the chronic immunoinflammatory response in the oral cavity that destroys the soft and hard tissues of the periodontium (ie. periodontitis) potentially resulting in exfoliation of the teeth.  While evaluation of the literature supports the common molecular components of the destructive inflammatory responses at the mucosal sites of these diseases minimal data is available comparing/contrasting their characteristics in a common model system.  Moreover there is a burgeoning literature regarding dietary strategies for manipulation of IBD/CD and other inflammatory diseases (eg. rheumatoid arthritis psoriasis) these approaches are minimally developed with regard to adjunctive therapeutics for periodontal disease.  Thus we have developed 2 specific aims for this proposal that utilize a well defined animal model of mucosal inflammation and evaluate the impact of controlling reactive oxygen species (ROS) generated by the inflammation for ameliorating the disease symptoms.
Specific Aim 1: To test the hypothesis that challenge of the periodontium with DSS or TNBS (agents that are known to elicit IBD in murine models) will stimulate periodontitis in these animals.
Specific Aim 2:  To test the hypothesis that treatment of mice with either Green tea polyphenols or 2-(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) which target antioxidant pathways will ameliorate periodontitis induced by DSS and TNBS.

project_terms:
Angioplasty Transluminal Percutaneous Coronary;Animal Model;Animals;Antioxidants;Biological Models;Carboxylic Acids;Characteristics;Chronic;Computer Retrieval of Information on Scientific Projects Database;Crohn's disease;Data;Disease;Epigallocatechin Gallate;Evaluation;Funding;Grant;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Institution;Intervention;Lesion;Literature;Modeling;Molecular;Mucositis;Mus;Oral;Oral cavity;Pathway interactions;Periodontal Diseases;Periodontitis;Periodontium;Psoriasis;Reactive Oxygen Species;Research;Research Personnel;Resources;Rheumatoid Arthritis;Source;Symptoms;Systemic disease;Testing;Therapeutic;Tissues;Tooth Exfoliation;United States National Institutes of Health;base;mucosal site;novel;response


application_id: 7960562
project_number: 2P20RR020145-06
project_title: RENOVATION AND ALTERATIONS
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6732
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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.Unexpended funds from previous years were redirected to fund a renovation and expansion of the DDKCRC Clinical Research Center for Oral Health Studies at the University of Kentucky College of Dentistry under the approval of NIH.  The UK Vice President for Research and the College of Dentistry also provided ~$300000 in matching funds for this renovation & expansion.  The DDKCRC clinic is a state-of-the-art clinical research center comprised of 3 dental operatories with full digital radiography capability office space for clinical coordinators secure records storage area and reception area for recruiting patients.  This facility has served as the NCRR/NIH dental core for the GCRC during the COBRE project.  The demands on this facility have grown beyond the capability of the facility "spilling out" to contiguous teaching clinics.  This R&A subproject will double the operatories and records storage and create a private waiting area and reception for our clinic patients.  Patient access will be improved and research activities will be easier to isolate from non-research activities.

project_terms:
Area;Arts;Centers of Research Excellence;Clinic;Clinical;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Dentistry;Digital Radiography;Educational process of instructing;Funding;Grant;Institution;Kentucky;Oral;Oral health;Patients;Records;Recruitment Activity;Research;Research Activity;Research Personnel;Resources;Secure;Source;Systemic disease;United States National Institutes of Health;Universities;base;college;improved


application_id: 7960561
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: INFLAMMATORY MEDIATORS LEVELS FULL MOUTH EXTRACTIONS
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6731
contact_pi_person_id: 2045756
contact_pi: CUNNINGHAM, LARRY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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.Hypothesis:  Full mouth tooth extraction in patients with advanced periodontal disease will lead to significantly decreased systemic inflammation determined by levels of C-reactive protein IL-6 and serum amyloid A.
The aims have been studied using a prospective longitudinal design to model the loss of systemic inflammatory risk factors related to dental therapy resulting in an edentate patient.  Patients (ages 18-80) who selected treatment plans that include extraction of all remaining teeth will be eligible for the study.  In this pilot study to provide preliminary data for proof of concept we will enroll approximately 40 patients with 20 in each group (eg. generalized periodontitis dental caries).  Patients who have elected to have all their teeth removed and to have dentures made will be recruited.  On the day of their surgery blood will be drawn for baseline levels of CRP IL-6 and SAA.  Extractions will then be completed as normal with separate standard surgical informed consent.  Post-surgery visits at 1 3 6 and 12 months will be scheduled coordinated with routine denture follow-up appointments for collection of blood and analysis of changes in CRP IL-6 and SAA.  The analysis of the mediators will be accomplished through the Core Translational Diagnostic Laboratory of the CBBOSD.

project_terms:
Age;Appointment;Blood;C-reactive protein;Centers of Research Excellence;Collection;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental caries;Dentures;Diagnostic;Enrollment;Funding;Grant;Inflammation;Inflammation Mediators;Inflammatory;Informed Consent;Institution;Interleukin-6;Laboratories;Lead;Mediator of activation protein;Modeling;Operative Surgical Procedures;Oral;Oral cavity;Patients;Periodontal Diseases;Periodontitis;Pilot Projects;Recruitment Activity;Research;Research Personnel;Resources;Risk Factors;Schedule;Serum amyloid A protein;Source;Systemic disease;Tooth Extraction;Tooth structure;United States National Institutes of Health;Visit;base;follow-up;longitudinal design;prospective;treatment planning


application_id: 7960560
project_number: 2P20RR020145-06
project_title: SMOKING: EFFECTS OF GENOTYPE ON PERIODONTITIS
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6730
contact_pi_person_id: 8534338
contact_pi: AL-SABBAGH, MOHANAD
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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.Specific Aim 1: To determine the distribution of select pro- and anti-inflammatory gene polymorphisms in smokers with and without periodontitis.
Specific Aim 2:  To determine the distribution of gene polymorphisms for select tissue remodeling genes in smokers with and without periodontitis.
Specific Aim 3:  To determine the distribution of gene polymorphisms for select factors controlling reactive oxygen species in smokers with and without periodontitis.
The objective of this proposal is that for more effective management of periodontitis it would be desirable to identify subsets of individuals at greatest risk for developing smoking-related periodontitis. Identification of genetic markers that confer increased risk to periodontitis in smokers would permit more effective allocation of healthcare resources and permit targeted interventions. It would also contribute to our general understanding of the mechanisms by which smoking confers risk.  We proposed to conduct a case-control study of 500 smokers with or without periodontitis. We will compare these groups with regard to certain genetic polymorphisms that may be associated with increased risk for periodontitis.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Case-Control Studies;Computer Retrieval of Information on Scientific Projects Database;Funding;Genes;Genetic Markers;Genetic Polymorphism;Genotype;Grant;Healthcare;Individual;Institution;Intervention;Oral;Periodontitis;Reactive Oxygen Species;Research;Research Personnel;Resources;Risk;Smoke;Smoker;Smoking;Source;Systemic disease;Tissues;United States National Institutes of Health;base


application_id: 7960559
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: VIRAL INFECTIONS IN CHRONIC ORAL DISEASES
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6729
contact_pi_person_id: 9185054
contact_pi: LI, MENGTAO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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 bacteria are the primary pathogens in periodontitis human herpesviruses have a purported relationship with inflamed periodontal tissues. This could be important because herpesviruses modulate host immune responses through a variety of mechanisms.  The goal of this research was to test the hypothesis that herpesviruses enhance the pathogenesis of periodontal diseases.  Our hypothesis is being examined using three approaches:  1) determine the role of herpesviruses in periodontitis by  analyzing clinical samples from patients with and without periodontal disease 2) investigating the ability of herpesvirus to enhance the progression of periodontitis in the rat model;  and 3) define mechanisms of immunomodulation by cytomegalovirus (CMV).  To address component 1 we are analyzing dental plaque from healthy and diseased sites and parallel saliva samples from 100 patients with periodontal disease.  Real-time PCR is being used to detect DNA of human herpesvirus in the samples obtained longitudinally over 6 months.  In the second project the rat CMV (RCMV) Maastricht strain has been obtained propagated and titered.  Animals have been inoculated with P. gingivalis and/or RCMV to establish infections and evaluate the periodontal response. In the study of molecular mechanisms of immunomodulation by CMV we have cloned and characterized novel isoforms of CMV vIL-10 gene and recently cloned EBV vIL-10. Because these viruses can modulate the immune response we have initiated studies that determine their role in modulating the host response of oral epithelia and gingival fibroblasts against invasion by periodontal bacterial pathogens.  Using human primary macrophages and THP-1 derived macrophage as models we have studied the effects of CMV and EBV infection on the function of macrophage in response to four oral microorganisms: P. gingivalis (Pg) and A. actinomycetemcomitans (Aa); opportunistic pathogen F. nucleatum (Fn); and non-pathogen S. gordonii (Sg) and have demonstrated that CMV and EBV alters the TNFa response of macrophages to these oral microorganisms. We are in the process of determining if lytic genes of CMV and/or EBV are required for the altered response and whether these viruses also inhibit the phagocytosis activity of macrophages to these bacteria.

project_terms:
Actinobacillus actinomycetemcomitans;Address;Animals;Bacteria;Centers of Research Excellence;Chronic;Clinical;Computer Retrieval of Information on Scientific Projects Database;Cytomegalovirus;Dental;Dental Plaque;Epstein-Barr Virus Infections;Fibroblasts;Funding;Fusobacterium nucleatum;Genes;Gingiva;Goals;Grant;Herpesviridae;Human;Immune response;Infection;Institution;Lytic;Modeling;Molecular;Mouth Diseases;Oral;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Phagocytosis;Porphyromonas gingivalis;Process;Protein Isoforms;Rat Cytomegalovirus;Rattus;Research;Research Personnel;Resources;Role;Saliva;Sampling;Site;Source;Streptococcus gordonii;Systemic disease;Testing;Time;Tissues;United States National Institutes of Health;Virus;Virus Diseases;base;human DNA;immunoregulation;macrophage;microorganism;novel;oral cavity epithelium;oral infection;pathogen;response


application_id: 7960558
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: DIETARY REGULATION OF INFLAMMATORY RESPONSES
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6728
contact_pi_person_id: 8263389
contact_pi: DAWSON, DOLPHUS R.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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.Periodontal disease is a chronic inflammatory condition that may have a significant negative impact on systemic conditions such as diabetes and cardiovascular disease.  Previous studies have suggested that controlling oral infection and inflammation may have beneficial systemic effects.  Studies have also shown that many well-recognized disorders are associated with excessive intake of dietary fat including obesity insulin resistance coronary heart disease and some forms of cancer.  While intake of saturated trans and arachidonic fatty acids has been linked to the development of chronic disease research shows n-3 polyunsaturated fatty acids (n-3 PUFA) specifically fish oils (e.g. Cold-water fish such as mackerel) can contribute to the prevention and treatment of disease.  Dietary n-3 PUFA provides a benefit by reducing inflammation and improving antibacterial and autoimmune responses in many chronic inflammatory medical conditions.  It is hypothesized that the use of n-3 PUFA as a dietary supplement could have an important impact on systemic health by reducing chronic periodontal disease and systemic inflammation either alone or when combined with periodontal therapy.  This project will study the effects of dietary n-3 PUFA capsules (1000 mg t.i.d.) compared to placebo (corn/soybean oil) capsules in 200 subjects with generalized periodontitis a condition known to have negative systemic outcomes and be associated with a hyper-inflammatory phenotype as demonstrated by elevated inflammatory cell function and elevated systemic levels of C-reactive protein (CRP).  Using a randomized double-blind placebo controlled intervention study of 4 groups (50 subjects per group) we will study the effects of combining n-3 PUFA or placebo with oral hygiene or scaling and root planing on systemic inflammation (measured by CRP); periodontal inflammation and clinical outcomes (clinical measures and inflammatory mediators in gingival crevicular fluid); and bacterial colonization of plaque (changes in levels of P. gingivalis T. denticola and T. forsythensis).  A three month period of study organization followed the notification of funding in September 2004. Therefore initial study recruitment did not begin until early 2005.  Currently there have been four subjects enrolled into the study; 104 subjects pre-screened and 30 qualified and ready for enrollment.  No data analysis has been done.

project_terms:
Anti-Bacterial Agents;Autoimmune Responses;C-reactive protein;Cardiovascular Diseases;Cell physiology;Centers of Research Excellence;Chronic;Chronic Disease;Clinical;Computer Retrieval of Information on Scientific Projects Database;Coronary heart disease;Data Analyses;Dental;Dental Hygiene;Development;Diabetes Mellitus;Dietary Fats;Dietary Supplements;Disease;Double-Blind Method;Enrollment;Fatty Acids;Fish Oils;Fishes;Funding;Gingival Crevicular Fluid;Grant;Health;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Institution;Insulin Resistance;Intake;Intervention Studies;Link;Malignant Neoplasms;Measures;Medical;N-3 polyunsaturated fatty acid;Notification;Obesity;Oral;Outcome;Periodontal Diseases;Periodontitis;Phenotype;Placebo Control;Placebos;Polyunsaturated Fatty Acids;Porphyromonas gingivalis;Prevention;Qualifying;Randomized;Regulation;Research;Research Personnel;Resources;Source;Soybean Oil;Systemic disease;Treponema denticola;United States National Institutes of Health;Water;base;capsule (pharmacologic);improved;oral infection;scaling and root planing


application_id: 7960557
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: IMPACT ON GESTATIONAL DIABETES
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6727
contact_pi_person_id: 1880406
contact_pi: NOVAK, KAREN F.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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 GENERAL HYPOTHESIS is that women with GDM are at higher risk for developing more severe periodontal disease than women without GDM and that the combination of GDM and periodontal disease will be associated with an increased negative impact on maternal and fetal health.  These prospective clinical data will be correlated with basic science laboratory evaluations of the microflora and host response to provide insight into the pathogenic mechanisms contributing to negative maternal and fetal outcomes associated with inflammatory periodontal disease and GDM.  
This project consists of three specific aims that are designed to study the effects of Gestational Diabetes Mellitus (GDM) on the clinical microbiologic and immunologic characteristics of periodontal disease and the associations between these potential risk factors and maternal and fetal health.  At enrollment the investigator performs a clinical periodontal examination to document the presence and severity of periodontitis (Specific Aim 1).   Patients who are enrolled early in their pregnancy (31 weeks) may only be seen for one visit.  Comparable examinations are performed on the controls without GDM who have been matched with the test subjects for age race/ethnicity and gestational week.  The subjects are stratified into four groups based on diabetic status and the presence or absence of periodontitis  Group 1:  GDM with periodontitis (GDM + PD); Group 2:  GDM without periodontitis (GDM  PD); Group 3: normal controls with periodontitis (NC + PD); and Group 4: normal controls without periodontitis (NC  PD).   In addition to performing the clinical examinations dental plaque and serum samples are collected as part of the baseline and 34 week examinations allowing us to characterize the subgingival biofilm microbiota (Specific Aim 2) and quantify levels of systemic inflammatory biomarkers (Specific Aim 3) in each group and at each time point. The study population consists of a group of ambulatory women aged 16-45 whose pregnancies are being managed through the University of Kentucky Clinics the Gordon and Salter Inc. practice in Richmond KY and the Georgetown Obstetrics and Gynecology practice in Georgetown KY.  We have currently enrolled 271 subjects into the following categories:  GDM + PD 56; GDM  PD 83; NC + PD 42; NC  PD 90.  The ethnic/racial profiles are 100 White 120 Hispanic/Latino 29 Black/African American and 22 Asian.  All of the data including maternal and fetal outcomes have been collected on 230 of these subjects.

project_terms:
African American;Age;Asians;Basic Science;Categories;Centers of Research Excellence;Characteristics;Clinic;Clinical;Clinical Data;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental Plaque;Discipline of obstetrics;Disease Association;Enrollment;Ethnicity aspects;Evaluation;Funding;Gestational Diabetes;Grant;Gynecology;Health;Hispanics;Immune response;Immunologics;Inflammatory;Institution;Kentucky;Laboratories;Latino;Oral;Outcome;Patients;Periodontal Diseases;Periodontitis;Population Study;Pregnancy;Race;Research;Research Personnel;Resources;Risk Factors;Sampling;Serum;Severities;Source;Systemic disease;Testing;Time;United States National Institutes of Health;Universities;Visit;Woman;aged;base;biomarker;design;diabetic;fetal;high risk;insight;oral infection;prospective;racial and ethnic;subgingival biofilm


application_id: 7960556
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: COX-2
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6726
contact_pi_person_id: 8351945
contact_pi: LOFTIN, CHARLES DAVID
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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.Specific Aim 1:. Determine the effect of non-selective COX and selective COX-2 inhibition on P. gingivalis-induced vascular disease in mice. 

Specific Aim 2:  Define the role of 12/15-lipoxygenases in P. gingivalis-induced periodontal disease and  atherosclerosis.

project_terms:
Arachidonate 15-Lipoxygenase;Atherosclerosis;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Funding;Grant;Institution;Mus;Oral;PTGS2 gene;Periodontal Diseases;Porphyromonas gingivalis;Research;Research Personnel;Resources;Role;Source;Systemic disease;United States National Institutes of Health;Vascular Diseases;base;oral infection


application_id: 7960555
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: DENTAL CLINICAL RESEARCH CENTER
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6725
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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 primary focus of the DDKCRC is to create a research infrastructure to: 1) develop and train clinical research professionals research coordinators and research staff and 2) define and impact oral health disparities in rural communities of Kentucky.  An initial emphasis will be on investigations to determine oral-systemic disease linkages in these rural populations and to define biological genetic and socio-behavioral factors contributing to these disparities.  The DDKCRC personnel have focused on the preparation and submission of forms for IRB approval for all projects.  These have all been obtained and the projects initiated.  The personnel contribute to the recruitment of patients for these same projects as well as collecting biological specimens for the projects.  Finally the laboratory personnel in the DDKCRC provide support for evaluation of host analytes in various biological fluids for all projects.  In addition the laboratory has developed a real-time quantitative PCR methodology for assessment of target microorganisms in the subgingival plaque.

project_terms:
Behavioral;Biological;Centers of Research Excellence;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Evaluation;Funding;Genetic;Grant;Human Resources;Institution;Investigation;Kentucky;Laboratories;Laboratory Personnel;Liquid substance;Methodology;Oral;Oral health;Patient Recruitments;Preparation;Research;Research Ethics Committees;Research Infrastructure;Research Personnel;Resources;Rural Community;Rural Population;Source;Specimen;Systemic disease;Time;Training;United States National Institutes of Health;base;health disparity;microorganism


application_id: 7960554
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: BIOINFORMATICS & BIOSTATISTICS CORE
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6724
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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 core provides expert advice on experimental design data management subject recruitment and data analysis to the clinical projects in this COBRE and it provides expertise on the analysis of the bioinformatics data generated in the basic science projects.  This advice promotes efficiency in terms of the minimal number of patients to be recruited to a clinical study or the minimum number of chips to be processed in a microarray experiment so that information is maximized. Advice rendered at an early stage in the design of the project makes a difference. It also significantly improves the chances that the project will be successful as evidenced by the role this core played in one success in each area. Inherent in this core is a training component since its personnel supervise graduate students trainees in their own discipline and work on a one to one basis with young investigators in the dental sciences.  The younger faculty in this core are also mentored by the senior faculty.  A journal paper summarizing a pilot project supporting a current clinical project and several abstracts based on related dental graduate student research have been submitted. An R01 application in the basic science area in which this core provided key technical support has been awarded and another application is in progress.  As the projects in this COBRE mature personnel in this core will analyze the data generated and when needed will create new methodology to help interpret the results.

project_terms:
Area;Award;Basic Science;Bioinformatics;Biostatistics Core;Centers of Research Excellence;Clinical;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Data;Data Analyses;Dental;Discipline;Experimental Designs;Faculty;Funding;Grant;Human Resources;Institution;Journals;Mentors;Methodology;Oral;Paper;Patients;Pilot Projects;Play;Process;Recruitment Activity;Research;Research Personnel;Resources;Role;Science;Source;Staging;Systemic disease;Training;United States National Institutes of Health;Work;abstracting;base;data management;design;graduate student;improved;research study;success


application_id: 7960553
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ADMINISTRATIVE AND EDUCATIONAL CORE
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6723
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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/Educational Core of the CBBO/SD has facilitated the research and training goals of the COBRE by: (1) To schedule and organize meetings for the CBBO/SD participants; (2) To organize meetings of the Scientific Advisory Committee (SAC); (3) To provide fiscal administration and accounting; (4) To interface with institutional administration in new faculty recruitment; (5) To oversee the funding of new pilot projects; (6) To interface and provide appropriate reporting to the NIH and other regulatory agencies; (7) To sponsor and organize research career development and training opportunities; and (8) To provide outcomes assessment of the CBBO/SD.

project_terms:
Accounting;Advisory Committees;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Faculty;Funding;Goals;Grant;Institution;Oral;Outcome Assessment (Health Care);Participant;Pilot Projects;Reporting;Research;Research Personnel;Research Training;Resources;Schedule;Source;Systemic disease;Training;United States National Institutes of Health;base;career development;meetings


application_id: 7960552
project_number: 2P20RR020145-06
project_title: UKY DENTAL COBRE: ORAL INFECTIONS AND HIV RECRUDESCENCE
administering_ic: NCRR
award_notice_date: 2009-09-28
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2009-09-30
project_end_date: 2010-07-30
study_section: ZRR1-RI-B(01)
subproject_number: 6722
contact_pi_person_id: 8367053
contact_pi: HUANG, CHIFU BRAD
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This 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.Specific Aim 1: To determine the capacity of selected oral microorganisms to activate HIV-1 in latently infected T lymphocytes and macrophages.
Specific Aim 2:  To determine the ability of selected oral microorganisms to elicit mediators from resident cell populations that can activate HIV-1 in latently infected T lymphocytes and macrophages.
Specific Aim 3:  To determine the target receptors for bacterial and host stimulation of the HIV promoter and HIV reactivation in latently infected T cells and macrophages.

project_terms:
Cells;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Funding;Grant;HIV;HIV-1;Institution;Mediator of activation protein;Oral;Population;Promotor (Genetics);Recrudescences;Research;Research Personnel;Resources;Source;Systemic disease;T-Lymphocyte;United States National Institutes of Health;base;macrophage;microorganism;oral infection;receptor


application_id: 7960503
project_number: 2P20RR020171-06
project_title: MECHANISMS OF PERIPHERAL REGULATORY T CELL GENERATION
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6673
contact_pi_person_id: 7732443
contact_pi: MARTI, FRANCESC
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.Peripherally induced Regulatory T cell (iTregs) is the predominant source of T cell suppressor activity in the human immune system. As such the possibility to control their development holds a tremendous therapeutic promise. Our lab has established a cell culture system that recapitulates the generation of functional iTregs ex vivo from primary human T cells. With this system and using a broad range of cellular molecular biochemical and imaging approaches we will elucidate phenotypic and functional properties of these newly generated suppressor T cells and will shed light upon the phenomenon of their occurrence. The ultimate goal is to control the shift of the T cell response from effector to tolerogenic or vice-versa. The Specific Aims of this proposal are: 

+Aim 1) Test the hypothesis that a distinctive population of functional human Treg cells can be generated in vitro from conventional CD4+CD25- T cells.
+Aim 2) Test the hypothesis that the induction of suppressor activity requires the molecular cross-talk and integration of different signaling pathways.

The results ought to provide a solid foundation to support the development of rational strategies to induce direct or restore the normal immunological activity in different pathologies such as autoimmunity chronic inflammation or cancer. This project has clear and direct relevance to human health: the capacity to modulate the development and/or response of Tregs may become instrumental in controlling the dynamic plasticity of the immune response.

project_terms:
Autoimmunity;Biochemical;Cell Culture System;Cells;Centers of Research Excellence;Chronic;Computer Retrieval of Information on Scientific Projects Database;Development;Foundations;Funding;Generations;Goals;Grant;Health;Human;Image;Immune response;Immune system;In Vitro;Inflammation;Institution;Light;Malignant Neoplasms;Molecular;Pathology;Peripheral;Population;Property;Research;Research Personnel;Resources;Signal Pathway;Solid;Source;Suppressor-Effector T-Lymphocytes;System;T-Lymphocyte;Testing;Therapeutic;United States National Institutes of Health;base;human disease;response


application_id: 7960502
project_number: 2P20RR020171-06
project_title: ROLE OF AMP-ACTIVATED PROTEIN KINASE IN LAFORA AND WOLFF-PARKINSON-WHITE DISEASE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6672
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
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.Lafora disease (LD) is caused by mutations in the carbohydrate phosphatase laforin.  A hallmark of LD is the accumulation of insoluble carbohyrate called Lafora bodies (LBs) in the cytoplasm of cells.  While LBs accumulate in most cells apoptosis only occurs in neurons and this eventually leads to epilepsy and death of the patient.  Wolff-Parkinson-White (WPW) syndrome is a cardiac hypertrophy caused by insoluble carbohydrate accumulations resulting from mutations in the cellular energy sensor and regulator AMP-activated protein kinase (AMPK).  We recently identified both a phenotypic and biochemical connection between LD and WPW.  We discovered that i) carbohyrate accumulations in LD and WPW are very similar ii) laforin contains an AMPK consensus phosphorylation site iii) AMPK phosphorylates laforin in vitro and iv) carbohydrates increase AMPK kinase activity towards laforin.  This proposal will define these events and determine the connection between LD and WPW.  Specific Aim 1 will identify the conditions that promote phosphorylation in vivo and map the in vivo phosphorylation site(s).  In specific Aim 2 we will determine if AMPK phosphorylation affects laforin binding to known substrates the localization of laforin and/or the phosphatase of laforin.  In specific aim 3 we will determine the mechanism of carbohydrate stimulated AMPK kinase activity.  In doing so we will define the fold increase in AMPK-kinase activity the carbohydrate(s) catalyst and the substrates affected.  Finally we will translate these findings into a mouse model of LD.  The studies proposed will define the connection between AMPK-WPW with laforin-LD.  In addition they will better characterize carbohydrate metabolism which is at the heart of multiple metabolic disorders including diabetes and yield insights into novel treatments.

project_terms:
5'-AMP-activated protein kinase;AMP-activated protein kinase kinase;Affect;Apoptosis;Binding (Molecular Function);Biochemical;Carbohydrates;Cells;Centers of Research Excellence;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Consensus;Cytoplasm;Diabetes Mellitus;Disease;Epilepsy;Event;Funding;Grant;Heart;Heart Hypertrophy;In Vitro;Institution;Lafora Disease;Maps;Metabolic Diseases;Molecular;Mutation;Neurons;Parkinson Disease;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Research;Research Personnel;Resources;Role;Source;Translating;United States National Institutes of Health;Wolff-Parkinson-White Syndrome;base;carbohydrate metabolism;catalyst;human disease;in vivo;insight;mouse model;novel;sensor


application_id: 7960501
project_number: 2P20RR020171-06
project_title: NEGATIVE REGULATION OF THE YEAST MRP YCF1P AND THE HUMAN MRPS BY CK2
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6671
contact_pi_person_id: 6926841
contact_pi: PAUMI, CHRISTIAN M
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 multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury arsenic lead and cadmium).  The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional "N-terminal extension" with a conserved region called L0 and 2) they transport substrates in the form of glutathione (GSH)-conjugates.  The overall goal of this work  is to determine how MRP function is regulated in vivo.   Specifically I am interested in defining the role of MRP-protein kinase interactors in regulating MRP function.   The aims if this proposal are identifying the mechanism by which an  MRP-protein kinase interactor the yeast casein kinase 2 (CK2) alpha subunit Cka1p  negatively regulates the function of the yeast MRP Ycf1p.   Cka1p has been shown to be catalytically active as a homodimer and a heterodimer with the CK2 alpha' subunit Cka2.  Therefore this proposal will determine if Cka1p regulation  ofYcf1p function requires Cka2p.  In addition the Paumi lab will examine the role of the homologous human kinase CKalpha in regulating human MRP1 and MRP6 function.  The studies described within this proposal will provide useful insight into the role of kinases in the regulation of MRP function the role of the MRPs in "metabolic quality control" and have the potential to establish new and more effective treatments for MRP related diseases such as cystic fibrosis multidrug resistance in cancer and pseudoxanthoma elasticum.

project_terms:
ABCC1 gene;ATP-Binding Cassette Transporters;Arsenic;Cadmium;Casein Kinase 2alpha;Casein Kinase 2alpha';Cells;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Cystic Fibrosis;Disease;Employee Strikes;Funding;Glutathione;Goals;Grant;Heavy Metals;Human;Institution;Lead;Malignant Neoplasms;Mercury;Metabolic;Molecular;Multi-Drug Resistance;Multidrug Resistance-Associated Proteins;N-terminal;Pharmaceutical Preparations;Phosphotransferases;Play;Protein Kinase;Pseudoxanthoma Elasticum;Quality Control;Regulation;Research;Research Personnel;Resources;Role;S100A12 gene;Source;Toxic Environmental Substances;United States National Institutes of Health;Work;Yeasts;base;casein kinase II;effective therapy;human disease;in vivo;insight;interest;protein function


application_id: 7960500
project_number: 2P20RR020171-06
project_title: ANTIBODY PRODUCTION AND MOUSE GENOTYPING CORE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6670
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 genotyping core will be based on the second floor of the BBSRB.  At present the core is still being set up.  We have developed the PCR-based methodology for genotype analysis and have optimized the DNA preparation protocols.  All of the technologies have been tested on a small scale (~50 animals).  The equipment heat blocks Robocycler PCR machine repeating pipette sets and large format agarose electrophoresis apparati are in place.  A detailed set of user instructions are being written to describe what services are to be provided and what the user needs to supply the core in terms of sample PCR primer sets and reaction conditions.  An advertisement for a technician to run the facility has been circulated and applicants are being interviewed.  The technician will handle the mouse genotyping and antibody production.

project_terms:
Advertisements;Animals;Antibody Formation;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;DNA;Electrophoresis;Equipment;Floor;Funding;Genotype;Grant;Heating;Institution;Instruction;Interview;Methodology;Molecular;Mus;Preparation;Protocols documentation;Reaction;Research;Research Personnel;Resources;Running;Sampling;Sepharose;Services;Source;Technology;Testing;United States National Institutes of Health;Writing;base;human disease


application_id: 7960499
project_number: 2P20RR020171-06
project_title: STRUCTURAL STUDIES OF NEUROPILIN SIGNALING
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6669
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
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.Neuropilin is an essential bi-functional mammalian cell surface receptor functioning in both angiogenesis and axon guidance.  Neuropilin is of particular medical importance since in addition to its normal roles it also is required for VEGF dependent tumor angiogenesis facilitating neo-vascularization and growth of solid tumors.  During both normal and tumor-angiogenesis neuropilin binds members of the VEGF family of ligands and functions as a co-receptor for the VEGF-R receptor tyrosine kinases. During neural development neuropilin binds members of the semaphorin III family of ligands and functions as a co-receptor for members of the plexin family of receptors.  We seek to understand neuropilin ligand binding specificity and receptor activation. Additionally we seek to inform ongoing studies to define novel anti-angiogenesis targets.  Fundamentally our goal will be to answer the following questions: How does neuropilin activate and regulate VEGF dependent angiogenesis and semaphorin dependent axon guidance?

Structural studies of neuropilin ligand binding will allow definition of the physical basis for interaction between core neuropilin and ligand domains.  These studies will define common features of ligand binding as well as unique features that determine specificity between different protein homologues and isoforms.  Further studies will characterize the mechanism(s) by which ligand binding to neuropilin couples to activation of VEGF-R and plexin signaling receptors.  Structural studies will primarily be based on X-ray crystallography but will also employ a variety of other structural techniques including NMR EM and SAXS. The latter two techniques will be particularly employed to study large and conformationally labile protein complexes. In addition other biophysical and biochemical techniques will be employed to characterize protein-protein interactions and the effects of mutations in this system.

project_terms:
Binding (Molecular Function);Biochemical;Cell Surface Receptors;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Couples;Family;Funding;Goals;Grant;Growth;Homologous Gene;Institution;Ligand Binding;Ligands;Mammalian Cell;Medical;Molecular;Mutation;Neuropilins;Protein Isoforms;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Research;Research Personnel;Resources;Role;Signal Transduction;Solid Neoplasm;Source;Specificity;System;Techniques;Tumor Angiogenesis;United States National Institutes of Health;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;X-Ray Crystallography;angiogenesis;antiangiogenesis therapy;axon guidance;base;human disease;member;neurodevelopment;novel;plexin;protein complex;protein protein interaction;receptor;receptor function


application_id: 7960498
project_number: 2P20RR020171-06
project_title: THE INHIBITORY ROLE OF INTEGRIN ?5 IN ADIPOCYTE DIFFERENTIATION
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6668
contact_pi_person_id: 6876032
contact_pi: LIU, JUN S
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.This study is directed toward understanding adipocyte differentiation a critical process that contributes to the development of excess adipose mass and obesity. While changes in the ECM and integrin receptor expression have been observed during adipocyte differentiation the ability of these processes to regulate adipogenesis is largely unexplored. The overall GOAL of this proposed study is to elucidate the anti-adipogenic function of integrin 5. This goal will be accomplished by determining (1) whether the loss of integrin 5 expression promotes adipocyte differentiation and obesity; and (2) the mechanism whereby the 5 integrins regulates the Rac activity in preadipocytes.

project_terms:
Adipose tissue;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Development;Extracellular Matrix;Funding;Goals;Grant;Institution;Integrins;Molecular;Obesity;Process;Research;Research Personnel;Resources;Role;Source;United States National Institutes of Health;adipocyte differentiation;base;human disease;lipid biosynthesis;receptor expression


application_id: 7960497
project_number: 2P20RR020171-06
project_title: REGULATION OF ALTERNATIVE PRE-MRNA PROCESSING BY SMALL NUCLEOLAR RNAS
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6667
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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 objective of the project is to determine how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome the most frequent genetic cause for life-threatening obesity. We will determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and elucidate the molecular basis by which one of these snoRNAs HBII-52 influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre-mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. We use overexpression of snoRNA-expressing constructs to validate bioinformatically predicted target genes. The proposed work is innovative because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current 'textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.

project_terms:
Alternative Splicing;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Defect;Drug Delivery Systems;Funding;Gene Targeting;Genes;Genetic;Grant;Individual;Institution;Knowledge;Life;Masks;Molecular;Obesity;Pattern;Prader-Willi Syndrome;Process;RNA Splicing;Regulation;Regulatory Element;Research;Research Personnel;Resources;Role;Site;Small Nucleolar RNA;Small RNA;Source;Textbooks;United States National Institutes of Health;Work;base;human disease;innovation;mRNA Precursor;novel;overexpression


application_id: 7960496
project_number: 2P20RR020171-06
project_title: ORGANIC SYNTHESIS CORE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6666
contact_pi_person_id: 9175312
contact_pi: WATT, DAVID
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 organic synthesis core is designed to provide access to novel compounds not available through commercial sources.  The well-trained technical staff as well as the core director will consult with investigators to understand the particular need and will design and synthesize the appropriate molecules.  The facility staff will undertake for example the synthesis and characterization of a novel probe a photoactive analog a better soluble version of a compound than one now in use a fluorescent analog that would replace a radiolabeled compound that is now in use a modified natural product that might covalently bind a receptor an unnatural peptide that would have better stability than its wild-type counterpart a polymer-bound compound needed for a particular purification etc.  The core is equipped with appropriate equipment to prepare and characterize organic compounds with molecular weights of 2 kDa or less and has access to appropriate chromatographic and analytical techniques including NMR and mass spectrometry that will be used to confirm structural assignments.

project_terms:
Binding (Molecular Function);Biological Factors;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Consult;Equipment;Funding;Grant;Institution;Mass Spectrum Analysis;Molecular;Molecular Weight;Organic Synthesis;Peptides;Polymers;Radiolabeled;Research;Research Personnel;Resources;Source;Techniques;Training;United States National Institutes of Health;analog;base;design;human disease;novel;radiotracer;receptor


application_id: 7960495
project_number: 2P20RR020171-06
project_title: STUDIES OF RILP AND RILP-BINDING PROTEIN DYNACTIN P150GLUED AND HUNTINGTIN
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6665
contact_pi_person_id: 7875223
contact_pi: SHIMOJO, MASAHITO
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.Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion in the huntingtin protein.  It was suggested that the longer polyglutamine domain induce conformational changes causing it to form intracellular aggregates as nuclear inclusions in most cases.  HD is characterized by disturbances in motor cognitive and psychiatric function.  It has been postulated that the expanded polyglutamine repeat causes huntingtin to interact abnormally with other cellular proteins.  Wild-type huntingtin was found to interact with the transcriptional regulator REST which represses most neuronal gene expression in non-neuronal cells.  The interaction between huntingtin and REST kept REST in the cytosol thereby preventing REST target genes repression.  It was shown that wild-type and mutant huntingtin mediate REST dependent neuronal gene expression of BDNF through its regulatory DNA element RE1.  We have cloned another REST interacting protein we called RILP for REST/NRSF-Interacting LIM domain Protein.  RILP is a novel protein which is required for the nuclear targeting and function of REST.  We have preliminarily identified another RILP-interacting protein which is dynactin p150Glued and have shown that huntingtin and dynactin p150Glued copurify with RILP.  Dynactin p150Glued is an accessory protein for the microtubule motor protein dynein which is thought to be involved in trafficking steroid receptors and some other transcription factors between the cytoplasm and nucleus in a dynactin dependent process.  We thus postulate that RILP dynactin p150Glued and huntingtin are involved in targeting cytoplasmically synthesized REST through the dynein-microtubule pathway to the nucleus.  Disruption of this function could contribute to the neuronal dysfunction and death seen in diseases such as Huntington's disease (HD).

project_terms:
Binding Proteins;Brain-Derived Neurotrophic Factor;Cell Nucleus;Centers of Research Excellence;Cessation of life;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Cytosol;DNA;Disease;Dynein ATPase;Elements;Funding;Gene Expression;Grant;Huntington Disease;Inherited;Institution;LIM Domain Protein;Mediating;Microtubule Proteins;Microtubules;Molecular;Motor;Neurodegenerative Disorders;Neuroglia;Neuronal Dysfunction;Neurons;Nuclear;Nuclear Inclusion;Pathway interactions;Process;Proteins;Research;Research Personnel;Resources;Source;Steroid Receptors;United States National Institutes of Health;base;dynactin;gene repression;human Huntingtin protein;human disease;mutant;novel;polyglutamine;prevent;trafficking;transcription factor


application_id: 7960494
project_number: 2P20RR020171-06
project_title: KY COBRE: PROTEOMICS CORE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6664
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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 proteomics core is designed to provide quantitative and qualitative protein profiling and identification analysis as well as post-translational modification and sequence analysis through a combination of 2D gel mass spectrometry and Edman sequencing analysis services. The core is equipped with Bio-Rad IPG and SDS-PAGE apparatus for 2D gel analysis a Typhoon phosphorimager/scanner system for detection and quantitation of fluorescent protein dyes (Cy-dyes) and stains (SYPRO-Ruby Pro-Q Diamond) used to analyze 1D and 2D gels a Ciphergen SELDI-TOF protein profiling system an ABI QSTAR II Q-TOF Mass Spectrometer with both MALDI and LC/ESI source capabilities Waters HPLC systems and multiple PCs for data acquisition and analysis including a site license for PDQuest software and a 5 station site license for Ciphergen software. Fully trained technical staff will assist investigators with the full range of proteomics analytical services. The staff will instruct investigators and their laboratory staff (students post-doctoral fellows and technicians) in sample preparation 2D gel analysis and quantitation by fluorescent staining methods. Protein fragmentation mass peptide mapping and protein sequencing by both MS/MS mass spectrometry and chemical sequencing will be performed by Dr. Beach on samples provided by individual investigators. Preparation and analysis of samples with the Ciphergen system will be facilitated by automated robotic work stations. Data analysis will be performed by investigators and their colleagues through multiple distant work stations connected to the Ciphergen system via the web.

project_terms:
Amino Acid Sequence;Centers of Research Excellence;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Computer software;Data Analyses;Detection;Diamond;Distant;Dyes;Funding;Gel;Grant;High Pressure Liquid Chromatography;Individual;Institution;Internet;Laboratories;Licensing;Mass Spectrum Analysis;Molecular;Peptide Mapping;Peptide Sequence Determination;Post-Translational Protein Processing;Postdoctoral Fellow;Preparation;Pro-Q aerosol foam;Proteins;Proteomics;Research;Research Personnel;Resources;Robotics;Sampling;Sequence Analysis;Services;Site;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Staining method;Stains;Students;System;Training;United States National Institutes of Health;Water;Work;aerobic respiration control protein;base;data acquisition;design;human disease;mass spectrometer;protein profiling


application_id: 7960493
project_number: 2P20RR020171-06
project_title: KY COBRE: IMAGING CORE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6663
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;Centers of Research Excellence;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;Molecular;Preparation;Publications;Research;Research Personnel;Resolution;Resources;Sampling;Slide;Source;Spottings;Staging;Techniques;United States National Institutes of Health;base;cellular imaging;digital;digital imaging;flexibility;human disease;image processing;instrument;tissue culture


application_id: 7960492
project_number: 2P20RR020171-06
project_title: KY COBRE: TISSUE CULTURE & PROTEIN PRODUCTION CORE
administering_ic: NCRR
award_notice_date: 2009-08-11
opportunity_number: RFA-RR-08-007
application_type: 2
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2009-09-01
project_end_date: 2010-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 6662
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;Cell Culture Techniques;Cells;Centers of Research Excellence;Chromatography;Computer Retrieval of Information on Scientific Projects Database;Equipment;Funding;Grant;Human Resources;Incubators;Individual;Institution;Laboratories;Mammalian Cell;Molecular;Production;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Services;Source;Training;United States National Institutes of Health;base;cost;design;human disease;instrumentation;member;tissue culture


application_id: 7960467
project_number: 5P20RR024489-02
project_title: MESENCHYMAL STEM CELL THERAPY FOR INFARCT
administering_ic: NCRR
award_notice_date: 2009-07-24
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6637
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Nearly two-thirds of diabetics suffer from overt cardiovascular conditions including coronary artery disease myocardial infarction (MI) and cardiomyopathy. Despite the known systemic nature of diabetes therapy for MI and ischemic cardiomyopathy are often not specifically tailored for diabetics and the feasibility and efficacy of stem cell therapy for infarct repair in diabetic patients remains unclear. Although mesenchymal stem cells (MSCs) have been shown to induce infarct repair the results have been variable and mechanisms remain controversial. The variability in MSC-mediated cardiac repair might have stemmed from the fundamentally heterogeneous nature of unfractionated 'MSCs'. We hypothesize that the use of a homogenous antigenically-defined MSC subpopulation with greater endothelial and cardiomyogenic differentiation potential and greater ability to secrete cardioprotective factors will result in superior cardiac repair in diabetics. These studies will identify the best MSC to use for infarct repair specifically in diabetics and the results would have enormous therapeutic implications for diabetic patients with ischemic heart disease and post-MI heart failure.

project_terms:
Cardiac;Cardiomyopathies;Cardiovascular system;Computer Retrieval of Information on Scientific Projects Database;Coronary Arteriosclerosis;Diabetes Mellitus;Funding;Grant;Heart failure;Infarction;Institution;Mediating;Mesenchymal Stem Cells;Myocardial Infarction;Myocardial Ischemia;Nature;Obesity;Research;Research Personnel;Resources;Source;Therapeutic;United States National Institutes of Health;diabetes mellitus therapy;diabetic;diabetic patient;repaired;stem;stem cell therapy


application_id: 7960466
project_number: 5P20RR024489-02
project_title: RENOVATIONS
administering_ic: NCRR
award_notice_date: 2009-07-24
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6636
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Renovations are to upgrade and improve existing space to accommodate the Core facilities for the Center for Excellence in Diabetes and Obesity Research.  These laboratories will house Core B: Imaging and Flow Cytometry Core C: Cardiovascular Pathology Core D: Animal Core Facility and Core E: Cardiovascular Imaging and Function.  The renovations will include replacing all the original casework and rerouting the distilled water dispensers as needed rewiring all the rooms to make them more functional for their current needs installing new acoustical ceilings upgrading lighting to current standards and replacing the quarry tile floors with chemical resistant VCT flooring designed for lab use.

project_terms:
Animals;Cardiovascular Pathology;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Diabetes Mellitus;Floor;Flow Cytometry;Funding;Grant;Housing;Image;Institution;Laboratories;Lighting;Obesity;Research;Research Personnel;Resistance;Resources;Source;United States National Institutes of Health;Water;cardiovascular imaging;design;improved


application_id: 7960465
project_number: 5P20RR024489-02
project_title: STEM CELLS AND DIABETIC CARDIOMYOPATHY
administering_ic: NCRR
award_notice_date: 2009-07-24
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6635
contact_pi_person_id: 8492518
contact_pi: HE, JIA-QIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.This application raises the possibility that diabetes is a disease process that negatively affects the growth reserve of the heart so that the enhanced cell death cannot be counteracted by repopulating cells that preserve the architecture and function of the myocardium.  Previous studies show that diabetes leads to the activation of the renin-angiotensin system (RAS) which increases ROS generation and leads to myocyte hypertrophy and cell death.  To test whether a similar sequence of events induces CPC senescence we will examine how diabetes affects myocardial function in murine models of type 1 and type 2 diabetes and determine whether hyperglycemia activates RAS and it regulator p53. In addition we will determine whether repopulating the diabetic heart with CPCs from non-diabetic hearts rescues the diabetic phenotype. These approaches represent a new view of cellular changes in the diabetic heart and may be able to identify a link between diabetes ROS premature CPC senescence and heart failure and may support the development of cell therapy for diabetic cardiomyopathy

project_terms:
Affect;Architecture;Cell Death;Cell Therapy;Cells;Computer Retrieval of Information on Scientific Projects Database;Development;Diabetes Mellitus;Disease;Event;Funding;Generations;Grant;Growth;Heart;Heart failure;Hyperglycemia;Hypertrophy;Institution;Link;Modeling;Mus;Muscle Cells;Myocardial;Myocardium;Obesity;Phenotype;Process;Renin-Angiotensin System;Research;Research Personnel;Resources;Source;Stem cells;TP53 gene;Testing;United States National Institutes of Health;diabetic;diabetic cardiomyopathy;non-diabetic;premature;senescence;type I and type II diabetes


application_id: 7960464
project_number: 5P20RR024489-02
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 5
administering_ic: NCRR
award_notice_date: 2009-07-24
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6634
contact_pi_person_id: 8146758
contact_pi: LI, YONG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Elucidation of the roles of miR-301a in hyperglycemic injury and secondary diabetic complications is the main focus of this project.  We have proposed three aims: Aim #1 will examine the role of miR-301a in proliferation and migration of SMC cultured in the presence of normal or high glucose and determine whether miR-301a is over expressed in injured carotid artery of diabetic and non-diabetic mice.  Aim #2 will delineate the molecular mechanism by which hyperglycemia and NF-kappaB regulates the expression of miR-301a.  Aim #3 will determine whether repressing miR-301a expression prevents hyperproliferation of SMC in situ.

project_terms:
Carotid Arteries;Complications of Diabetes Mellitus;Computer Retrieval of Information on Scientific Projects Database;Diabetes Mellitus;Diabetic mouse;Funding;Glucose;Grant;Hyperglycemia;In Situ;Injury;Institution;Molecular;NF-kappa B;Obesity;Research;Research Personnel;Research Project Grants;Resources;Role;Source;United States National Institutes of Health;diabetic;injured;migration;non-diabetic;prevent


application_id: 7960462
project_number: 5P20RR024489-02
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 1
administering_ic: NCRR
award_notice_date: 2009-07-24
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6632
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.One of the complications of diabetes is the production of excess reactive oxygen species (ROS) in cells.  ROS are highly reactive oxygen-containing molecules that can damage proteins or nucleic acids thereby resulting in cell death or abnormal function. Excess ROS are particularly harmful for cardiovascular tissues. ROS are produced as by products of proteins which metabolize glucose and are generally not a problem in individuals with normal blood glucose. In diabetic individuals however these metabolizing enzymes are overwhelmed and excess ROS results. A cell normally has mechanisms to counteract excess ROS production including nitric oxide (NO) whose levels are inversely proportional to ROS. In diabetic conditions however NO levels are also decreased which enhances the possibility of oxidative damage. In this project therefore we will utilize mouse models of diabetes and explore mechanisms to counteract high ROS levels.

project_terms:
Blood Glucose;Cardiovascular system;Cell Death;Cells;Complications of Diabetes Mellitus;Computer Retrieval of Information on Scientific Projects Database;Diabetes Mellitus;Diabetic mouse;Enzymes;Funding;Glucose;Grant;Individual;Institution;Nitric Oxide;Nucleic Acids;Obesity;Oxygen;Production;Proteins;Reactive Oxygen Species;Research;Research Personnel;Research Project Grants;Resources;Source;Tissues;United States National Institutes of Health;diabetic;oxidative damage


application_id: 7960388
project_number: 5P20RR021954-02
project_title: ANALYTICAL CORE
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6558
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.ANALYTICAL CORE: The purpose of the Analytical Core is to provide state of the art methodologies for measurement of a broad range of biomolecules to the participating investigators.  This goal has been accomplished by use of two complementary technologies: HPLC Tandem mass spectrometry and multiplex fluorescence ("Luminex")-based assays.
     The core is directed by Andrew Morris Ph.D. Professor of Internal Medicine and Molecular and Cellular Biochemistry.  Manjula Sunkara MS Research Associate is responsible for day to day operation of the core instrumentation.  Ms Sunkara has a background in analytical chemistry with additional experience in biomedical mass spectrometry gained with a pharmaceutical research company.  Ms Sunkara is supported entirely by the COBRE award.  Operating expenses of the core are cost shared by the participating investigators and supported in part by funds provided by the Vice President for Research to facilitate use of the instrument by other non-COBRE affiliated researchers.
     Using funds provided by a previously awarded NCRR Shared instrumentation grant (1S10RR024598-01 Andrew J. Morris PI) an interactive group of researchers at the University of Kentucky College of Medicine recently purchased an Applied Biosystems (ABI)/MDS Sciex 4000 Q-Trap hybrid triple quadrupole linear ion trap mass spectrometer.  The instrument is equipped with an ABI Turbo V electrospray ionization ion (ESI) source and interfaced with a Shimadzu multi pump HPLC system equipped with a column oven and autosampler.  A computer workstation running ABI Analyst Software is used for instrument control and data acquisition and processing.  The instrument was put into service about 6 months ago and in the intervening time we have set up multiple reaction monitoring mode HPLC tandem mass spectrometry assays for analysis and quantitation of a broad and expanding range of lipids and lipid-related molecules which include glycero and sphingo phospholipids fatty acids eicosanoids isoprenoids and sterols.  Data obtained using this instrument have been published in the Journal of Biological Chemistry and Molecular Pharmacology with other reports and grant applications arising from experiments conducted using the instrument currently under review.
     The core also contains a Luminex (BioRad) 200 multiplex fluorescence analyzer.  We provide assistance with calibration experimental design and are working with the appropriate vendors to develop "panels" for collections of analytes that are tailored to the needs of the participating investigators.

project_terms:
Analytical Chemistry;Applications Grants;Arts;Award;Biochemistry;Biological Assay;Calibration;Cardiovascular Diseases;Centers of Research Excellence;Collection;Computer Retrieval of Information on Scientific Projects Database;Computer Workstations;Computer software;Cost Sharing;Data;Doctor of Philosophy;Eicosanoids;Electrospray Ionization;Experimental Designs;Fatty Acids;Fluorescence;Funding;Goals;Grant;High Pressure Liquid Chromatography;Hybrids;Institution;Internal Medicine;Ions;Journals;Kentucky;Lipids;Mass Spectrum Analysis;Measurement;Medicine;Methodology;Molecular;National Center for Research Resources;Obesity;Operative Surgical Procedures;Pharmacologic Substance;Pharmacology;Phospholipids;Postdoctoral Fellow;Process;Publishing;Pump;Reporting;Research;Research Personnel;Resources;Running;Services;Source;Sterols;System;Technology;Time;United States National Institutes of Health;Universities;Vendor;Work;base;college;data acquisition;experience;instrument;instrumentation;ion source;isoprenoid;mass spectrometer;multiple reaction monitoring;professor;research study;tandem mass spectrometry


application_id: 7960387
project_number: 5P20RR021954-02
project_title: CENTER OF RESEARCH IN OBESITY AND CARDIOVASUCULAR DISEASE
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6557
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.ADMINISTRATIVE CORE. The administrative core coordinates research and training objectives of the Center. The aims of this core are to provide administrative leadership support for fiscal grant accounting and writing meeting organization oversite of the pilot project mechanism facilitation of hiring of new faculty
construction of a website coordination and organization of data for assessment statistical consultation and assistance with compliance issues. Progress in this core has been considerable. We have hired an administrative assistant Ms. Mary Lowell who has worked with the Program Director to achieve the goals of
the administrative core. These include set-up and administration of the sub-project accounts and grants management of these and research core accounts design and creation of a website for the center monthly meetings of all COBRE participants with presentations by junior investigators and updates on core facilities.
We have created a common site on a server accessed by all COBRE personnel for data sharing development of forms and processes for use of the research cores and access to protocols used within
specific projects and research cores. Several of the junior investigators have received statistical consulting from Dr. Richard Charnigo towards their projects. To assist junior faculty with compliance issues we have developed standard operating procedures for each measurement made in the research cores which have been approved by University veterinarians to assist with modification of animal protocols and use of new
measurements provided by the COBRE research cores. In the last 6 months the administrative core has assisted in hiring of a new faculty member with research interests in the area of obesity and cardiovascular disease. We have utilized the external advisory committee for input on 3 new investigators supported through the COBRE. We have also represented the COBRE through development of a newly formed Center at the University of Kentucky in the area of obesity and diabetes which encompasses clinical care as well as research (facilitated by the COBRE).
     Over the next period of support the administrative core will initiate the pilot project mechanism organize a retreat of the COBRE with evaluation by the external advisory committee and coordinate a symposia in conjunction with the retreat focused on research in the area of obesity and cardiovascular disease.

project_terms:
Accounting;Advisory Committees;Animals;Area;Cardiovascular Diseases;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Consult;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Disease;Evaluation;Faculty;Funding;Goals;Grant;Human Resources;Institution;Kentucky;Leadership;Measurement;Modification;Obesity;Participant;Pilot Projects;Procedures;Process;Protocols documentation;Research;Research Personnel;Research Project Grants;Research Training;Resources;Site;Source;United States National Institutes of Health;Universities;Update;Veterinarians;Work;Writing;clinical care;design;interest;meetings;member;programs;sharing data;symposium;web site


application_id: 7960386
project_number: 5P20RR021954-02
project_title: PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6556
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Obesity is associated with an increased risk of cardiovascular death independent of its other recognized consequences such as hypertension and hyperlipidemia. One potential contributing factor to this excess in cardiovascular deaths may be related to the pro-thrombotic and pro-inflammatory states induced by increases in adipose mass both of which are critical components of the pathogenesis of the clinic manifestations of atherosclerosis. Platelets play a central role in arterial thrombosis are activated in inflammatory states and are directly influenced by specific adipokines and therefore have the potential to serve as an essential mediator of the cardiovascular consequences of obesity. Consistent with this obesity has been associated with increases in platelet aggregation elevations in surface expression of markers of platelet activation such as P-selectin and heightened platelet microparticle formation. More importantly reduction in adipose mass leads to normalization of markers of enhanced platelet activation. However a causal role for platelet hyperactivation in obesity-related cardiovascular disorders remains to be established. Several characteristics and proven biological activities of platelets make them an appealing candidate for triggering and maintaining the inflammatory response of obesity. Activated but not resting platelets are able to alter the chemotactic properties of endothelial cells by inducing the secretion of monocyte chemoattractant protein (MCP-1). Similarly transforming growth factor- b (TGF-b)  is released from activated platelet a-granules and has been shown to augment the release of type-1 plasminogen activator inhibitor (PAI-1) from adipose tissue. Importantly a recent report indicates that the recruitment of inflammatory cells in adipose tissue is facilitated by platelet adhesion along activated endothelium. Based on these observations we propose the central hypothesis that platelet activation secondary to obesity plays a causal role in triggering and maintaining the pro-inflammatory and pro-thrombotic state of obesity creating a feedback loop involving adipose tissue activated platelets and vascular endothelium that culminates in an environment favorable for atherothrombotic vascular events.  We will test our central hypothesis and delineate mechanism(s) by which platelet activation contributes to the inflammatory and thrombotic consequences of obesity in the following specific aims: (1) To identify the role for platelets in the inflammatory response of adipose tissue; (2) To establish a role for platelet secretion in the pro-inflammatory and pro-thrombotic consequences of diet-induced obesity; (3) To determine the role platelet toll-like receptor 4 signaling on the inflammatory response in obesity.

project_terms:
Adhesions;Adipose tissue;Atherosclerosis;Biological;Blood Platelets;Blood Vessels;CCL2 gene;Cardiovascular Diseases;Cardiovascular system;Cells;Cessation of life;Characteristics;Clinic;Computer Retrieval of Information on Scientific Projects Database;Cytoplasmic Granules;Diet;Endothelial Cells;Endothelium;Environment;Event;Feedback;Funding;Grant;Hyperlipidemia;Hypertension;Inflammatory;Inflammatory Response;Institution;Mediator of activation protein;Monocyte Chemoattractant Proteins;Obesity;P-Selectin;Pathogenesis;Plasminogen Activator Inhibitor 1;Platelet Activation;Platelet aggregation;Play;Property;Reporting;Research;Research Personnel;Resources;Rest;Role;Secondary to;Signal Transduction;Source;Surface;Testing;Thrombosis;Transforming Growth Factors;United States National Institutes of Health;Vascular Endothelium;adipokines;base;cardiovascular risk factor;toll-like receptor 4


application_id: 7960385
project_number: 5P20RR021954-02
project_title: THROMBOSPONDIN 1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOT
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6555
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Obesity is becoming a global public health problem and is associated with an increased risk of cardiovascular diseases including atherosclerosis.  Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis.  Thrombospondin1 a multifunctional extracellular matrix protein has been shown to be up-regulated in adipose tissue of mice with diet or genetically induced obesity.  Moreover recent studies demonstrate that TSP1 expression is increased in adipocytes from obese humans and correlates positively to obesity and adipose tissue inflammation.   Preliminary data demonstrate that adipose tissue from high fat (HF)-fed TSP1 deficient mice exhibits reduced numbers of infiltrating macrophages compared to HF-fed wild type controls.  Importantly reductions in macrophage infiltration into adipose tissue of TSP1-/- HF-fed mice were observed even though mice exhibited similar levels of obesity as wild type controls.  In addition TNF-alpha and IL-6 levels in adipose tissue and plasma were reduced in HF-fed TSP1-/- mice compared to controls.  Expression of the cell adhesion molecule - ICAM was increased in aortic endothelial cells from HF-fed control but not TSP1-/- mice suggesting that TSP1 contributes to obesity-associated endothelial dysfunction.  Moreover incubation of cultured macrophages with TSP1 increased migration while macrophages from TSP1-/- mice exhibited reduced macrophage migration.  However the specific domains of TSP1 responsible for macrophage infiltration as well as the cell source of TSP1 contributing to obesity-induced macrophage infiltration are unknown.  Importantly effects of TSP1 deficiency on the development of atherosclerosis in the absence or presence of obesity have not been defined.  The central hypothesis of this proposal is that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice.  This hypothesis will be tested by determination of the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in aim 1.  In aim 2 we will determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity. These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis.  Understanding the role of adipose tissue TSP1 in regulation of adipose tissue inflammation and its role in the development and progression of atherosclerosis in mice with diet-induced obesity will lead to development of therapeutic targets for treatment of this disease.

project_terms:
Adhesions;Adipocytes;Adipose tissue;Adverse effects;Apolipoprotein E;Atherosclerosis;Cardiovascular Diseases;Cell Adhesion Molecules;Cells;Chronic;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diet;Disease;Endothelial Cells;Exhibits;Extracellular Matrix Proteins;Fatty acid glycerol esters;Functional disorder;Funding;Grant;Human;In-Migration;Infiltration;Inflammation;Institution;Interleukin-6;Lead;Mediating;Mus;Obesity;Plasma;Regulation;Research;Research Personnel;Resources;Role;Source;Testing;Thrombospondin 1;Tumor Necrosis Factor-alpha;United States National Institutes of Health;cardiovascular disorder risk;feeding;human TNF protein;intercellular cell adhesion molecule;macrophage;migration;novel;public health medicine (field);therapeutic target


application_id: 7960384
project_number: 5P20RR021954-02
project_title: DIETARY FAT PROMOTES CHYLOMICRON-DEPENDENT INTESTINAL ABSORPTION OF GUT ANTIGENS
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6554
contact_pi_person_id: 8628150
contact_pi: ECKHARDT, ERIK
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Obesity is a strong risk factor for atherosclerosis. As fat stores expand they become increasingly inflamed releasing inflammatory cytokines which then negatively affect blood vessel functioning. However the underlying cause of inflammation during the expansion of adipose tissue is currently unknown. One prominent event is the infiltration of macrophages though it is still unclear why this happens and what these macrophages do. Recent studies with mice have suggested that macrophage infiltration occurs relatively late during experimental obesity which suggests that there are earlier inflammatory events preceding and perhaps causing macrophage infiltration. We have observed that intestinal fat absorption is associated with the intestinal absorption of antigens from gut microflora. The absorbed antigen was associated with newly secreted chylomicrons which are the large lipoprotein particles that transport dietary fat via mesenteric lymph into the body proper. Since chylomicrons are prominently cleared in adipose tissue we will test in the current project the hypothesis that gut antigens are deposited into adipose tissue in a chylomicron-dependent manner. Increased fat feeding would then lead to increased adipose antigen enrichment followed by lymphocyte infiltration. Our preliminary data suggest that chylomicron formation promotes intestinal absorption and adipose deposition of dietary ovalbumin (OVA) a prototypical experimental T-cell antigen. Our preliminary data also show that adipose enrichment with such T-cell antigens is rapidly followed by T-cell infiltration which may be an important initial event in adipose inflammation and which may subsequently recruit macrophages.
 
If our hypothesis is correct it would not only put the spotlight on the adaptive immune system as an important contributor to adipose inflammation but also on the intestinal microflora and dietary antigens as potential sources for inflammation in fat tissue and in many other tissues. It may well be that individuals with reduced tolerance to bacterial or dietary antigens and who thus would respond to these antigens if they make their way into the body proper are especially sensitive to obesity-associated inflammation. Moreover the novel link between fat absorption and gut antigen absorption may profoundly affect our thinking on the way the gut microflora affects our body.

project_terms:
Adipose tissue;Affect;Antigens;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Chylomicrons;Computer Retrieval of Information on Scientific Projects Database;Data;Deposition;Dietary Fats;Event;Fatty acid glycerol esters;Funding;Grant;Immune system;Individual;Infiltration;Inflammation;Inflammatory;Institution;Intestinal Absorption;Intestines;Lead;Link;Lipoproteins;Lymph;Lymphocyte;Mesentery;Mus;Obesity;Ovalbumin;Recruitment Activity;Research;Research Personnel;Resources;Risk Factors;Source;T-Lymphocyte;Testing;Thinking function;Tissues;United States National Institutes of Health;absorption;cytokine;feeding;gut microflora;macrophage;novel;particle


application_id: 7960383
project_number: 5P20RR021954-02
project_title: CHROMATIN REMODELING AND ADIPONECTIN GENE EXPRESSION: REGULATION BY OBESITY
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6553
contact_pi_person_id: 8333955
contact_pi: SHAO, JIANHUA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Currently more than 44 million Americans are considered obese by body mass index (BMI) reflecting an increase of 74 percent since 1991. During the same time frame diabetes increased by 61 percent reflecting the strong correlation between obesity and the development of diabetes. Today an estimated 17 million people have diabetes in the United States according to the study by the Centers for Disease Control and Prevention. Obesity is associated with diabetes cardiovascular diseases and many other health problems. Recent studies indicate that adipose tissue is not simply a tissue for energy storage but also serves an important endocrine function. There are several hormones that are synthesized and secreted from adipose tissue and regulate energy metabolism of other organs or system such as food intake and insulin sensitivity. Adiponectin is an adipose-derived hormone that plays a critical role in maintaining energy and glucose metabolism. Diminished adiponectin gene expression and low blood concentrations have been well documented in both obesity and type 2 diabetes. However the molecular mechanisms that regulate adiponectin expression and the causative mechanisms that impair adiponectin gene expression in obesity and type 2 diabetes remain poorly understood. Our preliminary data demonstrate novel adipocyte-specific regulatory elements (enhancer) in the first intron of the human adiponectin gene and that the transcription factor C/EBP is required for regulating adiponectin expression. Furthermore it has been demonstrated that C/EBP recruits SWI/SNF chromatin-remodeling complexes into target genes and is involved in the adipogenic process. We propose to investigate the role of chromatin remodeling in controlling adiponectin gene expression during adipocyte differentiation and also to explore the molecular mechanisms that cause down-regulation of adiponectin expression in obesity. This study will provide novel insight into the regulation of adiponectin synthesis and ultimately may lead to a new therapy for obesity related diabetes and cardiovascular disease.  Importantly these studies will provide compelling preliminary data supporting an NIH R01 application. This COBRE project will also provide a unique opportunity for me to collaborate with other PIs to translate my research into obesity-associated cardiovascular disease.

project_terms:
Adipocytes;Adipose tissue;American;Blood;Body mass index;Cardiovascular Diseases;Centers for Disease Control and Prevention (U.S.);Centers of Research Excellence;Chromatin Remodeling Factor;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diabetes Mellitus;Down-Regulation;Eating;Endocrine;Energy Metabolism;Enhancers;Funding;Gene Expression;Gene Expression Regulation;Gene Targeting;Genetic Transcription;Grant;Health;Hormones;Human;Institution;Introns;Lead;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Obesity associated cardiovascular disease;Organ;Play;Process;Recruitment Activity;Regulation;Regulatory Element;Research;Research Personnel;Resources;Role;Source;System;Time;Tissues;Translating;United States;United States National Institutes of Health;adipocyte differentiation;adiponectin;chromatin remodeling;factor C;glucose metabolism;insight;insulin sensitivity;novel;transcription factor


application_id: 7960382
project_number: 5P20RR021954-02
project_title: ELEVATED SERUM AMYLOID A CONTRIBUTES TO OBESITY-INDUCED ATHEROSCLEROSIS
administering_ic: NCRR
award_notice_date: 2009-06-12
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 6552
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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.Clinical studies have demonstrated an association between elevated levels of serum amyloid A (SAA) and increased risk of cardiovascular events.  Moreover elevated levels of SAA are also associated with obesity which is a significant risk factor for cardiovascular disease.  Previous studies have demonstrated that plasma SAA concentrations correlate with atherosclerotic lesion size in hyperlipidemic mice.  Preliminary data demonstrate that overexpression of SAA in apoE-/- mice increases atherosclerosis.  To study the effect of obesity on atherosclerosis we have generated a model of diet induced obesity in apoE-/- mice.  The induction of obesity and increase in atherosclerosis in this model are associated with an increase in plasma and adipose tissue SAA concentrations.   A large percentage of plasma SAA was bound to the pro-atherogenic lipoproteins VLDL and LDL in obese apoE-/- mice compared to lean in which SAA is primarily associated with HDL. Lipoprotein binding to proteoglycans in the subendothelial space is suggested to increase lipoprotein retention in the vascular wall and facilitate the development of atherosclerosis.  SAA enriched HDL has increased binding to proteoglycans. Thus SAA enrichment of VLDL and LDL may promote atherosclerosis by increasing lipoprotein retention in the vascular wall and facilitating foam cell formation.  Therefore we propose that obesity induced inflammation augments adipose SAA production to increase atherosclerosis in apoE-/- mice.  To test this hypothesis we propose to: 1) Determine if adipocytes and/or macrophages infiltrating the adipose tissue during obesity are the source of increased adipose tissue SAA expression.  2) Determine if macrophages infiltrating the adipose tissue regulate SAA adipocyte expression. 3) Determine if SAA enrichment of pro-atherogenic lipoproteins increases proteoglycan binding thus facilitating macrophage foam cell formation.  4) Determine if SAA deficiency attenuates obesity-induced atherosclerotic lesion formation.

project_terms:
Adipocytes;Adipose tissue;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diet;Event;Foam Cells;Funding;Grant;High Density Lipoproteins;Inflammation;Institution;Lipoprotein Binding;Lipoproteins;Low-Density Lipoproteins;Modeling;Mus;Obesity;Plasma;Production;Proteoglycan;Research;Research Personnel;Resources;Risk Factors;Serum amyloid A protein;Source;Testing;United States National Institutes of Health;Very low density lipoprotein;cardiovascular risk factor;low density lipoprotein inhibitor;macrophage;overexpression


application_id: 7960127
project_number: 2P20RR016481-09
project_title: ANALYSIS OF POLYHYDROXYALKANOATE INCLUSION BIOGENESIS
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6300
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
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 research is to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis.  Polyhydroxyalkanoates (PHAs) are bacterial polymers that are synthesized in inclusions when carbon levels are high and another essential nutrient such as nitrogen is limited.  There is considerable commercial interest in PHAs because they comprise a family of polyesters that can be formed into plastics that are biodegradable. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an outer envelope that is the thickness of a membrane bilayer a middle network layer and an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic membrane as an envelope.

project_terms:
Atomic Force Microscopy;Biogenesis;Biomedical Research;Carbon;Cell membrane;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Electron Microscopy;Family;Funding;Genetic;Goals;Grant;Institution;Membrane;Modeling;Movement;Nitrogen;Nutrient;Plastics;Polyesters;Polymers;Proteins;Research;Research Personnel;Resources;Source;Structure;Thick;United States National Institutes of Health;interest;periplasm


application_id: 7960126
project_number: 2P20RR016481-09
project_title: MECHANISMS OF ACTION OF UMUD IN REGULATING DNA DAMAGE-INDUCED GENES IN A UMUC-DE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6299
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE 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 long term goal of this research is to understand the mechanisms by which cells respond to DNA damage. The link between DNA damage and human health is well-established: the inability to correctly repair damaged DNA can result in various forms of colon breast and ovarian cancers in humans. The existence of similar extensive DNA damage sensing and repair mechanisms in organisms ranging from humans to bacteria demonstrates this central role of DNA integrity. In the typical bacterial SOS response pathway after DNA damage the UmuD protein self-cleaves and then acts with its partner UmuC to function as a translesion synthesis DNA polymerase.

project_terms:
Bacteria;Biomedical Research;Breast;Cells;Cleaved cell;Colon;Computer Retrieval of Information on Scientific Projects Database;DNA;DNA Damage;DNA Repair;DNA-Directed DNA Polymerase;Funding;Genes;Goals;Grant;Health;Human;Institution;Link;Malignant neoplasm of ovary;Organism;Pathway interactions;Proteins;Research;Research Personnel;Resources;Role;SOS Response (Genetics);Source;United States National Institutes of Health;human DNA damage;repaired


application_id: 7960125
project_number: 2P20RR016481-09
project_title: IMMUNOMODULATION OF INFLUENZA A AND RESPIRATROY SYNCYTIAL VIRUS VIRONS
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6298
contact_pi_person_id: 9061178
contact_pi: MESTER, JOSEPH CHARLES
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.Work is ongoing to determine the effects of influenza A and respiratory syncytial virus (RSV) virions on human immune effector cells of the innate and adaptive immune lineages.  A summary of ongoing results was presented at the 27th Annual Meeting of the American Society for Virology.  Experimental results over the previous eight months verified that the continuous human cell lines under consideration demonstrate cytokine production patterns similar to primary human immune cells of their respective lineages in response to known mitogens.  Following exposure to either influenza A or RSV virions both expected and novel modulations of cytokine expression were observed.  Human natural killer (NK) cells in particular demonstrated marked immunoregulatory potential in response to virion exposure.  Interleukin (IL) 7 osteopontin and OX40 ligand expression by NK cells was significantly modulated following brief exposure to both virions.  Influenza A modulated IL-17A expre
 ssion and RSV modulated IL-5 and IL-13 receptor alpha expression of human NK cells.  These finding add greater detail to our understanding of human immune responses to viral pathogens and have direct implications for the design of virion-based vaccines and immunotherapies.

project_terms:
American;Biomedical Research;Cells;Computer Retrieval of Information on Scientific Projects Database;Effector Cell;Exposure to;Funding;Grant;Human;Human Cell Line;Immune;Immune response;Immunotherapy;Influenza;Institution;Interleukin-5;Interleukin-7;Interleukins;Mitogens;Natural Killer Cells;Pattern;Production;Research;Research Personnel;Resources;Respiratory syncytial virus;Societies;Source;United States National Institutes of Health;Vaccines;Viral;Virion;Virus;Work;base;cytokine;design;human IL13RA1 protein;immunoregulation;meetings;novel;osteopontin;pathogen;response;tumor necrosis factor ligand superfamily member 4;virology;viron


application_id: 7960124
project_number: 2P20RR016481-09
project_title: THE EFFECTS OF SOY ISOFLAVONES ON SREBP REGULATED GENE EXPRESSION IN VIVO
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6297
contact_pi_person_id: 9482332
contact_pi: MULLEN, EIMEAR 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.Soy is known to lower cholesterol levels and this corresponds to a decrease in cardiovascular disease risk.  However the mechanisms of this hypocholesterolemic effect as well as the components of soy that cause this effect are a source of controversy.   It is also unknown whether soy protein containing endogenous isoflavones would have the same effect as soy protein containing low isoflavones with isoflavones supplemented back to the protein source.
We have previously shown in a cell culture model that the isoflavones genistein and daidzein increase the processing of the Sterol Regulatory Element Binding Proteins (SREBPs) and the expression SREBP-regulated genes such as HMG CoA reductase HMG CoA synthase and the LDL receptor.  This study will address whether isoflavones cause a similar increase in SREBP processing and SREBP-regulated gene expression in an in vivo model.  We will use the C57BL/6J mouse and feed it an atherogenic diet for either 2 days 10 days or 6 weeks.  The diets will contain soy protein with low endogenous amounts of isoflavones with or without isoflavone supplementation or soy protein with high amounts of endogenous isoflavones.   The animals will be sacrificed and their plasma and liver tissue lipids will be analyzed.  The processing of SREBP-2 and the protein levels of HMG CoA reductase will be measured by immunoblotting.  The expression levels of SREBP-regulated genes will also be investigated 
 by quantitative real time PCR.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Address;Animals;Atherogenic Diet;Back;Binding Proteins;Biomedical Research;Cell Culture Techniques;Cholesterol;Computer Retrieval of Information on Scientific Projects Database;Diet;Funding;Gene Expression;Genes;Genistein;Grant;Hydroxymethylglutaryl-CoA reductase;Immunoblotting;Institution;Isoflavones;Lipids;Liver;Low Density Lipoprotein Receptor;Measures;Modeling;Mus;Plasma;Process;Proteins;Regulatory Element;Research;Research Personnel;Resources;SRE-2 binding protein;Source;Soy Proteins;Sterols;Supplementation;Time;Tissues;United States National Institutes of Health;cardiovascular disorder risk;daidzein;feeding;in vivo;in vivo Model;protein expression;soy;soy protein isolate


application_id: 7960123
project_number: 2P20RR016481-09
project_title: DRUG DELIVERY TO THE BRAIN USING NOVEL NANOMATERIALS
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6296
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.More than one million adults are diagnosed annually with chronic brain diseases disorders or injuries.  Unfortunately a majority of the therapies developed may only be administered by injecting them directly into the brain because the blood brain barrier (BBB) a tight seal of various cells impedes delivery of most drugs.  Nanoscience provides unique opportunities to address this issue. Dendrimers are highly customizable nanopolymers that appeal to biologists and chemists because of their precise architecture size/shape control high uniformity/purity high loading capacity low toxicity and low immunogenicity. These qualities also make them ideal for use in drug delivery. The purpose of this proposal is to design novel dendrimers that cross the BBB and to test their efficacy in doing so. Our hypothesis is that by modifying surface groups of generation 4 PAMAM and generation 3 Priostar" dendrimers with substances known to cross the BBB we may create potential drug delivery vehicles that may use endogenous transporter mechanisms to gain entrance to the brain.  In this study we will synthesize Priostar" dendrimers with a biotin surface groups.

project_terms:
Address;Adult;Architecture;Biomedical Research;Biotin;Blood - brain barrier anatomy;Brain;Brain Diseases;Cells;Chronic;Computer Retrieval of Information on Scientific Projects Database;Dendrimers;Diagnosis;Disease;Drug Delivery Systems;Funding;Generations;Grant;Injury;Institution;Pharmaceutical Preparations;Research;Research Personnel;Resources;Shapes;Source;Surface;Testing;Toxic effect;United States National Institutes of Health;design;immunogenicity;nanomaterials;nanoscience;novel;seal;therapy development


application_id: 7960122
project_number: 2P20RR016481-09
project_title: PROTEIN STRUCTURAL REFINEMENT USING COARSE-GRAINED MODELS OVER HIGH PERF COMPUT
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6295
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.

project_terms:
Biomedical Research;Cereals;Computer Retrieval of Information on Scientific Projects Database;Databases;Deposition;Funding;Grant;Homology Modeling;Institution;Methods;Modeling;Nuclear Magnetic Resonance;Research;Research Personnel;Resolution;Resources;Source;Structural Protein;Structure;Technology;United States National Institutes of Health;X-Ray Crystallography;knowledge base;protein folding;protein structure


application_id: 7960121
project_number: 2P20RR016481-09
project_title: TARGETING SODIUM-PROTON EXCHANGE TO TREAT BRAIN CANCER
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6294
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);Biomedical Research;Brain Neoplasms;Carrier Proteins;Cell Death;Cell Surface Proteins;Cell surface;Cells;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Diagnosis;Enzymes;Equilibrium;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;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;outcome forecast;tumor


application_id: 7960120
project_number: 2P20RR016481-09
project_title: SEX SPECIFIC PARENTAL ROLES AND THEIR MODULATION VIA NEUROPEPTIDES
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6293
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.The long term goal of this project is to determine the role of neuropeptides in male and female parental care. Parental care is known to be modulated via the mammalian neuropeptides arginine vasopressin (AVP) and oxytocin (OT). These neuropeptides have known homologues in all other vertebrate classes and are known to regulate the same behaviors seen in mammals. Within the hormone literature in general the social ecology of the systems focused on is typically overlooked in behavioral endocrine studeis and it is plausible that the interaction between these neuropeptides is dependant on social organization of the species in question. Here I am exploring parental care in a territorial monogamous system the convict cichlid Amatiliana siquia. In fish the homologue of AVP and OT is arginine vasotocin (AVT) and isotocin (IT) respectively.

project_terms:
Argipressin;Behavior;Behavioral;Biomedical Research;Caring;Cichlids;Computer Retrieval of Information on Scientific Projects Database;Ecology;Endocrine;Female;Fishes;Funding;Goals;Grant;Homologous Gene;Hormones;Institution;Literature;Mammals;Neuropeptides;Oxytocin;Research;Research Personnel;Resources;Role;Source;System;United States National Institutes of Health;Vasotocin;convict;male;parental role;sex;social;social organization


application_id: 7960119
project_number: 2P20RR016481-09
project_title: ALPHA-ACTIN REMODELING IN THE A7R5 SMOOTH MUSCLE CELL
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6292
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:
Biomedical Research;Cell Line;Computer Retrieval of Information on Scientific Projects Database;Contracts;Cytoskeleton;Exhibits;Filament;Funding;Goals;Grant;Institution;Muscle Smooth Vascular;Property;Research;Research Personnel;Resources;Slide;Smooth Muscle Myocytes;Smooth muscle (tissue);Source;United States National Institutes of Health;alpha Actin;theories


application_id: 7960118
project_number: 2P20RR016481-09
project_title: PHOTORECEPTORS INVOLVED IN CHLAMYDOMONAS REINHARDTII CIRCADIAN ENTRAINMENT
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6291
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:
Animal Model;Animals;Biochemical;Biological Models;Biomedical Research;Cell physiology;Chlamydomonas reinhardtii;Circadian Rhythms;Computer Retrieval of Information on Scientific Projects Database;Evolution;Funding;Grant;Green Algae;Hand;Human;Insecta;Institution;Mammals;Mouse-ear Cress;Neurospora crassa;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: 7960117
project_number: 2P20RR016481-09
project_title: ANALYSIS OF 25-DIALKYL HYDROQUINONES AS NOVEL ENZYME INHIBITORS
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6290
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:
Biomedical Research;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: 7960116
project_number: 2P20RR016481-09
project_title: STRUCTURAL AND FUNCTIONAL RECOVERY OF AUDITORY HAIR CELLS IN ZEBRAFISH
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6289
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;Biomedical Research;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: 7960115
project_number: 2P20RR016481-09
project_title: WKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6288
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:
Biomedical Research;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: 7960114
project_number: 2P20RR016481-09
project_title: BEHAVIOR AND MECHANISM IN ACUTE AMPHETAMINE WITHDRAWAL
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6287
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;Biomedical Research;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;Methods;Molecular;Procedures;Rattus;Research;Research Personnel;Resources;Source;Time;United States National Institutes of Health;Withdrawal;Work;depression;design;prodynorphin


application_id: 7960113
project_number: 2P20RR016481-09
project_title: A BUTTERFLY TRANSPOSON MUTAGENESIS SCREEN FOR THE STUDY OF WINGLESS SIGNAL
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6286
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:
Biomedical Research;Butterflies;Castanea dentata;Chromosome Mapping;Computer Retrieval of Information on Scientific Projects Database;Enhancers;Funding;Germ Lines;Grant;Institution;Laboratories;Mutagenesis;Research;Research Personnel;Resources;Signal Transduction;Source;Techniques;Transposase;United States National Institutes of Health;genome-wide


application_id: 7960112
project_number: 2P20RR016481-09
project_title: RNA-BASED MECHANISMS OF TRANSCRIPTION ELONGATION CONTROL
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6285
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:
Biomedical Research;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: 7960111
project_number: 2P20RR016481-09
project_title: NKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6284
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;web site


application_id: 7960110
project_number: 2P20RR016481-09
project_title: MOLECULAR MECHANISMS OF ESTROGEN-REGULATED BONE RESORPTION
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6283
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;Biomedical Research;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: 7960109
project_number: 2P20RR016481-09
project_title: CHARACTERIZATION OF PUTATIVE MAGNESIUM TRANSPORTING P-TYPE ATPASES
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6282
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 ion specificity and 3) determine their cellular and physiological roles in vivo using RNA interference (RNAi) and gene targeting technologies.

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


application_id: 7960108
project_number: 2P20RR016481-09
project_title: MECHANISMS OF TRANSCRIPTIONAL COORDINATION AMONG PHOSPHORYLASE KINASE GENES
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6281
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;Biomedical Research;Catalysis;Complex;Computer Retrieval of Information on Scientific Projects Database;Elements;Enzymes;Funding;Gene Expression;Genes;Glycogen;Grant;Hormonal;Human;Institution;Liver;Metabolic;Muscle;Muscle Form Glycogen Phosphorylase;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: 7960107
project_number: 2P20RR016481-09
project_title: GENETIC & METABOLIC ADAPTATION BY SALMONELLA TO THE NATURAL ENVIRONMENT
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6280
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:
Biomedical Research;Cobalamin;Computer Retrieval of Information on Scientific Projects Database;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;United States National Institutes of Health;Work;pathogen


application_id: 7960106
project_number: 2P20RR016481-09
project_title: ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6279
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;Biomedical Research;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;Methods;Microarray Analysis;Modeling;Molecular;Motor Activity;Pharmacology;Prefrontal Cortex;Proteins;Rattus;Reporting;Research;Research Personnel;Resources;Schizophrenia;Short-Term Memory;Site;Source;United States National Institutes of Health;base;frontal lobe;improved;protein expression;receptor;synaptic function;transcription factor


application_id: 7960105
project_number: 2P20RR016481-09
project_title: UK BIOINFOMRATICS
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6278
contact_pi_person_id: 8383697
contact_pi: PETERSON, MARTHA L.
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 bioinformatics core at UK supports multiple biomedical research activities and also supports development activities in the general area of bioinformatics.  The PI supervised the overall project and contributed primarily to organization of the University of Kentucky's Biomedical Informatics core for the recent Clinical and Translational Science Award.

project_terms:
Area;Bioinformatics;Biomedical Research;Clinical and Translational Science Awards;Computer Retrieval of Information on Scientific Projects Database;Development;Funding;Grant;Institution;Kentucky;Research;Research Activity;Research Personnel;Resources;Source;United States National Institutes of Health;Universities;biomedical informatics


application_id: 7960104
project_number: 2P20RR016481-09
project_title: EKU - LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6277
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 goal of this project is to provide INBRE support at Eastern Kentucky University. The PI provides research opportunities to undergraduate students and appropriate seminar speakers.

project_terms:
Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Faculty;Funding;Goals;Grant;Institution;Kentucky;Research;Research Personnel;Resources;Source;Students;United States National Institutes of Health;Universities


application_id: 7960103
project_number: 2P20RR016481-09
project_title: KBRIN -MOREHEAD STATE UNIVERSITY
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6276
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
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:
Applications Grants;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Funding;Grant;Institution;Research;Research Infrastructure;Research Personnel;Resources;Source;Students;United States National Institutes of Health;Universities;career


application_id: 7960102
project_number: 2P20RR016481-09
project_title: BRIN: UL: GENOMICS CORE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6275
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:
Biomedical Research;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: 7960101
project_number: 2P20RR016481-09
project_title: BIOINFORMATICS CORE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6274
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;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Computer software;Databases;Faculty;Funding;Genes;Genomics;Grant;Human Resources;Image Analysis;Institution;Lead;Research;Research Personnel;Resources;Source;Students;Training;United States National Institutes of Health;Universities;computer science;data mining;interest;meetings;member;tool development;web site


application_id: 7960100
project_number: 2P20RR016481-09
project_title: BRIN:KENTUCKY BRIN MENTORING & TRAINING CORE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6273
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: 7960099
project_number: 2P20RR016481-09
project_title: BRIN: UL: KENTUCKY BRIN ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2009-08-21
opportunity_number: PAR-08-150
application_type: 2
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2009-08-22
project_end_date: 2010-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 6272
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;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Development;Funding;Grant;Institution;Kentucky;Leadership;Newsletter;Office Management;Research;Research Personnel;Resources;Role;Science;Source;United States National Institutes of Health;Universities;Work;meetings;programs


application_id: 7959960
project_number: 5P20RR017702-07
project_title: INFANT AGE AT THE TIME OF CLEFT PALATE REPAIR: EFFECTS ON LANGUAGE DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6133
contact_pi_person_id: 10206963
contact_pi: TIWANA, PAUL
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.A preliminary study is proposed to investigate the potential temporal relationship between closure of cleft palate defects in infants and the neurophysiologic age of speech/language development.  Results of this study would allow for clinicians involved with the care of newborn infants with cleft palate to determine the most appropriate age for cleft palate surgical reconstruction to optimize speech/language production.  This study employs a novel approach in order to delineate a potentially critical relationship.  Such investigations are critical to providing infants afflicted with cleft palate the greatest opportunity for improving the outcome of cleft palate surgical reconstruction regarding speech/language development.


Specific Aim #1: To utilize standardized behavioral assessments of language development to determine whether the age of initial cleft palate repair in infants affects subsequent speech and language development.


Specific Aim #2:  To utilize electrophysiological (evoked response potentials) assessment of infant speech sound discrimination to determine whether the age of initial cleft palate repair affects subsequent speech and language development.

project_terms:
Affect;Age;Behavior assessment;Caring;Cleft Palate;Computer Retrieval of Information on Scientific Projects Database;Defect;Development;Discrimination (Psychology);Funding;Grant;Infant;Institution;Investigation;Language;Language Development;Molecular;Newborn Infant;Operative Surgical Procedures;Outcome;Production;Research;Research Personnel;Resources;Source;Speech;Speech Sound;Time;United States National Institutes of Health;improved;novel strategies;palate repair;reconstruction;response


application_id: 7959959
project_number: 5P20RR017702-07
project_title: BIOMARKERS OF NEUROTOXICITY ASSOCIATED WITH FETAL TOBACCO SMOKE EXPOSURE?
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6132
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.Nicotine a licit and highly addictive psychotropic drug is rapidly transported to the brain following tobacco smoke inhalation. The euphemistic reference to cigarettes (and other forms of smoking tobacco) as "nicotine delivery devices" acknowledges the addictive nature of cigarette smoking  a fact conceded by the tobacco industry. Though nicotine is the primary addictive component cigarette smoke contains approximately 4000 compounds including acrolein butadiene carbon dioxide (CO2) nitric oxide (NO) lead and cadmium that contribute to the overt toxicity of tobacco consumption. Approximately 20% of US adults (36 million) are active smokers. Despite extensive national publicity regarding the detrimental effects of tobacco use during pregnancy cigarette smoking continues in approximately 25% of all pregnancies in the USA.

Nationwide this percentage escalates to nearly 50% for women in lower socioeconomic groups. In the United States alone approximately one million infants are exposed prenatally to cigarette smoke each year. Tobacco smoke is known to contain neurotoxins such as nicotine exposure to which induces behavioral and cognitive abnormalities persisting well past the cessation of the toxic insult. Developmental cigarette smoke exposure is associated with decreased in utero brain growth and perturbations in both cellular and molecular neurodevelopment which are thought to mediate the increased rates of cognitive and behavioral problems that are observed in humans and rodent models. In the current proposal we will measure the impact of developmental tobacco smoke exposure on serum metabolome markers of offspring (in a unique animal model developed in our laboratory which simulates human maternal smoking during pregnancy) which parallel both hippocampal neurochemical alterations and the accompanying persistent behavioral/cognitive deficits.

Specific Aim 1: Examine the impact of developmental tobacco smoke exposure on the global serum metabolome in offspring from a mouse model which simulates maternal cigarette smoking during pregnancy. C57BL/6 mice will be exposed in utero beginning on gestational day 1 (GD 1) and continuing through postnatal day 14 (PN14)  an interval which spans initiation of brain development through differentiation of brain subregions including the hippocampus. At varying time points including immediately upon withdrawal of challenge 3 days post challenge and 2 months of age (neurocognitive defects in exposed offspring are discernable) serum will be fractionated for global metabolome profiling analysis. A two-pronged approach utilizing discrete metabolite chemical class extractions (polar--methanol extraction; neutral lipids--chloroform/methanol extraction) will be followed by high resolution/accuracy mass measurement coupled with retention time mapping and peak area quantitation from normalized spectra. Working hypothesis: temporal dysregulation of serum metabolome expression will be evident during exposure (nicotine metabolites are present) and persist through the development of neurocognitive deficits (nicotine metabolites not present). If
this hypothesis is correct we will have identified peripheral metabolite markers which are directly indicative of neurodevelopmental abnormalities and which are related to proteomic alterations (Specific Aim 2) and transcriptome alterations (See Preliminary Data) resulting from tobacco smoke exposure during brain morphogenesis. In addition we will have identified potential molecular markers of behavioral and neurocognitive abnormalities which may be broadly applicable to diseases other than drug intoxication.

Specific Aim 2: Examine the impact of developmental tobacco smoke exposure on global temporal metabolome and proteome expression profiles in hippocampus of offspring from a mouse model which simulates maternal cigarette smoking during pregnancy. Utilizing tissue collected as part of Specific Aim 1 hippocampal tissue metabolome and proteome profiles will be analyzed. Metabolome profiling in both Specific Aims 1 and 2 will employ LC-LIT/FTICR-MS followed by raw data chromatographic alignment integration and extraction of peak intensities. Spectral features of interest will be identified by accurate mass MS/MS fragmentation pattern (CID/IRMPD) and database searching (metabolites-HMDB METLIN and KEGG databases; proteins-NCBInr mammalian forward and reverse databases). Working hypothesis: temporal dysregulation of hippocampal proteome and metabolome expression in the developmental cigarette smoke exposure mouse model will be evident immediately after exposure and persist through the development of neurocognitive deficits. If this hypothesis is correct we will have identified brain structure-specific tissue biomarkers that are directly indicative of neurodevelopmental abnormalities and which are mirrored by peripheral metabolome alterations resulting from tobacco smoke exposure during brain morphogenesis. In addition we will have identified tissue molecular markers associated with behavioral and neurocognitive impairment which persist after withdrawal of the toxic exposure and which may be indicative of epigenetic alterations. These markers in turn could be targets for future investigations into the epigenetic effects of environmental neurotoxins on development of the brain behavior and cognitive abilities.

project_terms:
Acrolein;Adult;Age-Months;Animal Model;Area;Behavioral;Brain;Butadiene;C57BL/6 Mouse;Cadmium;Carbon Dioxide;Chemicals;Chloroform;Cigarette;Cognitive;Cognitive deficits;Computer Retrieval of Information on Scientific Projects Database;Coupled;Data;Databases;Defect;Development;Devices;Disease;Epigenetic Process;Exposure to;Fourier transform ion cyclotron resonance;Funding;Future;Gene Expression Profile;Grant;Growth;Hippocampus (Brain);Human;Impairment;Infant;Institution;Intoxication;Investigation;Laboratories;Lead;Lipids;Maps;Measurement;Measures;Mediating;Methanol;Molecular;Molecular Profiling;Morphogenesis;Nature;Neurocognitive;Neurocognitive Deficit;Neurotoxins;Nicotine;Nitric Oxide;Pattern;Peripheral;Pharmaceutical Preparations;Pregnancy;Problem behavior;Protein Databases;Proteome;Proteomics;Psychotropic Drugs;Research;Research Personnel;Resolution;Resources;Rodent Model;Serum;Simulate;Smoke;Smoker;Source;Structure;Time;Tissues;Tobacco;Tobacco Industry;Tobacco smoke;Tobacco use;Toxic effect;Toxicant exposure;United States;United States National Institutes of Health;Withdrawal;Woman;Work;biomarker;brain behavior;cigarette smoke;cigarette smoking;fetal;in utero;interest;maternal cigarette smoking;molecular marker;mouse model;neurochemistry;neurodevelopment;neurotoxicity;offspring;postnatal;prenatal exposure;smoke inhalation;socioeconomics


application_id: 7959958
project_number: 5P20RR017702-07
project_title: PHAGOCYTOSIS AND MERTK FAMILY OF THE RECEPTOR TYROSINE KINASE
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6131
contact_pi_person_id: 8875628
contact_pi: LU, QINGXIAN
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.While vertebrate eye development and functional differentiation is initiated in mid gestation it is of note that the retina is perhaps the last organ to complete functional development.  Most retinal differentiation occurs postnatally and in the mouse retinal development is not completed until two weeks after birth.  Thus developmental defects in the retina are not evident functionally until significantly after birth.  The retinal pigmenl epithelium (RPE) cells are highly polarized and they become tightly associated with the developing retinal photoreceptor cells. Once the retina becomes functional the RPE is essential for phagocytic clearance of the spent photoreceptor distal outer segment (OS) tips; this function is essential to maintain photoreceptor homeostasis. The RPE develops well before the retina but developmental defects in the RPE do not become evident until the postnatal period when the retina becomes functional.   Developmental defects in RPE phagocytosis of the OS leads to photoreceptor death and the postnatal disease retinitis pigmentosa (RP). The role of the RPE in rod OS turnover has been extensively studied due to the availability of the Royal College of Surgeons (RCS) rat model which displays an RP phenotype. The RPE cells in these rats carry an inherited defect in rod OS phagocytosis and the mutant gene is the MerTK receptor. The MerTK receptor tyrosine kinase is essential for RPE phagocytosis. MerTK null mutation causes photoreceptor degeneration not only in the RCS rat but also in MerTK gene knockout mice and human RP patients. In addition the MerTK mutation leads to general developmental defects in NK cell differentiation spermatogenesis and macrophage phagocytosis. To understand the molecular role of MerTK in phagocytosis in these developmental process we performed gene expression profiling to identify downstream targets of MerTK. One gene known as PTTG was ectopically expressed with MerTK mutation in RPE and macrophages. Interestingly PTTG regulates cytoskeletal changes in dividing cells PTTG stabilizes cytoskeletal structures such as the spindle apparatus which separates sister chromatids during mitosis. However PTTG must be degraded for this cytoskeletal structure to be disassembled at the end of mitotic metaphase. Thus PTTG is required for cytoskeletal changes to occur in the cell. We have now crossed the MerTK mutant mice into a PTTG heterozygous background to reduce ectopic expression of PTTG and we have found that photoreceptor loss in the MerTK mutant is largely prevented. These results point toward ectopic expression of PTTG as a critical factor in the RPE defects in the MerTK mutant. We hypothesize that ectopic expression of PTTG in the MerTK mutant RPE prevents the cytoskeletal rearrangements required to initiate phagocytosis (in a fashion analogous to that seen in cytoskeletal rearrangement defects seen in mitosis when PTTG becomes overexpressed).  We now focus this proposal on investigation of the potential role for PTTG ectopic expression in the MerTK mutant phenotypes and how the PTTG affect MerTK-mediated phagocytosis.
Specific Aim 1. Examination of developmental and circadian regulation of PTTG expression and its role in phagocytosis of photoreceptor OS in the MerTK-/- RPE cells in vivo.
In this Specific Aim we will investigate the developmental expression pattern and circadian regulation of PTTG in RPE cells at both mRNA and protein level. We will study the photoreceptor degeneration time course and determine if phagocytosis is restored in MerTK-/-PTTG+/- mice.
Specific Aim 2.  Investigate whether in vitro ectopic expression of PTTG leads to defects in RPE phagocytosis. 
We will ectopically PTTG in normal RPE cells to examine if it will cause RPE cell phagocytic defects. Conversely we will knockdown PTTG expression by RNA interference in the RPE cells with MerTK mutation and investigate whether decreased PTTG expression is sufficient to restore phagocytosis.
Specific Aim 3. Functional studies of the MerTK-/- and MerTK-/-PTTG+/- retina by visual test and ERG analysis.
We will perform electrophysiology and functional vision measurements on the MerTK-/-PTTG+/- mice. These physiological measurements will be correlated with a detailed morphological analysis of retinal markers and ultrastructual morphology.

project_terms:
Affect;Birth;Cell Differentiation process;Cells;Cessation of life;Circadian Rhythms;Computer Retrieval of Information on Scientific Projects Database;DNA Sequence Rearrangement;Defect;Development;Developmental Process;Disease;Distal;Ectopic Expression;Electrophysiology (science);Epithelium;Eye Development;Family;Funding;Gene Expression Profiling;Genes;Grant;Homeostasis;Human;In Vitro;Inherited;Institution;Investigation;Knockout Mice;MERTK gene;Measurement;Mediating;Messenger RNA;Metaphase;Mitosis;Modeling;Molecular;Morphology;Mus;Mutant Strains Mice;Mutation;Natural Killer Cells;Organ;PTTG1 gene;Patients;Pattern;Phagocytes;Phagocytosis;Phenotype;Photoreceptors;Physiological;Pregnancy;Proteins;RNA Interference;Rattus;Receptor Protein-Tyrosine Kinases;Regulation;Research;Research Personnel;Resources;Retina;Retinal;Retinal Photoreceptors;Retinitis Pigmentosa;Rod Outer Segments;Role;Sister Chromatid;Source;Spermatogenesis;Structure;Surgeon;Testing;Time;United States National Institutes of Health;Vision;Visual;college;human MERTK protein;in vivo;macrophage;mutant;null mutation;overexpression;photoreceptor degeneration;postnatal;prevent;receptor


application_id: 7959957
project_number: 5P20RR017702-07
project_title: REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6130
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
budget_start_date: 2009-06-01
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.We plan to study the role of signaling from the chemokine stromal cell-derived factor-1 (SDF-1) through its specific receptor CXCR4 in the migration of trunk neural crest cells to the dorsal root ganglia (DRG). The study will investigate the following hypotheses: [1] the chemokine guidance receptor CXCR4 is expressed in neural crest cells during migration into the DRG in distinct spatio-temporal patterns while its activating ligand SDF-1 is expressed along the pathways of neural crest migration; [2] loss of function of SDF-1/CXCR signaling during embryogenesis results in altered migration of neural crest cells into the developing DRG; [3] expression of the CXCR4 chemokine receptor and its activating ligand SDF-1 is regulated by the TGF superfamily members BMP4 and TGF1 respectively; [4] the downstream effects of SDF-1/CXCR4 signaling which govern migration of the neural crest cells to the DRG during embryogenesis are mediated by the phosphatidyl-inositide-3 phosphorylation signal transduction pathway.  

The neural crest is a progenitor cell population contributing to a multitude of cell and tissue types including the DRG and sensory nervous system.  Signaling of the chemokine SDF-1 through its specific receptor CXCR4 is required for the migration of many stem cell and progenitor cell populations from their respective sites of emergence to the regions where they will differentiate into complex tissues and organs. Deletion of the entire CXCR4 or SDF-1 gene in mice results in perinatal lethality at approximately gestational day 18.5 due to cerebellar cardiac and hematopoietic defects. The global objective of this research program is to determine whether the chemokine SDF-1 is required for migration of trunk neural crest cells to the DRG during embryogenesis and whether the disruption of SDF-1 signaling to its specific receptor CXCR4 results in altered neural crest migration and/or abnormal formation of the DRG. The research program will also investigate regulation of SDF-1 and CXCR4 expression by TGF1 and BMP4 in the embryo during the time of neural crest cell emigration from the dorsal aspect of the neural tube and neural crest cell migration to the dorsal root ganglia. BMP and TGF are two factors that play important roles in embryonic development and regulate SDF-1 and CXCR4 expression in a variety of adult cell types in culture. Finally the research program will investigate whether the downstream effects of SDF-1/CXCR4 signaling during embryonic neural crest cell migration to the DRG are mediated by the phosphatidyl-inositide-3 phosphorylation signal transduction pathway. 

Abnormal development of the peripheral nervous system in both mice and zebrafish following functional inactivation of the SDF-1 - CXCR4 chemokine signaling axis suggests a role of CXCR4/SDF-1 in migration of trunk neural crest cells to the forming DRG during embryogenesis.  However virtually no mechanistic information is available at present. In view of the deleterious physiological defects caused by aberrant DRG and sensory neuron development in conditions such as Waardenburg-Hirschsprung Disease and WHIM investigations of the regulation of trunk NCC migration and formation of the DRG by SDF-1-CXCR4 signaling are of potential biomedical importance.

project_terms:
Adult;Afferent Neurons;BMP4;CXCR4 Receptors;CXCR4 gene;Cardiac;Cells;Complex;Computer Retrieval of Information on Scientific Projects Database;Defect;Development;Dorsal;Embryo;Embryonic Development;Emigrations;Funding;Genes;Grant;Hematopoietic;Histocompatibility Testing;In-Migration;Institution;Investigation;Ligands;Mediating;Molecular;Mus;Nervous system structure;Neural Crest;Neural Crest Cell;Neural tube;Organ;Pathway interactions;Pattern;Perinatal;Peripheral Nervous System;Phosphorylation;Physiological;Play;Population;Regulation;Research;Research Personnel;Resources;Role;Sensory;Signal Transduction;Signal Transduction Pathway;Site;Source;Spinal Ganglia;Stem cells;Stromal Cell-Derived Factor 1;Time;Tissues;United States National Institutes of Health;Waardenburg-Hirschsprung disease;Zebrafish;cell motility;cell type;chemokine;chemokine receptor;loss of function;member;migration;neuron development;programs


application_id: 7959956
project_number: 5P20RR017702-07
project_title: PRE- AND POSTNATAL TOBACCO SMOKE EXPOSURE:EFFECTS ON NEUROCOGNITIVE DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6129
contact_pi_person_id: 1866555
contact_pi: PISANO, M. MICHELE
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.Maternal cigarette smoking has been associated with a variety of adverse fetal infant and childhood developmental outcomes.  In the United States alone approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight with its attendant complications for infant/childhood development a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined. In many cases cognitive or behavioral dysfunction in children of mothers who smoked during pregnancy has been attributed to the clinical antecedent of low birthweight. However emerging evidence indicates that exposure to cigarette smoke or components such as nicotine and carbon monoxide during pregnancy affects the structural molecular and/or functional development of the central nervous system at doses well below those at which perinatal growth alterations are elicited. This suggests that the magnitude of the problem regarding maternal smoking-induced neurobehavioral/cognitive impairment in children may be greatly underappreciated and may extend well beyond only smoke-exposed low birthweight offspring.  The global objective of the present research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuro/cognitive development. Since the hippocampus subserves a central role  across species   in neuro/cognition especially in the information processing involved in learning and memory the central hypothesis under investigation is that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus resulting in altered hippocampus-dependent learning and memory in the offspring. Four Specific Aims are proposed to determine whether: 1] Tobacco smoke exposure during development in a murine model simulating human active cigarette smoking results in neurobehavioral abnormalities involving hippocampus-dependent learning and memory; 2] Alterations in the establishment of normal cytoarchitecture and neurogenesis in the murine hippocampus are elicited by exposure to tobacco smoke during development in the absence of attendant effects on murine fetal/neonatal growth; 3] Tobacco smoke exposure during development results in hippocampal neuronal subtype-specific alterations in the expression of genes during murine ontogenesis that are critical mediators of neuronal developmental plasticity learning and memory; 4] Maternal smoking during pregnancy in humans results in adverse neurophysiological and neurobehavioral outcomes in infants which are associated with alterations in hippocampus-dependent basic perceptual skills known to place the infant at risk for learning disabilities during childhood. Successful completion of the proposed studies will aid in understanding the effects of and mechanisms underlying in utero tobacco smoke exposure on neuro/cognitive development in infants and children and  long-term   will facilitate the diagnosis of and intervention into learning disabilities and other cognitive impairments in children affected by prenatal maternal tobacco abuse.

project_terms:
Affect;Behavioral;Carbon Monoxide;Child;Childhood;Clinical;Cognition;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Defect;Development;Diagnosis;Dose;Exposure to;Functional disorder;Funding;Gene Expression;Grant;Growth;Hippocampus (Brain);Human;Impaired cognition;Infant;Institution;Intervention;Investigation;Learning;Learning Disabilities;Low Birth Weight Infant;Mediator of activation protein;Memory;Modeling;Molecular;Mothers;Mus;Neonatal;Neuraxis;Neurocognitive;Neurons;Nicotine;Outcome;Perinatal;Pregnancy;Research;Research Personnel;Resources;Risk;Risk Factors;Role;Simulate;Smoke;Source;Tobacco;Tobacco smoke;United States;United States National Institutes of Health;cigarette smoke;cigarette smoke-induced;cigarette smoking;developmental plasticity;fetal;fetal tobacco exposure;in utero;information processing;maternal cigarette smoking;maternal tobacco abuse;maternal tobacco use;neurobehavioral;neurogenesis;neurophysiology;offspring;postnatal;prenatal;prenatal exposure;programs;skills


application_id: 7959955
project_number: 5P20RR017702-07
project_title: HYPOXIA-MEDIATED OLIGODENDROCYTE DEFECTS:MURINE MODEL OF GESTATIONAL SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6128
contact_pi_person_id: 9256836
contact_pi: CAI, JUN
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.Obstructive sleep apnea (OSA) is a highly prevalent disorder that may occur at any age from neonate to older adult which is characterized by intermittent hypoxia (IH) as one of the hallmarks. It has been rising among middle-aged adults due to the increasing prevalence of obesity in the USA. Furthermore the incidence of OSA is particularly increased during pregnancy with potential consequences to both mother and fetus. Clinical evidence indicates that IH leads to decelerations in the rhythm of fetal heart and impose a high risk to have a baby with growth retardation. However little is known about how oligodendrocytes (OLs) in central nervous system (CNS) respond to gestational IH exposure during sleep. 

In this proposal we will focus our efforts on developmental deficits of OLs in sleep apnea-associated IH and hypothesize that OL development is susceptible to maternal sleep apnea-associated IH and that gestational IH results in postnatal disruption of myelin sheaths and neural function in CNS which may underlie increased vulnerability to sleep apnea or other diseases such as ADHD Alzheimer's disease and bipolar disorder later in life. Three aims are proposed to test these hypotheses and to characterize the molecular and cellular mechanisms underlying IH-mediated OL injury due to gestational OSA-related IH exposure:
Specific aim 1: to examine OL generation proliferation and differentiation in mouse forebrain and spinal cord at different embryonic stages following IH exposure during gestation.
Specific aim 2: to determine consequences of maternal IH exposure on myelin-forming process and myelin architecture in developing and adult mice as well as local effects on axonal development that maybe induced or deteriorated by myelin deficit.
Specific aim 3: to explore signaling molecules invovled in IH-mediated OL injury occurring in maternal sleep apnea during pregnancy.

The study will be performed using wild-type/transgeneic murine models of sleep apnea. Quantitative PCR RNA in situ hybridization Western blotting immunohistochemistry and electron microscopy will be performed to study gene expression and myelin structure in OL development. Electrophysiological and behavioral assessments will be used to establish functional correlates. In addition in ovo electroporation EMSAs and mass spectrometric analysis will be applied for investigation of IH-elicited molecular mechanisms.

project_terms:
Adult;Age;Alzheimer's Disease;Architecture;Attention deficit hyperactivity disorder;Behavior assessment;Bipolar Disorder;Clinical;Computer Retrieval of Information on Scientific Projects Database;Deceleration;Defect;Development;Disease;Elderly;Electron Microscopy;Electroporation;Embryo;Fetal Heart;Fetus;Funding;Gene Expression;Generations;Grant;Growth;Hypoxia;Immunohistochemistry;In Situ Hybridization;Incidence;Injury;Institution;Investigation;Life;Mediating;Modeling;Molecular;Mothers;Mus;Myelin;Myelin Sheath;Neuraxis;Neurophysiology - biologic function;Obesity;Obstructive Sleep Apnea;Oligodendroglia;Pregnancy;Prevalence;Process;Prosencephalon;RNA;Research;Research Personnel;Resources;Signaling Molecule;Sleep;Sleep Apnea Syndromes;Source;Spinal Cord;Staging;Structure;Testing;United States National Institutes of Health;Western Blotting;high risk;middle age;neonate;postnatal


application_id: 7959954
project_number: 5P20RR017702-07
project_title: THE ROLE OF TGF-? MODULATORS IN VERTEBRAL DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6127
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
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.Vertebral malformation associates with a large number of distressful human birth defects. Elucidation of the developmental and genetic mechanisms underlying normal vertebral formation will undoubtedly have great impacts on human health. The formation of vertebral system is a complex process involving the morphogenesis of neural tube notochord somites and cell  cell signaling events among these tissues. In particular the formation and differentiation of somites play a critical role in vertebral development and vertebral disorders. Each somite has to establish an anterior-posterior (A-P) polarity and disruption of this A-P polarity during development often leads to the abnormal fusions between vertebrae bodies and ribs resulting in serious vertebral and spinal cord disorders. The development of vertebrate tail provides an excellent model system to study somite formation and differentiation due to its simple anatomic structure compared with the trunk vertebral system. The abnormal fusion between vertebrae bodies usually cause tail bending kinky tail that can be easily visualized. The A-P differentiation of somites can be examined by a set of well established molecular markers. In this study we will focus on the regulation of TGF-b signaling pathway in somitogenesis by exploring the functions of two Smads interacting factors: Zfhx1a and TGIF. Zfhx1a also called dEF1 encodes a zinc finger protein that contains multiple DNA and protein binding domains including homeodomain and Smad binding domain. In vitro studies showed that members of Zfhx protein family can bind to Smads proteins and recruit transcription activator p300 or repressor CtBP. Depending on the types of recruited co-factors activators or repressors Zfhx proteins can either up- or down- regulate TGF-b activity. Biochemical studies have revealed that TGIF antagonizes TGF-b signaling by binding to Smad2. Our recent studies with Zfhx1a and TGIF mutant mice uncovered that loss of Zfhx1a or TGIF function leads to a severe kinky tail phenotype strongly indicating that these genes play important roles the A-P differentiation of somites. We therefore propose here to examine the functional requirements of Zfhx1a and TGIF during mouse somitogenesis and vertebral development. In addition we will employ Zebrafish system to determine the specificity of Zfhx1a and TGIF mediated TGF-b suppression in vivo namely which TGF-b member(s) activity is regulated by Zfhx1a and TGIF in vertebrate somitogenesis.

Results from the proposed research will be significant as it address the regulation of an important pathway TGF-b signaling in a fundamental biological process vertebrate body segmentation. In addition the project features several advantages that fit the purpose of this COBRE application suitably: 1) It is a suitable project for the investigator to enter a new area of birth defect research vertebral disorders; 2) An additional model system Zebrafish will allow the investigator to conduct more mechanistic studies as Zebrafish is more accessible to embryonic and genetic manuscript; 3)  Since Zebrafish system is a popular and powerful model system in developmental biology having a zebrafish model system in the laboratory will improve the research strength to a great extend.

project_terms:
Address;Anatomic structures;Anterior;Area;Binding (Molecular Function);Biochemical;Biological Models;Biological Process;Centers of Research Excellence;Complex;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;DNA;Defect;Development;Developmental Biology;Disease;EP300 gene;Embryo;Event;Funding;Genes;Genetic;Grant;Health;Human;In Vitro;Institution;Laboratories;Manuscripts;Mediating;Molecular;Morphogenesis;Mus;Mutant Strains Mice;Neural tube;Pathway interactions;Phenotype;Play;Process;Protein Binding Domain;Protein Family;Proteins;Recruitment Activity;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Somites;Source;Specificity;Spinal Cord Diseases;System;Tail;Tissues;Transcription Coactivator;United States National Institutes of Health;Zebrafish;Zinc Fingers;developmental genetics;homeodomain;improved;in vivo;intercellular communication;malformation;member;molecular marker;notochord;rib bone structure;somitogenesis;spine bone structure;vertebra body


application_id: 7959953
project_number: 5P20RR017702-07
project_title: THE ROLE OF PATCHED 1 AND SUPPRESSOR OF FUSED IN THE OVARY
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2009-06-01
project_end_date: 2010-05-31
subproject_number: 6126
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
budget_start_date: 2009-06-01
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.Folliculogenesis and oogenesis are complex processes which occur in the ovary and result in the production of fertilizable female germ cells.  These processes require proper intercellular communication between many cell types including oocyte granulosa theca and luteal cells within the ovary. Many intraovarian growth factors and endocrine factors such as insulin-like growth factor epidermal growth factor steroids members of the transforming growth factor b family the Wnt/Frizzled family and gonadotropins are involved in these processes affecting female reproduction. Here we propose that the hedgehog (Hh) signaling pathway one of the major signaling pathways in driving cell proliferation and directing cell differentiation during embryonic and postnatal development will play a role in folliculogenesis and oogenesis to regulate female fertility in mammals. There are many components of the Hh signaling pathway. In this proposal we will focus on characterization of the roles of patched-1 (Ptc) and suppressor of fused (Sufu) two negative regulators of Hh signaling in the ovary. Ptc is expressed in oocytes and theca cells in mouse ovary. Mice containing a natural occurring Ptc mutation (Ptcmes) display female sterility. Sufu is also highly expressed in mouse oocytes.  Putative Gli DNA response elements are present in the promoters of Growth Differentiation Factor-9 (GDF-9) and cytochrome P450 17alpha-hydroxylase (Cyp17) which are known to play an important role in normal ovarian functions. Based on this information we hypothesized that Hh signaling molecules Ptc and Sufu will play a role in folliculogenesis and oogenesis likely by regulating GDF-9 and Cyp17 expression in oocytes or thecal cells affecting female fertility in mammals. Genetically modified Ptc and Sufu mouse models will be used to determine their ovarian roles in this study. The specific aims are to (1) Characterize the ovarian phenotypes of sterile Ptc mutation mice carrying a spontaneous mesenchymal dysplasia (mes) mutation (Ptcmes/mes); and (2) Investigate the synergistic effects of Ptc and Sufu in the ovaries from Sufu+/-;Ptcmes/mes mutant mice. Fertility analysis in combination with morphological histological and molecular analyses will be performed to characterize ovarian phenotypes of these Sufu and Ptc mutant mice. It is expected that deletion of Ptc and/or Sufu will mimic ectopic Hh signaling in oocytes and/or thecal cells to stimulate their growth or proliferation result in aberrant folliculogenesis and oogenesis and eventually lead to female infertility. Introduction of a mutant Sufu allele into Ptcmes/mes mice will cause more severe ovarian phenotypes than Ptcmes/mes alone. The goal of this study is to explore whether Hh signaling is functional in the ovary. This study would substantially advance our knowledge about ovarian function and female fertility. Knowledge gained from this study could be used in diagnosis and treatment of female idiopathic infertility.

project_terms:
Affect;Alleles;Automobile Driving;Cell Differentiation process;Cell Proliferation;Cells;Complex;Computer Retrieval of Information on Scientific Projects Database;Cytochrome P450;DNA;Defect;Development;Diagnosis;Dysplasia;Embryo;Endocrine;Epidermal Growth Factor;Erinaceidae;Family;Female;Female infertility;Female sterility;Fertility;Funding;Germ Cells;Goals;Gonadotropins;Grant;Growth;Growth Differentiation Factor 9;Growth Factor;Infertility;Institution;Knowledge;Lead;Mammals;Mesenchymal;Mixed Function Oxygenases;Molecular;Mus;Mutant Strains Mice;Mutation;Oocytes;Oogenesis;Ovarian;Ovary;Phenotype;Play;Process;Production;Promotor (Genetics);Reproduction;Research;Research Personnel;Resources;Response Elements;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Somatomedins;Source;Sterility;Steroids;Theca-Lutein Cells;Transforming Growth Factors;United States National Institutes of Health;base;cell type;folliculogenesis;intercellular communication;intraovarian;member;mouse model;mutant;postnatal;smoothened signaling pathway;theca cell


application_id: 7959812
project_number: 5P20RR018733-07
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE E: BIOPHYSICAL FACILITY
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5985
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
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 Biophysics Core Facility is located on the fourth floor of the Brown Cancer Center in a newly renovated 504 square-foot laboratory.  This state-of-the-art facility provides the capability to perform calorimetry electronic spectroscopy rapid kinetics and hydrodynamics determinations.   Expertise is provided by the director Dr. J. Brad Chaires and by Dr. Nichola Garbett the facility manager both of whom have considerable experience in this area.  In addition to the instrumentation this facility provides training in biophysical methods and data analysis and is integrated with the molecular modeling and structural biology cores at the Brown Cancer Center to enhance drug discovery efforts.  The Biophysics Core Facility provides a unique resource to all MT-COBRE investigators.

project_terms:
Area;Arts;Biophysics;Calorimetry;Cancer Center;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Data Analyses;Electronics;Floor;Funding;Grant;Institution;Kinetics;Laboratories;Methods;Molecular Models;Molecular Target;Research;Research Personnel;Resources;Source;Spectrum Analysis;Training;United States National Institutes of Health;drug discovery;experience;instrumentation;molecular modeling;square foot;structural biology


application_id: 7959811
project_number: 5P20RR018733-07
project_title: COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5984
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: 2009-07-01
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 a 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 VSELs 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 VSELs may contribute to aging of the central nervous system (CNS) resulting in less effective repair.  To investigate these issues four specific aims were proposed.
     Specific Aim 1. Neural differentiation of bone marrow-derived VSELs. We have presented evidence that BM contains a population of VSELs and that these epiblast-derived cells are deposited there early in development during rapid body growth/expansion. We will first optimize their isolation from bone marrow and neural differentiation (ability to grow neurospheres). Next we will evaluate the age-related presence of VSELs in bone marrow tissue. Once it is determined whether VSELs 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 VSELs into peripheral blood. Since mobilized peripheral blood (mPB) may be a source of VSELs 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+ VSELs are mobilized and subsequently chemo-attracted into a damaged brain in an SDF-1-dependent manner. 
      Specific Aim 3. Develop an approach to expand VSELs.  Since the number of VSELs 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 VSELs will better engraft and regenerate brain cells.  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 layers 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 VSELs in brain regeneration in vivo in a murine model of sleep apnea (SA).  The contribution of VSELs 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 VSELs isolated from enhanced green immunofluorescence protein (EGFP+) transgenic mice to rescue brain cells damaged by hypoxia and the role of the SDF-1CXCR4 axis in this process.  We will employ freshly isolated VSELs from BM or mPB as well as VSEL expanded in ex vivo cultures.  As a readout of brain regeneration we will use selected behavioral tests.

project_terms:
Aging;Animals;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Brain;Brain Injuries;CXCR4 gene;Cell Count;Cell Line;Cell Therapy;Cells;Centers of Research Excellence;Chronic Brain Damage;Coculture Techniques;Computer Retrieval of Information on Scientific Projects Database;Data;Deposition;Development;Disease;Effectiveness;Epiblast;Funding;Germ Cells;Grant;Growth;Growth Factor;Human;Hypoxia;Immunofluorescence Immunologic;Individual;Institution;Investigation;Ischemia;Ligands;Longevity;Marrow;Membrane;Methodology;Modeling;Molecular Target;Mus;Natural regeneration;Nerve Regeneration;Neuraxis;Neurons;Patients;Play;Population;Process;Research;Research Personnel;Resources;Role;Sleep Apnea Syndromes;Source;Stem cells;Stromal Cell-Derived Factor 1;System;T140 peptide;Testing;Tissue Differentiation;Tissues;Transgenic Mice;United States National Institutes of Health;Vascular Endothelial Growth Factors;age related;base;behavior test;brain cell;cell injury;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: 7959810
project_number: 5P20RR018733-07
project_title: COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5983
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: 2009-07-01
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
This project will use structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence.

This subproject has three specific aims:
1. Model Development:  Update existing SAR models for rodent carcinogenicity that will serve as "control" models and a set of "experimental" SAR models based on target tissue-specific chemical carcinogenesis. The control models will be based on the traditional SAR approach of contrasting carcinogens to noncarcinogens and the experimental models will be based on a new approach of contrasting chemical carcinogens from one site to those of all other sites. In essence the control models will handle the question of "What makes a chemical a carcinogen?" and the experimental models will tackle the problem of "What makes a carcinogen target a specific tissue?" This aim will use the Core C facility (Molecular Modeling) to carry out this approach.
2. Toxicophore Identification:  Based on information developed in Aim 1 we will identify toxicophore-defined sets of compounds (i.e. with similar structure and biological activity) associated with tissue-specific carcinogenesis. Then we will refine toxicophores from these models with ligand-based 3D SAR methods and develop small libraries of suitable compounds for in vitro testing. This aim will use Core C (Molecular Modeling).
3. Genome/Proteome Target Identification:  Using the compounds from the toxicophore libraries developed in Aim 2 as chemical probes we will assay site-matched cell lines in order to identify the molecular targets with which they interact. Comparative toxicogenomics and proteomics will be used to identify the specific molecular targets associated with tissue-specific carcinogenicity. This aim will use Cores B (Microarray facility) and previous Core E facility (Proteomics) to accomplish these procedures.

project_terms:
Biological;Biological Assay;Carcinogens;Cell Line;Centers of Research Excellence;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Experimental Models;Funding;Genome;Grant;Institution;Libraries;Ligands;Methods;Modeling;Molecular Models;Molecular Target;Procedures;Proteome;Proteomics;Research;Research Personnel;Resources;Rodent Model;Site;Source;Structure;Structure-Activity Relationship;Tissues;Toxicogenomics;United States National Institutes of Health;Update;base;carcinogenesis;carcinogenicity;chemical carcinogen;chemical carcinogenesis;comparative;in vitro testing;model development;molecular modeling;novel strategies;three dimensional structure


application_id: 7959809
project_number: 5P20RR018733-07
project_title: COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5982
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: 2009-07-01
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 of this project 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 from 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;Centers of Research Excellence;Complex;Computer Retrieval of Information on Scientific Projects Database;Data;Defect;Development;Dysplasia;Embryo;Frequencies (time pattern);Funding;Genetic;Goals;Grant;Homeostasis;Immunoprecipitation;Institution;Knockout Mice;Knowledge;Loss of Heterozygosity;Mass Spectrum Analysis;Molecular;Molecular Target;Mus;NF-kappa B;Phosphotransferases;Predisposition;Proteins;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Source;Testing;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;clinically relevant;keratinocyte;tumor


application_id: 7959808
project_number: 5P20RR018733-07
project_title: COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5981
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: 2009-07-01
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;Centers of Research Excellence;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;Molecular Target;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;ras Oncogene;ras Proteins;small molecule;tumor growth


application_id: 7959807
project_number: 5P20RR018733-07
project_title: COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5980
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: 2009-07-01
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 Project 6

      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 much 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;Centers of Research Excellence;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Development;Endoplasmic Reticulum;Funding;Grant;Institution;Malignant Neoplasms;Mitochondria;Molecular;Molecular Target;Pathway interactions;Play;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Source;United States National Institutes of Health;design;endoplasmic reticulum stress;programs


application_id: 7959806
project_number: 5P20RR018733-07
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE D: NMR & PROTEIN PURIFICATION FACILITIES
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5979
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: 2009-07-01
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 realizing 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:
Affinity Chromatography;Apoptotic;Bacteria;Biological;Biophysics;Calmodulin;Cells;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Crystallography;Cytosine;DNMT3B gene;Data Collection;Differentiation and Growth;Ensure;Enzymes;Escherichia coli;Fibroblasts;Funding;Gene Expression Profile;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;Molecular Target;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 Crystallography;X-Ray Diffraction;base;bronchial epithelium;cancer cell;cell type;interest;metabolomics;programs;protein expression;protein purification;regenerative therapy;research study;sphingosine kinase


application_id: 7959804
project_number: 5P20RR018733-07
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE B: MICROARRAY FACILITY
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5977
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: 2009-07-01
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 Microarray Facility is located in the Baxter II Biomedical Research Building one block from the Brown Cancer Center. This facility contains both Affymetrix and Agilent microarray instrument systems which are available to all MT-COBRE members. The Facility is under the direction of Dr. Wolfgang Zacharias and has been fully operational for the past eight years since Spring 2001. It includes a full-time Facility Manager Sabine Waigel and two research technologists Vennila Arumugam and Xiaohong Li. They provide administrative support project logistics and management technical assistance in platform-specific sample processing and hybridization as well as data collection analysis and storage. Dr. Zacharias is available for assistance with experimental design data analysis and collaborative or consultant support for grant applications.

The Microarray Facility has close interactions with other Core Facilities and Bioinformatics personnel. Also the close relationship with the Tissue Biorepository in the J.G. Brown Cancer Center allows the preparation of samples with known pathologic characteristics and appropriate control specimens. Plans are underway for the development of a tissue array component of this facility as well. The high-resolution Affymetrix Scanner 3000 upgrade allows all COBRE investigators to use the newest generation of high-density whole genome v2.0 arrays and SNP 6.0 arrays for human or mouse. The Facility continues to organize and hold software/data analysis workshops on campus to train microarray technology users.

project_terms:
Applications Grants;Bioinformatics;Biomedical Research;Cancer Center;Centers of Research Excellence;Characteristics;Computer Retrieval of Information on Scientific Projects Database;Computer software;Core Facility;Data Analyses;Data Collection;Development;Educational workshop;Experimental Designs;Funding;Generations;Genome;Grant;Human;Human Resources;Institution;Logistics;Microarray Analysis;Molecular Target;Mus;Pathologic;Preparation;Process;Research;Research Personnel;Resolution;Resources;Sampling;Source;Specimen;System;Time;Tissue Microarray;Tissues;Training;United States National Institutes of Health;biobank;density;instrument;member


application_id: 7959803
project_number: 5P20RR018733-07
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE A:ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2009-06-17
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2009-07-01
project_end_date: 2010-06-30
subproject_number: 5976
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: 2009-07-01
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


application_id: 7959681
project_number: 5P20RR015576-10
project_title: ROLE OF ESTROGEN AND PROGESTERONE IN SCI PAIN
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5854
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;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;repaired;response;spinal cord injury pain


application_id: 7959680
project_number: 5P20RR015576-10
project_title: ROLE OF HSP 25 IN THE ASTROCYTE RESPONSE AND RECOVERY FROM SPINAL CORD INJURY
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5853
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;Brain Hypoxia-Ischemia;Cell Death;Cell Hypoxia;Cell Survival;Cell model;Computer Retrieval of Information on Scientific Projects Database;Cytoprotection;Embryo;Funding;Genes;Grant;Heat shock proteins;Hypoxia;Injury;Institution;Intervention;Ischemia;Molecular Profiling;Neuroglia;Neurons;Oligodendroglia;Pathway interactions;Proteins;Proteomics;Recovery;Research;Research Personnel;Resources;Rodent;Role;Signal Pathway;Source;Spinal Cord;Spinal cord injury;Stress;Testing;United States National Institutes of Health;novel therapeutic intervention;oligodendrocyte precursor;overexpression;protein expression;protein protein interaction;repaired;response;white matter;white matter injury


application_id: 7959679
project_number: 5P20RR015576-10
project_title: MICROVASCULAR REGULATION OF FUNCTIONAL RECOVERY FOLLOWING SCI
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5852
contact_pi_person_id: 8559743
contact_pi: BENTON, RICHARD
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.Subproject Description

Following traumatic spinal cord injury (SCI) significant vascular disruption occurs at the site(s) of injury.  This interruption of vascular support to spinal tissue has been proposed to be a key mediator of multiple secondary injury cascades all of which contribute to tissue damage and subsequent loss of function.  While the precise molecular effector(s) governing this vascular dysfunction are not well understood a small group of candidate molecules has been identified and include transforming growth factor-1 (TGF-1) vascular endothelial cell growth factor (VEGF) and matrix metalloproteases (MMPs).  Importantly the bioactivity of all these established effectors is modulated by plasminogen activator class of serine proteases although little data exist regarding their expression following SCI.  Preliminary data have identified endothelial (EC) over-expression of plasminogen activator system (PAS) components uPA and its endogenous inhibitor PAI-1 as early regulators of neurovascular unit (NVU) pathology and may regulate functional recovery after SCI.  In the current proposal we will utilize these novel approaches combined with in vivo treatment with small molecule inhibitors of PAS components to address the following hypotheses:  1)  Microvascular expression of PAS components negatively impacts EC survival microvascular function and white matter sparing/function following contusive thoracic SCI.  2)  PAS induction in the EC compartment is the consequence of tissue ischemia initiated by traumatic SCI which is responsible for evolving penumbral microvascular dysfunction giving rise to inflammation and tissue loss.  3)  Antagonism of PAS proteolytic induction following traumatic gray matter injury will result in enhanced EC survival improved microvascular function and decreased loss of neuropil due to secondary injury an effect which is in part due to decreased activation of MMP-9.  Results from these studies will provide critical insight into the pathologic transformation of the NVU resulting in decreased microvascular function following SCI which is an invaluable initial step for designing effective vasoactive therapies for the treatment of SCI.

project_terms:
Address;Blood Vessels;Computer Retrieval of Information on Scientific Projects Database;Data;Fibroblast Growth Factor;Functional disorder;Funding;Grant;Inflammation;Injury;Institution;Interruption;Ischemia;Mediator of activation protein;Metalloproteases;Molecular;Neuropil;Pathologic;Pathology;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Plasminogen Inactivators;Recovery of Function;Regulation;Research;Research Personnel;Resources;Secondary to;Serine Protease;Site;Source;Spinal;Spinal cord injury;System;Thoracic spinal cord structure;Tissues;Transforming Growth Factors;United States National Institutes of Health;Vascular Endothelial Cell;design;gray matter;improved;in vivo;inhibitor/antagonist;insight;loss of function;neurovascular unit;novel strategies;repaired;small molecule;white matter


application_id: 7959678
project_number: 5P20RR015576-10
project_title: GSK3B AS A TARGET FOR PRO-NEURONAL SURVIVAL IN CNS NEURONS
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5851
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;Contusions;Demyelinations;Endoplasmic Reticulum;Functional disorder;Funding;Grant;Institution;Intervention;Lead;Mutant Strains Mice;Nerve Degeneration;Neurons;Oligodendroglia;Outcome;Pathology;Pathway interactions;Proteins;Research;Research Personnel;Resources;Source;Spinal cord injury;Testing;United States National Institutes of Health;biological adaptation to stress;endoplasmic reticulum stress;nervous system disorder;neuronal survival;oligodendrocyte precursor;oxidative damage;precursor cell;protein misfolding;repaired;response;stroke;tool


application_id: 7959677
project_number: 5P20RR015576-10
project_title: COBRE: UL: CELL INSTRINSIC MECHANISMS REGULATING SENSORY AXON REGENERATION
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5850
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;Centers of Research Excellence;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;Sensory;Source;Staging;Testing;United States National Institutes of Health;Work;axon growth;axon regeneration;base;combinatorial;dorsal column;programs;repaired;transcription factor


application_id: 7959676
project_number: 5P20RR015576-10
project_title: COBRE: UL: MICROSCOPY CORE: CORE E
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5849
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;Research;Research Personnel;Resources;Source;United States National Institutes of Health;repaired


application_id: 7959675
project_number: 5P20RR015576-10
project_title: COBRE: MECHANISMS OF PLASTICITY & REPAIR AFTER SCI D: BEHAV & ELECTROPHYS CORE
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5848
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);Funding;Grant;Hair;Hindlimb;Hypersensitivity;Injury;Institution;Joints;Lateral;Limb structure;Locomotion;Magnetism;Measures;Motor Evoked Potentials;Mus;Pathway interactions;Rattus;Reflex action;Research;Research Personnel;Resources;Sensorimotor functions;Sensory;Somatosensory Evoked Potentials;Source;Spinal Cord;Swimming;Testing;Thermal Hyperalgesias;United States National Institutes of Health;Walking;kinematics;novel;repaired;tool;white matter


application_id: 7959674
project_number: 5P20RR015576-10
project_title: COBRE: UL: MECHANISMS OF PLASTICITY AND REPAIR AFTER SCI/ C: SURGICAL CORE
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5847
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;Centers of Research Excellence;Cephalic;Computer Retrieval of Information on Scientific Projects Database;Contusions;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;Rattus;Research;Research Personnel;Resources;Source;Spinal Cord;Tissue Fixation;United States National Institutes of Health;Urinary tract;Veterinary Surgery;design;implantation;nutrition;prevent;repaired


application_id: 7959673
project_number: 5P20RR015576-10
project_title: COBRE: CELL CULTURE AND MOLECULAR BIOLOGY: CORE B
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5846
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;Cell Culture Techniques;Centers of Research Excellence;Complementary DNA;Computer Retrieval of Information on Scientific Projects Database;Embryo;Ensure;Fetus;Fluorescence-Activated Cell Sorting;Funding;Genes;Grant;Green Fluorescent Proteins;Human;In Vitro;Institution;Label;Laboratories;Lentivirus Vector;Messenger RNA;Methods;Molecular Biology;Quality Control;Reagent;Research;Research Personnel;Resources;Retroviridae;Small Interfering RNA;Source;Spinal Cord;Subfamily lentivirinae;Time;Transgenes;United States National Institutes of Health;in vivo;interest;meetings;precursor cell;repaired;stem


application_id: 7959672
project_number: 5P20RR015576-10
project_title: COBRE: UL: MECHANISMS OF PLASTICITY AND REPAIR AFTER SCI: A ADMIN CORE
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
project_start_date: 2009-06-01
project_end_date: 2010-05-31
study_section: ZRR1-RI-8(02)
subproject_number: 5845
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;meetings;repaired


application_id: 7959501
project_number: 5P20RR015592-10
project_title: HORMONE REGULATION OF CARDIAC INJURY
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5674
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;Cardiac Myocytes;Caveolae;Caveolins;Centers of Research Excellence;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;Knockout Mice;Mediating;Modification;Molecular;Myocardial Ischemia;Nitric Oxide;Nitric Oxide Synthase;Orchiectomy;Ovariectomy;Process;Production;Reporting;Research;Research Personnel;Resources;Role;Source;Testing;Testosterone;United States National Institutes of Health;Wild Type Mouse;Woman;Women's Health;adenylate kinase;alpha caveolin;caveolin 1;hormone regulation;men;novel;uptake


application_id: 7959500
project_number: 5P20RR015592-10
project_title: PILOT PROJECTS
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5673
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 COBRE in Women's Health funds new pilot projects in promising areas of research that complement the goals of the COBRE program to increase the critical mass of investigators with expertise and experience in women's health research

project_terms:
Area;Centers of Research Excellence;Complement;Computer Retrieval of Information on Scientific Projects Database;Funding;Goals;Grant;Institution;Pilot Projects;Research;Research Personnel;Resources;Source;United States National Institutes of Health;Women's Health;experience;programs


application_id: 7959499
project_number: 5P20RR015592-10
project_title: HORMONE ACTIONS ON BEHAVIOR: CLINICAL NEUROPHARMACOLOGY
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5672
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;Centers of Research Excellence;Clinical;Cognition;Computer Retrieval of Information on Scientific Projects Database;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;Regulation;Research;Research Personnel;Resources;Series;Sex Behavior;Sex Characteristics;Site;Sleep;Source;Steroids;Traumatic Stress Disorders;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;neurosteroids;non-genomic;receptor


application_id: 7959498
project_number: 5P20RR015592-10
project_title: HORMONAL CONTROL OF TRANSCRIPTIONAL REGULATION
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5671
contact_pi_person_id: 8288294
contact_pi: KILGORE, MICHAEL
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;Centers of Research Excellence;Clinical;Computer Retrieval of Information on Scientific Projects Database;Data;Disease;Disease Progression;Estradiol;Estrogens;Female;Funding;Genetic Transcription;Goals;Gonadal Steroid Hormones;Grant;HIV;HIV Infections;HIV-1;Hormonal;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;Transcriptional Regulation;United States National Institutes of Health;Viral;Viral Load result;Woman;Women's Health;Women's Role;design;men;multicatalytic endopeptidase complex;novel;tool


application_id: 7959497
project_number: 5P20RR015592-10
project_title: EFFECTS OF ESTRADIOL & ANTIDEPRESSANTS IN HIPPOCAMPAL NEUROGENESIS
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5670
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;Centers of Research Excellence;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;Neurons;Parahippocampal Gyrus;Postmenopause;Prefrontal Cortex;Promotor (Genetics);Research;Research Personnel;Resources;Selective Serotonin Reuptake Inhibitor;Serotonin;Severities;Site;Source;Synaptic Cleft;Testing;Transcript;United States;United States National Institutes of Health;Untranslated Regions;Woman;Women's Health;cholinergic neuron;dentate gyrus;depression;depressive symptoms;neurogenesis;social


application_id: 7959496
project_number: 5P20RR015592-10
project_title: HORMONE MEDIATED REGULATION OF OVARIAN FUNCTION
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5669
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;Computer Retrieval of Information on Scientific Projects Database;DNA Microarray Chip;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;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;Women's Health;granulosa cell;inhibitor/antagonist;matrix metalloproteinase 19;migration;novel;receptor;research study;theca cell;tool


application_id: 7959495
project_number: 5P20RR015592-10
project_title: KY COBRE: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
project_start_date: 2009-03-01
project_end_date: 2010-02-28
study_section: ZRR1-RI-8(02)
subproject_number: 5668
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;Centers of Research Excellence;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: 7948788
project_number: 1R01DK089178-01
project_title: Inhibition of ATGL-Mediated Lipolysis by G0S2
administering_ic: NIDDK
award_notice_date: 2010-07-14
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DK
serial_number: 089178
program_official: HAFT, CAROL R
project_start_date: 2010-07-15
project_end_date: 2015-06-30
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 8794215
contact_pi: LIU, JUN
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Adipose tissue triacylglycerol (TAG) is the major source of energy in higher eukaryotes. The ability of adipocytes to mobilize free fatty acids (FFAs) from TAG stores during times of demand is essential for survival. The altered rates of FFA release are strongly associated with the development of obesity and type 2 diabetes both in humans and in rodents. Lipolysis the process in which TAG is hydrolyzed to FFAs and glycerol has been a subject of intense investigation for decades with much focus on hormone-sensitive lipase (HSL). With the discovery of adipose triglyceride lipase (ATGL) as the rate-limiting enzyme in lipolysis a clearer understanding of the molecular processes governing TAG mobilization emerged. Although recent studies identified CGI-58 as a co-activator of ATGL the mechanisms that regulate the ATGL enzyme action remain insufficiently understood. In this regard our preliminary studies have uncovered a novel mechanism for the control of ATGL-mediated lipolysis. We have obtained compelling evidence that a protein encoded by G0/G1 switch gene 2 (G0S2) is a selective regulator of ATGL. G0S2 is highly expressed in adipose tissue and differentiated adipocytes. It specifically interacts with ATGL leading to the inhibition of its TAG lipase activity. Knockdown and overexpression experiments demonstrate that G0S2 functions to attenuate ATGL-mediated lipolysis in both adipocytes and nonadipocyte cells. The overall goal of this proposal is to further explore the molecular details of ATGL inhibition by G0S2 and more importantly the physiologic roles of G0S2 in TAG lipolysis in the context of various functional settings. The goal will be accomplished by (1) determining the biochemical mechanisms by which ATGL activity is regulated by G0S2; (2) testing the hypothesis that G0S2 and CGI-58 play opposing roles in ATGL-mediated lipolysis; and (3) evaluating the effects of adipose overexpression of G0S2 on energy metabolism and insulin sensitivity. In aim 1 we will perform both enzyme kinetic studies and substrate interaction assays. We will also map the precise sequence motif(s) in ATGL for G0S2 binding. For aim 2 we will manipulate relative levels of G0S2 and CGI-58 in various cellular setting and examine the effects on ATGL-mediate lipolysis and the related functional consequences. Aim 3 will be accomplished through diet treatment studies using a transgenic animal model overexpressing G0S2 fat specifically. These studies will contribute to our understanding of TAG metabolism and to the development of new therapeutic strategies against obesity and type 2 diabetes.  
  
PUBLIC HEALTH RELEVANCE: Obesity is a prevalent disorder of energy balance in which excess energy in the form of triacylglycerol accumulates in adipose tissue. Despite a need for therapeutic approaches to treat obesity little is known about the mechanisms that control fat storage and release from adipose tissue. The proposed study will focus on investigating the important role of a new protein that regulates ATGL the key enzyme for fat mobilization in adipose tissue.

project_terms:
Adipocytes;Adipose tissue;Animal Model;Attenuated;Binding (Molecular Function);Biochemical;Biological Assay;Body Weight;Cells;Characteristics;Chimeric Proteins;Data;Development;Diet;Disease;Energy Metabolism;Energy-Generating Resources;Enzyme Kinetics;Enzymes;Equilibrium;Eukaryota;Fatty acid glycerol esters;Glucose;Glycerol;Goals;Hepatocyte;Hormone Responsive;Human;Hydrolysis;In Vitro;Insulin;Insulin Resistance;Investigation;Label;Light;Lipase;Lipolysis;Maps;Measurement;Mediating;Metabolic;Metabolism;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Obesity;Physiological;Play;Point Mutation;Process;Proteins;Recombinant Proteins;Relative (related person);Resistance;Rodent;Role;Series;Small Interfering RNA;Stretching;Substrate Interaction;Switch Genes;Testing;Therapeutic;Time;Transgenic Animals;Triglycerides;adenoviral-mediated;base;cell type;energy balance;in vivo;insight;insulin sensitivity;insulin tolerance;mutant;novel;novel therapeutics;overexpression;public health relevance;research study;response;sterol esterase

public_health_relevance:
Project NarrativeObesity is a prevalent disorder of energy balance in which excess energy in the form of triacylglycerolaccumulates in adipose tissue. Despite a need for therapeutic approaches to treat obesity little is known aboutthe mechanisms that control fat storage and release from adipose tissue. The proposed study will focus oninvestigating the important role of a new protein that regulates ATGL the key enzyme for fat mobilization inadipose tissue.


application_id: 7945811
project_number: 1R01NS070899-01
project_title: Regulation signaling and dynamics of glucan phosphatases.
administering_ic: NINDS
award_notice_date: 2010-05-03
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: NS
serial_number: 070899
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The objective of this grant is to elucidate the regulation downstream signaling and structural dynamics of the glucan phosphatase laforin. Mammalian cells store readily mobilized energy in the form of glycogen a water-soluble carbohydrate. Recessive mutations in genes encoding the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin disrupt glycogen metabolism and result in a fatal neurodegenerative epilepsy called Lafora disease (LD). A hallmark of LD is poorly branched hyperphosphorylated insoluble carbohydrate accumulations called Lafora bodies (LBs) thought to be the causative agent of LD.  We established that malin is a single-subunit E3 ubiquitin ligase that ubiquitinates and triggers the degradation of multiple proteins involved in glycogen metabolism. In addition we discovered that laforin is the founding member of a unique class of phosphatases that dephosphorylate phospho-glucans. These results allowed us to propose molecular mechanisms that cause LD: 1) loss of malin results in LBs due to an imbalance in glycogen metabolism proteins i.e. protein levels are not properly maintained; 2) loss of laforin results in LBs due to glucan hyperphosphorylation that inhibits glucan branching; 3) laforin also acts as a targeting subunit for malin so that loss of laforin disrupts some malin-directed ubiquitination events. While we have made significant strides in determining the molecular mechanisms of LD we lack an understanding of how these enzymes are regulated. This proposal will elucidate the deficiencies in our current knowledge.  We recently identified novel phosphorylation and ubiquitination events on laforin. Phosphorylation and ubiquitination are post-translational modifications that direct changes in protein concentration enzymatic activity protein localization protein-protein interactions and structural dynamics. In Aim 1 we will define the in vivo conditions triggering laforin phosphorylation and characterize the functional consequences. We will utilize 1) overexpression and endogenous protein levels in tissue culture cells to monitor the status of laforin localization and modification 2) assay laforin function in vitro using purified proteins and 3) utilize a LD mouse model to verify our results. In Aim 2 we will utilize a similar strategy to determine the affects of ubiquitination on laforin function. In addition we will define the role of laforin in malin directed ubiquitination as we have recently discovered that laforin acts as a targeting protein for malin. In Aim 3 we will determine how perturbations of the structural components of glucan phosphatases contribute to LD. We will utilize Hydrogen- Deuterium exchange mass spectrometry to define the structural dynamics of laforin and x-ray crystallography to determine the structure of a glucan phosphatase. This proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intercalated events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better understanding of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.  
  
PUBLIC HEALTH RELEVANCE:  The focus of our work is to determine how loss of function of either of two proteins leads to the fatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intertwined events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better comprehension of these complex events and will produce therapeutic insights for epilepsy and neurodegeneration.

project_terms:
5'-AMP-activated protein kinase;Affect;Binding (Molecular Function);Biological Assay;CNS degeneration;Carbohydrates;Cardiac;Cells;Cessation of life;Complex;Comprehension;Crystallography;Deterioration;Deuterium;Disease;Energy Metabolism;Enzymes;Epilepsy;Event;Family suidae;Figs - dietary;Genes;Glucans;Glycogen;Glycogen (Starch) Synthase;Glycogen Debranching Enzyme;Grant;Human;Hydrogen;In Vitro;Knowledge;Lafora Disease;Life;Link;Mammalian Cell;Mass Spectrum Analysis;Metabolism;Modification;Molecular;Monitor;Motor;Mutation;Myocardium;Myoclonic Epilepsies;Nerve Degeneration;Neurodegenerative Disorders;Neurologic;Parkinson Disease;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Post-Translational Protein Processing;Progressive Myoclonic Epilepsies;Proteins;Regulation;Review Literature;Role;Seizures;Series;Signal Transduction;Single Seizures;Skeletal muscle structure;Specificity;Structure;Symptoms;Therapeutic;Tonic - clonic seizures;Ubiquitin;Ubiquitination;Water;Wolff-Parkinson-White Syndrome;Wolves;Work;base;design;glycogen metabolism;in vivo;insight;loss of function;loss of function mutation;member;mouse model;novel;overexpression;protein protein interaction;public health relevance;research study;sensor;tissue/cell culture;ubiquitin-protein ligase


application_id: 7945285
project_number: 5RC2GM092521-02
project_title: Advancing Drug Development from Medicinal Plants using Transcriptomics and Metabo
administering_ic: NIGMS
award_notice_date: 2010-09-23
opportunity_number: RFA-OD-09-004
application_type: 5
activity_code: RC2
ic: GM
serial_number: 092521
program_official: JONES, WARREN
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: ZGM1-PPBC-X(TR)
contact_pi_person_id: 8279550
contact_pi: CHAPPELL, JOE
other_pis: DELLAPENNA, DEAN ;O'CONNOR, SARAH E
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Medicinal plants produce a wealth of pharmaceutical compounds such as taxol vincristine and morphine. Unfortunately the specialized secondary metabolic pathways leading to such compounds remain poorly understood and progress in elucidating and manipulating these taxonomically restricted metabolic pathways has been correspondingly slow. This has been exacerbated by the limited development of "omics"-level resources for medicinal plants which has meant that as a group research in medicinal species have not benefited to the same extent from the genomics revolution as have research in model plants and agronomic crop species. This proposal describes the combined use of state-of-the-art sequencing technologies metabolomics capabilities and bioinformatics to develop an unrestricted public resource to address this growing gap in our knowledge base of species-specific plant metabolism and accelerate the identification and functional analysis of genes involved in natural product biosynthesis in 20 widely used medicinal plant species. This resource will provide the research community with user-friendly access to the DNA sequences and expression profiles of each plant's transcriptome and associated metabolome which we anticipate will have a translational effect on drug development. To achieve this goal we will utilize next generation sequencing approaches to determine the near-complete set of mRNAs encoded by each medicinal plant species. Transcriptome profiling of up to 20 chemically diverse tissues/treatments per species using the RNA-Seq method from Illumina will be performed and correlated with metabolite profiles generated through LC-TOF and GC-MS for these same samples. All sequence and gene expression data will be deposited into NCBI and made available along with metabolite profiling data at medicinalplantgenomics.msu.edu a custom website developed by the research consortium. Thus this NIH Grand Opportunities Grant will provide searchable and downloadable databases for medicinal plant gene sequences expression profiles and metabolites that can be accessed and utilized by the research community to facilitate discovery of the pathways and genes responsible for biosynthesis of key pharmaceuticals. High throughput sequencing of genomes and transcriptomes has revolutionized and accelerated the pace and progress of research across the life sciences and this proposal will for the first time extend these advances into the medicinal plant arena on a broad scale.  
PUBLIC HEALTH RELEVANCE: This proposal describes the combined use of state-of-the-art DNA sequencing technologies metabolomics capabilities and bioinformatics to develop an unrestricted public resource to advance our knowledge base of species-specific plant metabolism and accelerate the identification and functional analysis of genes involved in natural product biosynthesis in 20 widely used medicinal plant species. This resource will provide the research community with user-friendly access to the DNA sequences and expression profiles of each plant's transcriptome and associated metabolome which we anticipate will have a translational effect on drug development.

project_terms:
Address;Agricultural Crops;Aliquot;Anabolism;Animal Model;Arabidopsis;Arts;Bioinformatics;Biological Factors;Biological Sciences;Bone callus;Communities;Custom;DNA Sequence;Data;Data Set;Databases;Deposition;Development;Flowers;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Genome;Genomics;Goals;Grant;Health;Human;Knowledge;Libraries;Link;Maize;Maps;Medicinal Plants;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular Profiling;Morphine;Organism;Paclitaxel;Pathway interactions;Pharmacologic Substance;Plant Genes;Plant Leaves;Plant Model;Plant Roots;Plants;Process;Production;Quality Control;RNA;Reading;Relative (related person);Research;Resources;Rice;Sampling;Sorghum (Plant);Technology;Time;Tissue Sample;Tissues;Titanium;Transcript;United States National Institutes of Health;Variant;Vincristine;Work;abstracting;biological research;candidate identification;drug development;gene function;genome sequencing;improved;insight;knowledge base;metabolomics;next generation;novel;stem;tool;transcriptomics;user-friendly;virtual;web site

public_health_relevance:
NarrativeThis proposal describes the combined use of state-of-the-art DNA sequencingtechnologies metabolomics capabilities and bioinformatics to develop anunrestricted public resource to advance our knowledge base of species-specificplant metabolism and accelerate the identification and functional analysis ofgenes involved in natural product biosynthesis in 20 widely used medicinal plantspecies. This resource will provide the research community with user-friendlyaccess to the DNA sequences and expression profiles of each plant'stranscriptome and associated metabolome which we anticipate will have atranslational effect on drug development.


application_id: 7944580
project_number: 1P20CA150343-01
project_title: Targeted Inhibition of P13K Pathway Components as Novel Treatment of Colectoral C
administering_ic: NCI
opportunity_number: PAR-08-020
application_type: 1
activity_code: P20
ic: CA
serial_number: 150343
project_start_date: 2009-09-28
project_end_date: 2012-08-31
study_section: ZCA1-RPRB-M(O1)
subproject_number: 5642
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-28
project_abstract:
Colorectal cancer is the second leading cause of cancer deaths in the United States. When localized to the
mucosa and submucosa of the bowel wall (Stage I) the five year survival approaches 100%; however
metastasis to lymph nodes (Stage 111) results in a precipitous decrease in five year survival and systemic
metastasis to the liver (ie Stage IV) is associated with a five year survival that is less than 5%. Activation of
phosphatidylinositol 3-kinase (PI3K) a ubiquitous lipid kinase composed of an 85 kDa regulatory subunit
(p85) and a 110 kDa catalytic subunit (p110) and its downstream effector protein Akt is associated with
the growth and progression of a number of cancers including colorectal cancer. We have shown that
inhibition of PISK/Akt decreases viability and growth increases differentiation and apoptosis of human
colorectal cancer cells. Furthermore PISK/Akt inhibition decreases colon cancer xenograft growth in
athymic nude mice and sensitizes these cancers to the apoptotic effects of chemotherapeutic agents (eg 5-
FU). Moreover we have shown altered PISK/Akt expression in colorectal cancers and surrounding stroma
with increased expression of the p8Sa subunit and Akt2 in colorectal cancers of increasing stage. Targeted
inhibition of either p8Sa or p110a by RNA interference (RNAi) increased sensitivity of resistant colorectal
cancers to the effects of chemotherapy and significantly suppressed colorectal cancer metastasis to the
liver in preclinical animal models. The central hypothesis of this project is that colorectal cancer growth
and progression are augmented by increased p85a and Akt2 expression; the selective inhibition of PISK/Akt
components can suppress colorectal cancer growth and metastasis and can sensitize resistant colorectal
cancers to chemotherapeutic agents. The long-term qoai is to develop more selected therapies for
colorectal cancer progression and metastasis based on a systematic analysis of colorectal cancers tumor
stroma and surrounding mucosa for expression of piSK/Akt pathway components. To examine our hypothesis and address the long-term goal we have designed experiments with the following Specific
Aims: 1) To provide clinical validation of the pattern and significance of PISK/Akt/PTEN pathway component expression in polyps and colorectal cancers of different stages. 2) To assess novel strategies of selective PISK component inhibition on in vivo tumor growth and liver metastasis using preclinical animal models. 3) To evaluate the therapeutic efficacy of RNAi to the PISK pathway in combination with conventional chemotherapy. The cumulative information derived from ttiese studies will lead to better targeted therapeutics and treatment paradigms for colorectal cancer.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Animal Model;Apoptosis;Apoptotic;Cancer Etiology;Catalytic Domain;Cessation of life;Classification;Clinical;Colon Carcinoma;Colorectal Cancer;Goals;Growth;Human;Intestines;Lead;Lipids;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Metastatic Neoplasm to Lymph Nodes;Metastatic Neoplasm to the Liver;Mucous Membrane;Neoplasm Metastasis;Nude Mice;PTEN gene;Pathway interactions;Patients;Pattern;Phosphatidylinositols;Phosphotransferases;Polyps;Proto-Oncogene Proteins c-akt;RNA Interference;Reproduction spores;Resistance;Signal Pathway;Staging;Submucosa;Therapeutic Agents;Treatment Efficacy;United States;Validation;Xenograft procedure;base;cancer cell;chemotherapeutic agent;chemotherapy;design;in vivo;novel;novel strategies;novel therapeutics;pre-clinical;research study;selective expression;therapeutic target;tumor;tumor growth;tumor progression


application_id: 7944563
project_number: 1P20CA150343-01
project_title: Hepatitis C and Tumor Suppressors in Hepatocellular
administering_ic: NCI
opportunity_number: PAR-08-020
application_type: 1
activity_code: P20
ic: CA
serial_number: 150343
project_start_date: 2009-09-28
project_end_date: 2012-08-31
study_section: ZCA1-RPRB-M(O1)
subproject_number: 5626
contact_pi_person_id: 1884112
contact_pi: LEMON, STANLEY M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-28
project_abstract:
This project seeks to determine the clinical relevance and potential role in hepatic carcinogenesis of
interactions between host cell and hepatitis C virus (HCV) proteins that have been identified in previous cell
culture-based experiments. The retinoblastoma susceptibility protein (pRb) and the cellular DEAD-box RNA
helicase DDXS play critical roles in regulating the cell cycle. Our previous work indicates that the HCV RNA
polymerase NS5B fc^nns a complex with pRb targeting it for ubiquitination and proteasome-dependent
degradation activating E2F-responsive promoters and stimulating cell proliferation. Similarly HCV cofe
protein expression alters the cellular abundance and localization of DDX3. Our hypothesis is that these and
other interactions with host proteins (p53 and DDX5) promote proliferation of hepatocytes and impair DNA
damage responses tljiereby contributing to HCV carcinogenesis. In Aim 1 we will develop and validate
fluorescent quantum dot probes capable of sensitive detection of HCV proteins expressed in virus-infected
cells. We will also determine whether HCV protein expression conrelates with altered tumor suppressor
expression in transgenic mice. Aim 2 will utilize these novel probes in laser scanning confocal and multi
photon microscopy studies of liver tissue from patients with chronic hepatitis C and ask whether the
abundance and cellular localization of pRb p53 DDXS or DDXS is altered in infected hepatocytes. In Aim 3
we will determine whether HCV infection is associated on a single-cell basis with increased expression of the
proliferation markers Ki-67 and PCNA. We will also determine whether the proportion of cells displaying
proliferation markers is reduced after standard-of-care peg-IFN/ribavirin therapy. These results will be
correlated with oligonucleotide microarray and quantitative RT-PCR assays to determine whether liver
specimens with a high proportion of HCV-infected cells display transcriptional patterns indicative of
hepatocellular proliferation and/or E2F transcription factor activation. RELEVANCE TO PUBLIC HEATH:'
Liver cancer is one qf the most rapidly increasing types of cancers in the United States reflecting an
increased prevalence ^nd risk of liver cancer in persons with chronic hepatitis C. This project seeks a better
understanding of the interaction of HCV proteins with important regulators of cell proliferation (pRb p53
DDXS and DDXS) anc( the role of such interactions in liver cancer caused by HCV infection.
PERFORMANCE SITE

project_terms:
African American;Antiviral Therapy;Binding (Molecular Function);Biological Assay;Boxing;Cancer Etiology;Caring;Cell Culture Techniques;Cell Cycle;Cell Cycle Regulation;Cell Nucleus;Cell Proliferation;Cells;Chronic Hepatitis C;Complex;Cultured Cells;Cytoplasm;DNA Damage;DNA Modification Process;DNA-Directed RNA Polymerase;Detection;Diagnostic;E2F transcription factors;Event;Freezing;Goals;Hepatic;Hepatitis C;Hepatitis C virus;Hepatocyte;Hispanics;Human;In Vitro;Incidence;Lasers;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Methods;Microscopy;Mitochondria;Oligonucleotide Microarrays;Oxidative Stress;Paraffin Embedding;Patients;Pattern;Persons;Play;Predisposition;Prevalence;Preventive;Principal Investigator;Proliferation Marker;Promotor (Genetics);Protein Binding;Protein p53;Proteins;Quantum Dots;RNA Helicase;RNA-Directed RNA Polymerase;Reproduction spores;Retinoblastoma;Reverse Transcriptase Polymerase Chain Reaction;Ribavirin;Risk;Role;Scanning;Semiconductors;Series;Specimen;TP53 gene;Testing;Therapeutic;Tissues;Transgenic Mice;Tumor Suppressor Proteins;Ubiquitination;United States;Viral;Viral Core Proteins;Viral Proteins;Virus;Work;adduct;base;cancer type;carcinogenesis;clinically relevant;hepatitis C virus nucleocapsid protein;imaging modality;improved;in vivo;interferon therapy;liver cell proliferation;male;multi-photon;multicatalytic endopeptidase complex;novel;performance site;prevent;programs;protein expression;research study;response;viral RNA


application_id: 7944172
project_number: 5P30CA147886-02
project_title: Supporting New Faculty Recruitment Through Biomedical Research Core Center
administering_ic: NCI
award_notice_date: 2010-07-14
opportunity_number: RFA-OD-09-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 147886
program_official: PERKINS, SUSAN N
project_start_date: 2009-09-30
project_end_date: 2013-08-31
study_section: ZCA1-PCRB-G(O9)
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (Provided by the applicant): The strategic plan of the University of Kentucky (UK) P30 application in response to RFA-OD-09-005 is to provide support for the recruitment of 2 junior investigators who will be immersed into a highly collaborative interdisciplinary group of investigators focused on the diagnosis prevention and treatment of gastrointestinal (Gl) cancers. This productive group consists of basic and clinical scientists including molecular and cell biologists clinician-scientists (surgeons gastroenterologists and medical oncologists) Gl pathologists epidemiologists biostatisticians and investigators in the School of Pharmacy with successful programs in drug design and delivery. The purpose of this program is to support promising junior investigators who will participate in translational Gl cancer research projects as part of our recently-funded P20 program (P20 CA127004) which provides support for the development of a fully-funded P50 Gl cancer SPORE application. Our goal is to develop a cadre of future Gl cancer investigators who can participate at the intersection of molecular biology drug discovery and clinical care to become leaders in integrative and team approaches to understand the complex issues of Gl cancer as it relates to potential prevention and treatment strategies. This proposal builds upon the momentum and existing strengths at the Markey Cancer Center and is further supported by substantial institutional state and philanthropic support.

project_terms:
Biology;Biomedical Research;Cancer Center;Cancer Research Project;Cells;Clinical;Complex;Development;Diagnosis;Drug Design;Epidemiologist;Faculty;Financial Support;Funding;Future;Gastroenterologist;Goals;K-Series Research Career Programs;Kentucky;Leadership;Malignant Neoplasms;Medical Oncologist;Mentors;Molecular;Molecular Biology;Outcome;Pathologist;Patients;Pharmacy Schools;Prevention;Recruitment Activity;Reproduction spores;Research;Research Infrastructure;Research Personnel;Scientific Advances and Accomplishments;Scientist;Strategic Planning;Surgeon;TNFRSF5 gene;Translating;Translations;Universities;clinical care;drug discovery;gastrointestinal;improved;multidisciplinary;programs;ranpirnase;response;treatment strategy

public_health_relevance:
Although tremendous strides have been made towards understanding the basic biology of Gl cancers very
few of these advances have been translated into improved outcomes for patients. To accelerate translation
of scientific advances into improved clinical outcomes it is necessary that an investigator function effectively
as part of a multidisciplinary team. The goal of this proposal is to develop talented junior investigators into
productive academic Gl investigators.


application_id: 7943910
project_number: 5RC2DA028984-02
project_title: Transdermal Cannabinoid Prodrug Treatment for Cannabis Withdrawal and Dependence
administering_ic: NIDA
award_notice_date: 2010-09-17
opportunity_number: RFA-OD-09-004
application_type: 5
activity_code: RC2
ic: DA
serial_number: 028984
program_official: PARK, MOO KWANG
project_start_date: 2009-09-30
project_end_date: 2013-08-31
study_section: ZDA1-JXR-D(9F)S
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: WEBSTER, LYNN
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Cannabis use disorders affect approximately 1.5% of the United States population and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of delta-9-tetrahydrocannabinol (THC) as an adjunct treatment for marijuana withdrawal and dependence. While the approved THC (Marinol) capsule provides potentially effective treatment for cannabis use disorders oral drug delivery is not desirable because of the peak plasma level related side effects and short duration of action. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing/duration flexibility and also have fewer drug side effects (i.e. no THC plasma peak level related euphoria). Initial positive preliminary data has encouraged AllTranz to seek funding to develop new THC prodrugs and optimize their use through a transdermal drug delivery system. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. Transdermal formulations also provide more abuse deterrence than immediate release dosage forms. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches and gels do not require swallowing eliminating oral side effects and bitter taste concerns; nor do they require skin puncture by needles eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers. Specifically we aim to synthesize skin permeable prodrugs of THC. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal prodrugs will be evaluated for chemical stability and performance in adhesive patch formulations. The best prodrug candidate will undergo synthesis scale-up optimization prototype patches will be manufactured and preclinical toxicology testing will be completed. An IND will be submitted to the FDA so that a Phase I clinical trial can be completed. A proof of concept study in marijuana withdrawal can be completed under this two-year plan. We will create a marketable transdermal drug that will significantly aid in the treatment of marijuana dependence and withdrawal.  
  
PUBLIC HEALTH RELEVANCE: Cannabis use disorders affect approximately 1.5% of the United States population and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of THC as an adjunct treatment for marijuana withdrawal and dependence. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing flexibility and also have fewer drug side effects (i.e. no THC plasma peak level-related euphoria).

project_terms:
Adhesions;Adhesives;Adverse drug effect;Adverse effects;Affect;Back;Blood Circulation;Cannabinoids;Cannabis;Cannabis Abuse;Clinical;Clinical Trials;Data;Deglutition;Dependence;Development Plans;Diffusion;Disease;Dosage Forms;Dose;Drug Addiction;Drug Approval;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug abuser;Euphoria;FDA approved;Funding;Gel;Grant;Human;In Vitro;Individual;Investigational New Drug Application;Liver;Maintenance;Marihuana;Marijuana Dependence;Marijuana Smoking;Marketing;Methods;Mouth Diseases;Needles;Oral;Pain;Parents;Pathway interactions;Patients;Performance;Pharmaceutical Preparations;Phase I Clinical Trials;Physicians;Plasma;Population;Prodrugs;Property;Puncture procedure;Relapse;Replacement Therapy;Research;Residual state;Route;Safety;Skin;Stomach;Stratum corneum;System;Taste Perception;Testing;Tetrahydrocannabinol;Time;Toxicology;Transdermal substance administration;United States;Visit;Withdrawal;Withdrawal Symptom;capsule (pharmacologic);chemical stability;chronic pain;clinical effect;design;effective therapy;experience;flexibility;improved;marijuana user;pre-clinical;prototype;scale up

public_health_relevance:
Narrative:Cannabis use disorders affect approximately 1.5% of the United States population and more thanhalf of the individuals addicted to marijuana experience significant withdrawal symptoms if they try toquit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking fundingto create a transdermal delivery system of THC as an adjunct treatment for marijuana withdrawal anddependence. The transdermal system would be a non-invasive non-oral dosage form with ultimatedosing flexibility and also have fewer drug side effects (i.e. no THC plasma peak level-relatedeuphoria).


